Flector plaster is a new transdermal delivery system medicated with diclofenac hydroxyethylpyrrolidine salt, an NSAID which seems to possess suitable physiochemical properties for easy release by the plaster matrix for percutaneous absorption. The paper deals with local tolerability and pharmacokinetic (percutaneous absorption) studies carried out both on animals and on volunteers. The results obtained in the safety studies demonstrate the absence of local skin reactions and of sensitization phenomena. The kinetic evidence, obtained at the steady-state, reveals a profile typical of a sustained-release formulation, able to maintain constant plasma levels of the drug up to the next application (12 h). The amount of drug bioavailable for targeting the sites of action is effectively lower than via the oral route, however the estimated absorbed dose of 5-10 mg per application appears to be adequate for the foreseen therapeutic use, taking into account the great advantage in having no undesirable side effects.
The activity of a new non-hormonal anti-fertility agent, 2-(3-ethoxyphenyl)-5,6-dihydro-s-triazolo[5,1-a]isoquinoline (DL 204-IT), effective in terminating pregnancy after i.m. or s.c. treatment, was tested after single and multiple oral doses given to rats and hamsters. Although the compound was absorbed well from the gastrointestinal tract and the plasma levels of the radioactivity administered were rather high and sustained, the oral activity was by two orders of magnitude lower than the parenteral one. The plasma profile of the metabolites found after both p.o. and i.m. administration indicates that the compound is rapidly metabolized. Seven metabolites (I-VII) were isolated from the urine of pregnant rats and fully characterized by MS, IR and NMR spectroscopy. They are 2-(3-hydroxyphenyl)-5,6-dihydro-s-triazolo[5,1-a]isoquinoline (I); 2-(3,4-dihydroxyphenyl)-5,6-dihydro-s-triazolo[5,1-1]isoquinoline (II); 2-(3-hydroxyphenyl)-5,6-dihydro-6 beta-hydroxy-s-triazolo[5,1-a]isoquinoline (III); metabolite I-sulphate ester (IV); metabolite III-3-sulphate ester (V); metabolite I-beta-D-glucuronide (VI) and metabolite II-3-beta-D-glucuronide (VII). Metabolite I was shown to be from 1/10 (rat) to 1/30 (hamster) as active as the parent compound, while metabolites II and III were completely inactive. The very low oral activity of DL 204-IT seems to be due mainly to its rapid biotransformation.
The metabolism of the anti-hypertensive drug, mopidralazine, N-(2',5'-dimethyl-1H-pyrrol-1-yl)-6-(4"-morpholinyl)-3-pyridazinamine, was reinvestigated in rats using the [2'(5')-13CH3]-labelled drug to determine the significance of the pharmacologically active intermediate 3-hydrazino-6-(4-morpholinyl)pyridazine. The previously proposed mesonic structure of the major metabolite I, i.e., 5'-hydroxy-3',6'-dimethyl-1'-[6-(4"-morpholinyl)-3-pyridazinyl]pyrida zinium hydroxide inner salt, was confirmed by chemical synthesis, X-ray diffraction analysis and 1H n.m.r. of the [3',6'-13CH3]-labelled metabolite I. Metabolite II, 3-methyl-6-(4-morpholinyl)-triazolo [4,3-6 b]pyridazine and metabolite VII, 3-methyl-7-(4-morpholinyl)-3H-pyridazino[1,6-c]pyridazine, were shown to retain the 13CH3 labelling of mopidralazine, whereas metabolite X, 3-acetyl-hydrazino-6-(4-morpholinyl)-pyridazine, loses the labelling, indicating that their formation involves two different pathways. It is hypothesized that the oxidation of the pyrrole leads to ring opening followed by a chemical rearrangement giving rise directly to metabolites II and VII or, with the intermediacy of the pharmacologically active 3-hydrazino-6-(4-morpholinyl) derivative and an enzymic acetylation or conjugation with pyruvic acid, to metabolites X, II and VII.
3-(2-ethylphenyl)-5-(3-methoxyphenyl)-1H-1,2,4-triazole (ST1959) has shown therapeutic effects in several animal models of autoimmune diseases. In this study the effects of ST1959 were further investigated in a murine model of colitis. The evidence obtained indicates that the beneficial effects exerted by ST1959 rely upon a decreased local immunological response. The cellular effects of ST1959 were additionally investigated on human peripheral blood mononuclear cells and Jurkat T cells by measuring cytokine production, cell proliferation and activation of a set of transcription factors. ST1959 decreases human T cell proliferation and inhibits cytokine expression at the transcriptional level. Moreover, at doses inhibiting cytokine production, ST1959 blocks phorbol 12-myristate 13-acetate (PMA) and ionomycin-induced nuclear factor protein of activated T cell (NFAT1) activity, without impairing AP-1-and NF-κB-dependent transcription. Immunofluorescence data show that ST1959 inhibits the nuclear residency of NFAT1 in both Jurkat and human peripheral blood mononuclear cells activated with PMA/ionomycin. leptomycin B, an inhibitor of CRM1/exportinlα-dependent nuclear export, reverted the inhibitory effect of ST1959 on NFAT1 nuclear localization. This indicates that ST1959 may increase the nuclear export of NFAT1, downregulating NFAT1 activity via a mechanism different from that of cyclosporin A, since it does not affect NFAT phosporylation/dephosphorylation steps. These findings provide new insights into the molecular mechanisms underlying the immunomodulatory activity of ST1959.
Abstract A highly sensitive gas chromatographic–mass spectrometric method for the determination of etodolic acid, as methyl ester, in plasma was developed. The feasibility and specificity of the method was ascertained monitoring the concentration levels in plasma samples collected from 12 male healthy volunteers given epicutaneously 5 g of 10% etodolac gel formulation.
The kinetics and metabolic fate of 2'-14C-deflazacort, a new steroidal antiinflammatory agent, were studied in the cynomolgus monkey after both p.o. and i.v. administration (5 mg/kg). There is no unchanged deflazacort in the plasma or urine after either p.o. or i.v. treatment. As judged from the plasma AUC and urinary elimination values, the oral availability of both total 14C and metabolites seems to be lowered because of a route-dependent first-pass. Both radioactivity and the main metabolite (21-desacetyl deflazacort) are eliminated from the plasma with half-lives of 2--3-5 h. The i.v. administered 14C is eliminated mainly in the urine (52--55% of dose), but biliary excretion is also quantitatively important. Six metabolites were isolated from urine and identified by physico-chemical analysis. Among them desacetylated deflazacort and its 6 beta-hydroxy derivative were shown to be the major radioactive products in plasma and urine, respectively. Minor metabolites were: 21-desacetyl, 6 alpha-hydroxy deflazacort; 21-desacetyl, 5 alpha, 1-eno, deflazacort; 21-desacetyl, 20 beta hydroxy deflazacort; and 21-desacetyl, 11-keto deflazacort.
