A once-a-day dosage form for the delivery of insulin through the nasal route: in vitro assessment and in vivo evaluation.

An in situ thermogelling, mucoadhesive formulation based on N-trimethyl chitosan chloride has been evaluated for its potential to affect the transmucosal delivery of insulin via the nasal route. In vitro studies at a physiologically relevant temperature (ca. 35 °C) have shown that the formulation releases most of its insulin load (ca. 70%) in a non-Fickian manner during the timescale over which the sol-to-gel transition (ca. 8 min) takes place, and also that, once gelation is complete, the release of the remainder of the therapeutic content follows first order kinetics over at least sixty minutes. Investigations on the effects of the application of the same formulation to a modelled nasal mucosa (Calu-3 cell monolayer) have indicated the capability of the formulation to induce the transient opening of tight junctions. Cytotoxic investigations have shown that the formulation exhibits negligible detrimental effects to the integrity of these monolayers. The in vivo potential of the nasal formulation to act as a once-a-day dosage form for the intranasal delivery of insulin has been demonstrated in a diabetic-rat model.

Synthesis of some novel pyrazole derivatives as potential antiinflammatory agents with minimum ulcerogenic activity.

Two novel isomeric series, N-substituted-5-amino-4-(3,4-dimethoxyphenyl)-3-hydroxy-1 H-pyrazole-1-carboxamides (or thiocarboxamides) 6a-e, 7a, b and N-substituted-3-amino-4-(3,4-dimethoxyphenyl)-5-hydroxy-1 H-pyrazole-1-carboxamides or (thiocarboxamides) 9a-c were synthesized. Moreover, the pyrazolo-[1,5-a]-1,3,5-triazine derivative 8 was also prepared. The new compounds were tested biologically for their in vivo antiinflammatory activity (AI) against carrageenan-induced rat paw oedema. All the investigated compounds exhibited significant AI activity in the range of 23-65%. The most potent compounds were further evaluated for their ulcerogenic liability and acute toxicity. They were found to be less toxic and nearly devoid of ulcerogenic activity as compared to phenylbutazone and indometacin.

Synthesis, estrogen receptor binding affinity and biological evaluation of some 2-substituted estrone derivatives.

This report details the preparation of modified estrogens which are structurally designed to possess estrogenic and/or antiestrogenic activity. The prominent feature of these estrogens is the introduction of a novel side chain in the 2-position of ring A of the steroid nucleus. Their synthesis includes the use of transformations based upon Mannich base chemistry: preparation of the intermediate 2-dimethylamino-methylestrone via aminomethylation of estrone and introduction of various functionalities via reaction of this Mannich base with different reagents. When evaluated for their interaction with the estrogen receptor by competitive binding assays, the tested products were found to be relatively weak competitors at 0 degree C. The uterotrophic and post-coital antifertility assays indicated effects varying in magnitude relative to estradiol. Ethyl[(2'-acetyl-3'-(3-hydroxyestra-17-oxo-1,3,5 (10)-trien-2-yl)]propionate (15) showed uterotrophic and antiimplantation activities of 95% and 20% respectively.

4',17-dioxo-5'H-estra-1(10),4-dieno[3,2-b]furan: synthesis, binding affinity to the estrogen receptor, uterotrophic and antiimplantation activities.

4',17-Dioxo-5'H-estra-1(10),4-dieno[3,2-b]furan (3) has been prepared by several routes starting from 2-bromoacetylestrone (2). Performance of the reaction with thiourea at elevated temperature provided compound 3 in good yield. When other reagents such as thiosemicarbazide, morpholine, sodium hydroxide or sodium hydride were treated with 2-bromoacetylestrone at room temperature, the furano derivative 3 was also obtained as the sole product. This new type of structural modification provided an estrogen nucleus deprived of the 3-hydroxyl function which was previously thought to be an essential requisite for binding to the estrogen receptor (ER). When evaluated in vitro for binding to the ER and in vivo for uterotrophic and antifertility activities, the furano derivative 3 was capable of inhibiting [3H]E2 binding by 16% while still eliciting high uterotrophic (99%) and postcoital antiimplantation (100%) activities relative to estradiol.

Neuromuscular blocking profile of the vecuronium analogue, Org-9487, in the rat isolated hemidiaphragm preparation.

1. The neuromuscular effects of the short-acting aminosteroid muscle relaxant Org-9487 have been studied in the in vitro rat phrenic nerve/hemidiaphragm preparation by use of twitch tension and electrophysiological recording techniques. 2. Org-9487 (5-100 microM) produced a concentration-dependent decrease in the amplitude of twitches (0.1 Hz) and tetanic contractions (50 Hz) evoked by motor nerve stimulation. The compound produced fade of force during both 50 Hz stimulation and train-of-four stimulation at 2 Hz, indicating a prejunctional component of action. 3. Anticholinesterases only partially reversed the effect of Org-9487 on twitch responses. This was possibly because, at the concentrations required to block twitches in the rat, Org-9487 itself was found to possess significant anticholinesterase activity. 4. Org-9487 (3 microM) increased the rundown of endplate current amplitudes during a 2 s train of 50 Hz nerve stimulation. This was because Org-9487 increased the quantal content of the first endplate current in the train without affecting acetylcholine release towards the latter part of the train. 5. Org-9487 (10 microM) produced a voltage-dependent decrease in the time constant of decay of endplate currents at 32 degrees C and 0.5 Hz, indicative of a block of endplate ion channels. The blocking rate constant increased with membrane hyperpolarization.