Drug design and delivery最新文献

The present review discusses the available clinical information dealing with the treatment of migraine with calcium entry blocking agents. The data on prophylactic therapy are limited to 3 compounds, of which flunarizine is the most extensively studied and the only substance whose activity is well established. Clinical experience with these agents in the acute treatment of migraine attacks is still very limited.

Analogues of GABA and the GABA uptake inhibitors, nipecotic acid and guvacine, carrying N-(mono)- or N-(diarylmethoxy)alkyl substituents were synthesized and tested in vitro as inhibitors of synaptosomal GABA uptake and GABAA receptor binding. Whereas the N-(diphenylmethoxy)ethyl derivative GABA (compound 23) (see Figures 1 and Scheme 1 for structures) was only a moderately potent inhibitor of GABA uptake, corresponding derivatives of nipecotic acid and guvacine compounds 7e and 16, respectively) were potent inhibitors having IC50 values in the low micromolar range. In the case of 7e, (a) the (R)-isomer (10) was three times more potent than the (S)-isomer (13), (b) the bis-4-chlorophenyl analogue (compound 7g) was more potent than 7e, (c) the introduction of an additional methylene group into the linkage between the nipecotic acid and benzhydryl ether moiety (to give 7f) did not significantly affect in vitro biological activity, and (d) removal of one of the phenyl groups, or replacement of the benzhydryl ether group by the conformationally restrained fluorenyloxy group (to give 7i), resulted in substantial loss of activity. None of the compounds synthesized showed detectable affinity for GABAA receptor sites.

The object of this study was to develop a sustained release implantable dosage form of a new silicone gel (PHYCON 6600R) which undergoes addition polymerization to produce a solid gel at ordinary temperature. Implantable PHYCON-drug composites were studied as a means of tumor therapy using 3',5'-diesters of 5-fluoro-2'-deoxyuridine (FUdR-Cn) as a model for antitumor drugs. Using an in vitro dissolution test, we found that the release characteristics of drugs from these preparations could be controlled by the addition of powdered L-alanine. In vivo studies of antitumor activity were carried out, using preparations containing the dodecyl ester (FUdR-C12) by measuring the lifespan of lymphoma-inoculated mice. Antitumor activity, reflected in increased lifespan, was shown to be greater following intraperitoneal administration of the PHYCON formulations (drug and L-alanine) than following injections of the drug alone. Our results suggest that sustained release implantable formulations of antitumor drugs in PHYCON might be suitable for tumor chemotherapy.

Considerable progress is now being made in studies of the interactions between the immune and neuroendocrine systems, and the relevance of the results to many disease processes is increasingly recognised. Recent published, and hitherto unpublished, work on one aspect of this topic--the production and function of neuroendocrine hormone by cells of the immune system--is herein summarised by a foremost investigator and his colleagues. Evidence is presented that several peptide hormones (ACTH, endorphins, thyrotropin, chorionic gonadotropin, growth hormone) are produced constitutionally, or in response to stimulation, by cells of the immune system, and there is speculation as to their roles in local immune response, endotoxic shock, antibody production, pregnancy, and in the diagnosis of specific psychiatric and neuroendocrine disorders. The review and commentary contribute to fuller understanding of the underlying molecular biology, from which new opportunities in rational drug design will undoubtedly emerge.

5-(1-Hydroxy-2-haloethyl)- (4), 5-(1-methoxy-2-haloethyl)- (5) and 5-(1-hydroxy-2-methoxyethyl)uracils (6) (see Figure 2 for structures) were synthesized to investigate the effect of the C-5 substituents on cytotoxic and antiviral activity. The bromo compounds (4b and 5b) exhibited greater cytotoxic activity than the chloro or iodo analogues in the in vitro L1210 assay. Replacement of the hydroxyl substituent of 4b (bromo) and 4c (iodo) by a methoxyl substituent (5b-c), or substitution of their halogen substituents by methoxyl (providing 6) increased the potency. However, the cytotoxic activity of all the compounds was weak, the most active (6) producing a 45% decrease in cell survival at a concentration of 50 micrograms/ml, as compared with a 97% decrease when the reference standard (melphalan) was tested at 1 microgram/ml. They were inactive antiviral agents against herpes simplex virus type 1 (HSV-1) infected Vero cells at 10 micrograms/ml; in the same test, the reference standard (acyclovir) exhibited an ID50 of 0.01 micrograms/ml.

The design and preparation of two drug formulations which float in gastric juice are described. One, a buoyant tablet, consisted of powdered soybean protein, drug and sodium bicarbonate. The other, a laminated film-type preparation, consisted of a drug film, an effervescing film containing sodium bicarbonate and outer drug release regulating films. Cinnarizine, an acid-soluble drug, was chosen as model drug, and carboxyvinyl polymer, ethyl cellulose and hydroxypropyl cellulose were used in the preparation of the films. Both formulations showed favorable buoyancy in an in vitro acidic dissolution test medium and also sustained release properties. In an absorption study using beagle dogs, cinnarizine was found in the blood even 24 hr after oral administration of the buoyant tablet or film-type preparation. Similar buoyant tablets containing barium sulfate were administered orally to a healthy volunteer, and it was confirmed by roentgenography that the tablets floated for almost three hours.

In vitro release of physostigmine from an emulsion was more prolonged than from a tablet. This prolongation was attributed to the retention capacity of the dispersed oil droplets. Increase of the oily phase volume ratio from 20 to 50% did not substantially decrease the rate of release, and decrease of the mean oil droplet size did not affect the release profile, indicating that the drug was mainly localized in the external phase of the emulsion. The profiles agreed with those predicted from our earlier mathematical equation based on a three compartment model system. In rabbits there were no significant differences in the Tmax and AUC values obtained by use of a tablet and the emulsion form, but the emulsion form elicited less enzyme inhibition. T20 (the therapeutic occupancy time) was markedly extended following use of the emulsion form.

New approaches in the design of analgesics emerged from the discovery that serotonin (5HT) is involved in the descending system (brain to spinal cord) that inhibits signals from peripheral nociceptors. However, the simple hypothesis that 5HT is a transmitter in this system requires elaboration, since not all agonists of 5HT are analgesics. In this commentary, the following questions are discussed: (a) do 5HT systems influence all responses to all types of noxious stimuli?, (b) is a 5HT synapse a necessary link in the analgesic system, (c) what is the location of the relevant 5HT receptor?, and (d) what is the relevant 5HT receptor subtype? The need for more adequate definition of the relevant 5HT receptor is stressed. Once this is achieved, a more rational approach to analgesic drug discovery will be provided by the design of selective agonists of this receptor.

The interaction of artemisinin, a new sesquiterpine lactone antimalarial drug, with some target macromolecules represented by calf thymus deoxyribonucleic acid (DNA) and the dinucleotide guanylyl (3----5) cytidine (GpC) was studied by 1H-NMR. There was no intercalation between artemisinin and DNA or GpC as judged by the lack in change of chemical shifts (delta delta) or coupling constants (delta J) of the C-13, C-14, and C-15 methyl groups of artemisinin. This conclusion was substantiated by studying the optical rotatory dispersion (ORD) between artemisinin and these target macromolecules. It is suggested that artemisinin exerts its antimalarial action via a mechanism different from that of the aminoquinolines antimalarial agents, possibly through the peroxygen linkage which is essential for artemisinin biological activity.

Medications currently available for the prophylaxis and treatment of migraine provide only limited relief. The pathophysiology of migraine is still poorly understood but it is widely accepted that various 'triggers', including fluctuations in the concentrations of circulating ovarian steroid levels, may initiate alterations in the activity of the intracranial vasculature and its efferent and afferent innervation. Recent pharmacological studies utilizing human intracranial artery preparations have addressed two distinct therapeutic stratagems. First, aspirin-like analgesics, which inhibit prostanoid synthesis, are widely used to treat migraine headache. Recent findings suggest that the ability of mefenamic acid to antagonise certain prostanoid actions, in addition to inhibiting synthesis, enhances its effectiveness. Thus, development of selective antagonists of the intracranial vasoconstrictor and the hyperalgesic actions of prostanoids could provide effective and selective migraine remedies. Second, with regard to prophylaxis, particularly of menstrually-related migraine, drugs which mimic the vascular smooth muscle 'stabilizing' action of ovarian steroids, possibly by enhancing potassium channel activation, are likely to be effective if used at concentrations that have minimal hypotensive effects.