Study of wave motion on the emergence of veering, locking, and coupling in periodic composite panels.

This research proposes the effect of micropolar-Cosserat (MC) parameters (length-scale parameters and Cosserat shear modulus) on the dispersion characteristics of propagating wave modes in periodic composite panels (PCPs). These inbuilt parameters are due to the assumption of the length-scale boundary conditions that allow for capturing the micro-rotational (MR) wave mode along with the flexural ones. A significant contribution of this study is the transformation of the two-dimensional (2-D) periodic composite problem into a series of one-dimensional (1-D) ones using the MC continuum theory. The analysis employs the transfer matrix method in the framework of the state-space approach to investigate periodic systems in the eigenvalue domain. Additionally, Bloch-Floquet's periodic boundary conditions (PBCs) are applied to the unit cell to ensure the periodicity of the system. The main innovation lies in observing veering, locking, and coupling phenomena, which occur due to alterations in lamina orientation and MC parameters. Moreover, the presence of inbuilt parameters renders the dispersion characteristics highly sensitive to even minor coefficient variations, with a mere 1% change significantly impacting eigenmode fluctuations. The sudden bandgap (BG) disappearing nature could be used to identify the accurate value of the coefficient for designing and analyzing PCPs.

Fungal degradation of an acetolactate synthase (ALS) inhibitor pyrazosulfuron-ethyl in soil.

Owing to reported phytotoxicity of some sulfonylurea class of herbicides in number of sensitive crops and higher persistence in soil, present study was conducted to isolate and identify pyrazosulfuron-ethyl degrading fungi from soil of rice field. Penicillium chrysogenum and Aspergillus niger, were isolated and identified from rhizospere soil of rice field, as potent pyrazosulfuron-ethyl degrading fungi. Degradation of pyrazosulfuron-ethyl by P. chrysogenum and A. niger, yielded transformation products/metabolites which were identified and characterized by LC/MS/MS. The rate of dissipation of pyrazosulfuron-ethyl was found higher in soil of rice field and soil inoculated with P. chrysogenum. This showed important route of degradation of pyrazosulfuron-ethyl by microbes apart from chemical degradation.

Probability amplitude description of the dynamics of charged particles in a magnetic field in the macrodomain.

The set of Schrödinger-like equations obtained earlier by the author [Phys. Rev. Lett. 26, 417 (1971), Phys. Rev. A 31, 3951 (1985)] for the charged particle dynamics in an inhomogeneous magnetic field in the macrodomain, are derived here starting from the quantum-mechanic Schrödinger equation in its path-integral representation. This derivation enables a generalization of the equations to include a curl-free vector potential in the Schrödinger-like equations. In view of the amplitude character of the latter equations, which now descends directly from that of the quantum-mechanic Schrödinger equation, they now predict the existence in the macrodomain of all such phenomena, which are characteristic of a probability amplitude theory, e.g., the interference, and the observation of a curl-free vector à la Aharonov-Bohm. A discrete energy structure, predicted as interference maxima and minima has already been observed by the author with his co-workers [Mod. Phys. Lett. A 8, 167 (1993)]. A prediction is now made for the observability of a curl-free vector potential in the macrodomain, in the context of the present problem.

The p16 status of tumor cell lines identifies small molecule inhibitors specific for cyclin-dependent kinase 4.

Loss of p16 functional activity leading to disruption of the p16/cyclin-dependent kinase (CDK) 4:cyclin D/retinoblastoma pathway is the most common event in human tumorigenesis, suggesting that compounds with CDK4 kinase inhibitory activity may be useful to regulate cancer cell growth. To identify such inhibitors, the 60 cancer cell lines of the National Cancer Institute drug screen panel were examined for p16 alterations (biallelic deletion, intragenic mutations, or absent p16 protein), and the growth-inhibitory activity of more than 50,000 compounds against these 60 cell lines was compared with their p16 status. One compound, 3-amino thioacridone (3-ATA; NSC 680434), whose growth-inhibitory activity correlated with the p16 status of the cell lines had an IC50 of 3.1 microM in a CDK4 kinase assay. In addition, four compounds structurally related to 3-ATA inhibited CDK4 kinase with IC50s ranging from 0.2-2.0 microM. All five of these compounds were less potent inhibitors of cell division cycle 2 and CDK2 kinases, with IC50s 30- to 500-fold higher than that for CDK4. ATP competition experiments demonstrated a noncompetitive mode of inhibition for 3-ATA (K(i) = 5.5 microM) and a linear mixed mode for benzothiadiazine (NSC 645787; K(i) = 0.73 microM). We have successfully demonstrated a novel approach to identify specific CDK4 kinase inhibitors that may selectively induce growth inhibition of p16-altered tumors.

Synthesis of analogs of 2-methoxyestradiol with enhanced inhibitory effects on tubulin polymerization and cancer cell growth.

A new series of estradiol analogs was synthesized in an attempt to improve on the anticancer activity of 2-methoxyestradiol, a naturally occurring mammalian tubulin polymerization inhibitor. The compounds were evaluated as inhibitors of tubulin polymerization and the binding of [3H]colchicine to tubulin, as well as for in vitro cytotoxicity in human cancer cell cultures. Overall, the most potent of the new compounds were 2-(2',2',2'-trifluoroethoxy)-6-oximinoestradiol, 2-ethoxy-6-oximinoestradiol, and 2-ethoxy-6-methoximinoestradiol. These agents lacked significant affinity for the estrogen receptor. The cytotoxicities of the compounds correlated in general with their abilities to inhibit tubulin polymerization, thus supporting inhibition of tubulin polymerization as the primary mechanism causing inhibition of cell growth.

Design and synthesis of ellipticinium salts and 1,2-dihydroellipticines with high selectivities against human CNS cancers in vitro.

9-Methoxy-2-methylellipticinium acetate (6), along with the 9-methyl and 9-chloro derivatives (7, and 8, respectively) have shown remarkable selectivities in vitro against the NCI human CNS cancer subpanel. In order to target these types of compounds to the CNS in vivo, a series of 1,2-dihydroellipticines was synthesized. 9-Methoxy-2-methyl-1,2-dihydroellipticine (9) retained the potency and selectivity of the parent compound 6 but was unstable toward oxidation to 6. In order to improve the stability of 9, it was converted to the vinylogous amide 33 by introduction of a formyl group in the 4-position. Compound 33 proved to be much more stable than 9, but it was also less potent than 9 by about 1 order of magnitude, and it was less selective for the CNS subpanel than 9. To overcome the limited water solubilities of the ellipticines and dihydroellipticines, several ellipticine analogues incorporating polar groups on the N-2 nitrogen were prepared. The 2-(methoxymethyl)ellipticinium salts 24 and 25, as well as the (methylthio)methyl congener 26, were relatively potent anticancer agents which displayed cytotoxicity selectivity profiles similar to compound 6. The cytotoxic dihydroellipticines 9 and 10 exhibited potencies approaching that of ellipticine itself in facilitating the formation of a "cleavable complex", while the least cytotoxic ellipticine derivatives exhibited no cleavage above background.

Effect of flutonidine on ouabain-induced arrhythmias and lethality in guinea-pig.

Flutonidine (10, 20 and 40 micrograms/kg) was studied for its efficacy against the cardiotoxic effects induced by slow intravenous infusion of ouabain in guinea-pigs. Flutonidine increased the dose of ouabain required to cause ventricular premature beats, ventricular tachyarrhythmias and lethality. Flutonidine further inhibited the rate of ouabain-induced rise in blood pressure. Alpha 1 adrenoceptor antagonist, corynanthine (1 mg/kg), could not alter the protective action of flutonidine; whereas idazoxan (100 micrograms/kg), the alpha 2 adrenoceptor blocker, showed significant inhibition of this effect. It is suggested that the reduction in the arrhythmogenic and lethal effects of ouabain by flutonidine may be due to its ability to reduce sympathetic tone by interfering with the neural components of ouabain action mediated through alpha 2 adrenoceptors.

St-93 hyperglycemia in Wistar rats.

The alpha 2-adrenoceptor agonist St-93 was evaluated for its effect on blood glucose levels in Wistar rats. A dose-dependent increase in blood glucose was observed in rats after intraperitoneal administration of St-93. The hyperglycemic effect of St-93 was not altered by prazosin and propranolol, whereas idazoxan significantly inhibited this effect. Pretreatment with reserpine did not affect the hyperglycemic effect of St-93. There was no significant increase in the blood glucose values with St-93 in streptozotocin-diabetic rats. It may be concluded that the hyperglycemia induced by St-93 is mediated through alpha 2-adrenoceptors, possibly located on pancreatic beta-cells.

Isolated paced guinea pig left atrium: a new ouabain-induced arrhythmia model.

Ouabain (1.0 x 10(-6) M) produced a uniform, consistent and reproducible arrhythmia on paced guinea pig left atrium bathed in Ringer-Locke solution. A second spell of arrhythmia of similar intensity and pattern, which had the same latency to onset, was reproduced 60 min after the first spell of arrhythmia. Lignocaine (3.46 x 10(-5) M) and propranolol (1.69 x 10(-5) M) gave full protection against the second spell of arrhythmia, whereas lower doses of these drugs were able to delay the onset and reduce the duration. Clonidine (3.75 x 10(-5) M), however, was found to be ineffective. This model can be used for the detection and assessment of directly acting antiarrhythmics in very low concentrations, since this is a sensitive and reliable method.

Pre-clinical toxicity of IDPH-791: a new centrally acting muscle relaxant in rats.

IDPH-791, a novel centrally acting muscle relaxant, in doses up to 500 mg/kg (po) for 14 days did not result in any appreciable adverse effect on body weight gain, food or water consumption including biochemical and haematologica parameters in rats. Variations observed in the biochemistry and haematology were either comparable to controls or were within normal limits.

Effect of various hypotensive agents on locomotor activity and blood pressure of rats.

The effect of various hypotensive agents were simultaneously tested on locomotor activity and blood pressure of unanaesthetised (conscious) rats. The agents viz clonidine, prazosin, furosemide and hexamethonium were found to reduce significantly the locomotor activity as well as blood pressure, 30 min post administration. Phenoxybenzamine and alpha-methyldopa produced similar type of effect but after 60 and 120 min post administration respectively. Aminophylline and propranolol failed to reduce locomotor activity as well as blood pressure, 60 and 90 min post administration. The findings of the present study are strongly indicative that hypotensive agents reduce locomotor activity and that the reduction is sequel to the fall in blood pressure.

Biotransformation of tipredane, a novel topical steroid, in mouse, rat, and human liver homogenates.

The in vitro biotransformation pathways of 3H-tipredane (3H-TP) were studied. 3H-TP, at concentrations of 1 and 250 microM, was incubated with the 10,000g supernatant fraction of the liver homogenates of mice, rats, and one human. The incubation mixtures were deproteinated with methanol and, after removal of methanol by evaporation, extracted with dichloromethane. The dichloromethane extracts were then fractionated by HPLC. 3H-TP was extensively biotransformed by the liver homogenates of the three species studied; 17 metabolites were isolated and characterized by their retention times on HPLC compared to those of the reference standards. Fourteen metabolites were identified using MS and, for some, NMR spectroscopy. Three major biotransformation pathways of TP were identified: 1) sulfoxidation, 2) elimination of the alkylthio groups, and 3) hydroxylation of the steroid nucleus. Combinations of these processes and subsequent reactions resulted in the formation of numerous metabolites whose biological activities were significantly less than that of TP. The separation of local anti-inflammatory activity from systemic side effects observed for TP in animals and humans is most probably due to its metabolic inactivation, primarily in the liver.

A test for analgesics: incoordination in writhing mice.

Acetic acid administered to mice resulted in post-writhing incoordination and a subsequent fall in the rota-rod test. This fall from rota-rod induced by 3% acetic acid was dose-dependently protected by the non-narcotic analgesics. While suprofen was found to be the most potent (ED50 = 15.29 mg/kg), aspirin was found to be the least potent (ED50 = 81.54 mg/kg). The model appears to be more sensitive than the conventional methods for testing non-narcotic analgesics.

Androstene-17-thioketals. 1st communication: glucocorticoid receptor binding, antiproliferative and antiinflammatory activities of some novel 20-thiasteroids (androstene-17-thioketals).

The unique replacements of the alpha-hydroxyl and beta-ketol groups of corticoids at C17 with selected, simple alkylthio or (2-fluoroalkyl)thio groups resulted in the structurally novel steroids, C17-alkylthioketals of 9 alpha-fluoro-11 beta-hydroxy-androsta-1,4-diene-3,17-dione. The described androstene-17-thioketals (20-thiasteroids) had high affinities for the glucocorticoid receptor protein of rat liver cytosol. Most were more potent than triamcinolone acetonide, a clinically moderately potent corticoid, in antiproliferative and antiinflammatory activities in mice. Specifically, (11 beta, 17 alpha)-17-(ethylthio)-9 alpha-fluoro-11 beta-hydroxy-17-(methylthio) androsta-1,4-dien-3-one (tipredane, SQ 27,239) and (11 beta, 17 alpha)-17-(ethylthio)-9 alpha-fluoro-17-[2-(fluoroethyl)thio] - 11 beta - hydroxy-androsta-1,4-dien-3-one (SQ 28,300), topically applied, were as potent as halcinonide, a clinically highly potent corticoid, in inhibition of croton oil-induced edema in the mouse. It is suggested that both thiasteroids could be moderately to highly potent topical antiinflammatory agents in man.

Androstene-17-thioketals. 2nd communication: pharmacological profiles of tipredane and (11 beta, 17 alpha)-17-(ethylthio)-9 alpha-fluoro-17-[2-(fluoroethyl)thio]-11 beta-hydroxy-androsta-1,4-dien-3-one, structurally novel 20-thiasteroids possessing potent and selective topical antiinflammatory activity.

Two structurally novel alkylthio-substituted steroids, (11 beta, 17 alpha)-17-(ethylthio)-9 alpha-fluoro-11 beta-hydroxy-17-(methylthio)andro-1,4-dien-3-one (tipredane, SQ 27,239) and (11 beta, 17 alpha)-(ethylthio)-9 alpha-fluoro-17-[2-(fluoroethyl) thio]-11 beta-hydroxy-androsta-1,4-dien-3-one (SQ 28,300) were compared to presently available topical corticosteroids for in vitro and in vivo glucocorticoid and antiinflammatory activities. Based upon results of in vitro assays, in vivo antiinflammatory tests in mice, and human vasoconstriction measurements, the thiasteroids most closely resemble moderately potent to highly potent corticoids. These compounds display more modest activity in topical antiinflammatory assays using rats. Both tipredane and SQ 28,300 exhibit favorable separation of local antiinflammatory activity from systemic effects on thymus and hypothalamic-pituitary-adrenal axis function, most probably due to rapid metabolic inactivation. As such, these compounds represent potentially safer therapy for topical treatment of corticoid-responsive skin diseases and bronchopulmonary conditions in humans.

Solvent artifacts likely to be induced by dimethylformamide.

Dimethylformamide (DMF) is widely used as a drug solvent. We found DMF to have wide-spread pharmacological effects including depressant effect on CNS evidenced by a decrease in locomotor activity, body and limb tone and rectal temperature, and potentiation of pentobarbitone sleep. A dose-dependent hypotensive effect was seen in cats and rats. In rats, it was partially blocked by atropine and was associated with bradycardia. DMF antagonised the contractions of smooth muscle induced by many agonists. An atropine sensitive spasmogenic effect was observed on rabbit ileum at 20 ml/l and a direct relaxant effect at 50 ml/l. A positive inotropic effect on guinea pig atria was observed with 5 ml/l. The results indicate DMF concentrations that may not perhaps produce 'solvent artifacts' when used as a solvent.