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Biomedical subjects

R K Varma

Publications and source records attributed to R K Varma.

At least 19 recordsLinked to original sources
PubMed2001

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.

Journal Article↗
PubMed1999

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.

Antineoplastic Agents↗
PubMed1997

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.

2-Methoxyestradiol↗
PubMed1994

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.

Brain Neoplasms↗
PubMed1991

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.

Animals↗
PubMed1991

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.

Animals↗
PubMed1987

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.

Acetates↗
PubMed1986

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.

Adrenalectomy↗
PubMed1986

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.

Administration, Topical↗
PubMed1985

Polysorbate 80: a pharmacological study.

Polyoxyethylene (20) sorbitan monooleate (polysorbate 80, Tween 80), a surfactant, has been widely used as a solvent for pharmacological experiments. In the present study, polysorbate 80 was found to have toxicity of a low order in both the mice and rats when given by i.p. and p.o. routes. It produced mild to moderate depression of the central nervous system with a marked reduction in locomotor activity and rectal temperature, exhibited ataxia and paralytic activity and potentiated the pentobarbital sleeping time. On intravenous administration in dogs, it had a dose-dependent hypotensive effect. Polysorbate 80 did not have a direct stimulant or relaxant effect on either guinea pig ileum or rat uterus, however, it antagonised the contractions induced by acetylcholine, histamine, barium, 5-hydroxytryptamine and carbachol in a dose-dependent manner. A direct relaxant effect was observed on rabbit jejunum. A dose-dependent myocardial depressant effect was observed on guinea pig and rabbit paired atrial preparations. On the electrically-driven guinea pig left atrial preparation, polysorbate 80 exhibited a dose-dependent negative inotropic action. Polysorbate 80 did not induce diuresis in rats upto a dose of 2.5 ml/kg. The results of the present study indicate that polysorbate 80 can neither be used as a solvent for isolated tissue experiments nor when considered for intravenous administration. However, polysorbate 80 can be employed safely as a vehicle for neuropsychopharmacological experiments in doses not exceeding 1 ml/kg.

Animals↗
PubMed1983

Acetic acid and phenylquinone writhing test: a critical study in mice.

Studies were planned to establish the dose-effect relationship with both acetic acid and phenylquinone and to find out suitable concentrations for these two chemicals for pre- and post screening. The LD50 of acetic acid and phenylquinone were found to be 3.16% and 0.23%, respectively. Based on the studies conducted, the prescreening and postscreening concentrations of 0.5% is recommended for acetic acid, while for phenylquinone, prescreening concentration of 0.005% and postscreening concentration of 0.02% is advocated. Using this criterion in the acetic acid writhing test, analgin was the most potent analgesic while aspirin was the least. However, suprofen was most potent and paracetamol least among analgesics employed against phenylquinone induced writhing.

Acetates↗
PubMed1982

A pharmacological study of propane-1,2-diol.

Propane-1,2-diol (propylene glycol, PG), considered to be a safe solvent and commonly used as a vehicle in pharmacological and toxicological investigations, showed various neuropsychopharmacological activity in albino mice and rats. In lower concentrations (10-20%), at dose level of 10 ml/kg, PG did not show any significant neuropsychopharmacological activity either by i.p. or p.o. routes. But higher concentrations (50-100%), at same dose level by i.p. route, were found to have moderate to marked effect. There was decrease in locomotor activity, body and limb tone, respiration, rectal temperature and suppression of secondary conditioned responses. Significant potentiation of pentobarbitone (pentobarbital) hypnosis, slight increase in d-amphetamine toxicity in aggregated mice and pronounced analgesic and anti-inflammatory activity were also observed. Most of the above effects were also observed on p.o. treatment but the effects were of lesser degree. PG did not produce any effect on dog or cat blood pressure up to 100% concentration at the dose level 0.5 ml/kg. However, it potentiated the adrenaline (epinephrine) and noradrenaline (norepinephrine) response. On isolated smooth muscle preparations, in 50-100% concentrations, a dose-dependent non-specific blockade was observed against agonists viz. acetylcholine, histamine, 5-HT and barium chloride. No effect was seen on cardiac tissue preparation. On the basis of present findings, it is suggested that propylene glycol as a solvent be used only in low concentration of not more than 10% for pharmacological and toxicological investigations.

Analgesics↗