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S Tripathi

Publications and source records attributed to S Tripathi.

At least 37 records · Page 2Linked to original sources
PubMed1997

Considerations for toxicology studies of respiratory drug products.

The standard approaches for the preclinical development of chronically administered drugs also apply to most respiratory drugs. Modifications from the standard preclinical development plan, however, may be necessary if the drug is administered intranasally or by inhalation. Administration by these routes may result in airway toxicity and the intended patient population is often particularly susceptible. Current and former representatives of the Division of Pulmonary Drug Products (CDER, U.S. FDA) present this article to describe general principles of preclinical development for respiratory drug indications. The article addresses drugs intended for administration by the intranasal or inhalation routes. The article describes the types of studies recommended, considers the initial human dose, and discusses dose-escalation strategies in clinical trials. Other areas of special concern with intranasal or inhalation administration include immunotoxicity, reproductive toxicity, types of dosing apparatus, excipients and extractables, and formulation changes. The approaches described in this article are intended as general information and should be adapted to the scientific considerations and circumstances of a particular drug under development.

Humans↗
PubMed1997

Delay in improvement of ankle-arm index and ankle waveforms after lower-extremity revascularization.

Ankle-arm index (AAI) and pulse volume recording (PVR) are commonly used in the early postoperative period to measure the outcome after lower-extremity revascularization. They are also used in addition to duplex scan for long-term follow-up of these patients. We noticed that in some patients the AAI and/or PVR after revascularization procedures did not improve immediately after surgery, but took 24 hours or longer to do so. We retrospectively reviewed the records of 47 patients who underwent various lower-extremity revascularization procedures and found that out of 20 patients who had AAI and/or PVR measured in the recovery room, 8 patients took 24 hours and 1 patient took more than 24 hours for maximal improvement of their AAI and/or PVR. This may be related to vascular spasm, and knowledge of this delayed improvement is important in preventing errors during follow-up.

Aged↗
PubMed1997

Role of macrophage colony-stimulating factor in atherosclerosis: studies of osteopetrotic mice.

Previous in vitro and in vivo studies have suggested that macrophage colony-stimulating factor (M-CSF) plays a role in atherogenesis. To examine this hypothesis, we have studied atherogenesis in osteopetrotic (op/op) mice, which lack M-CSF due to a structural gene mutation. Atherogenesis was induced either by feeding the mice a high fat, high cholesterol diet or by crossing op mice with apolipoprotein E (apo E) knockout mice to generate mice lacking both M-CSF and apo E. In both the dietary and apo E knockout models, M-CSF deficiency resulted in significantly reduced atherogenesis. For example, in the apo E knockout model, homozygosity for the op mutation totally abolished aortic atherogenesis in male mice and reduced the size of the lesions approximately 97% in female mice. Mice heterozygous for the op mutation also exhibited a significant decrease in lesion size. Among apo E knockout mice, the frequency of atherosclerosis in aortic arch was 0/6 (op/op), 1/15 (op/+), and 12/16 (+/+). The effect of the M-CSF on atherosclerosis did not appear to be mediated by changes in plasma lipoproteins, as the op mice exhibited higher levels of atherogenic lipoprotein particles. The effects of the op mutation on atherogenesis may have resulted from decreased circulating monocytes, reduced tissue macrophages, or diminished arterial M-CSF.

Animals↗
PubMed1995

Ion binding constants for gramicidin A obtained from water permeability measurements.

Gramicidin A pores are permeable to water and small monovalent cations. For K, Rb, and Cs there is good evidence from conductances and permeability ratios that a second ion can enter a pore already occupied by another, but for Na this evidence is inconclusive and comparison of tracer fluxes and single channel conductances suggests that second ion entries are prohibited. Partly as a result of the complications of second ion entry there have been widely differing estimates for the dissociation constants for the first ion in the channel. Dani and Levitt (1981, Biophys. J. 35: 485-499) introduced a method for calculating ion binding constants from simultaneous measurements of water fluxes and membrane conductance. They found no evidence for second ion binding and calculated dissociation constants of 115 mM for Li, 69 mM for K, and 2 mM for Tl. It is shown here that the two-ion, four-state model predicts a dependence of water permeability on ion concentration that is difficult to distinguish from the predictions of block by a single ion. Using a modified technique that allows measurement of higher conductances, the first ion dissociation constants have been determined as 80 mM for Na, 40 mM for Rb and 15 mM for Cs. These values and those of Dani and Levitt fall in a smooth sequence. The dissociation constant for Cs is consistent with single channel conductances and flux ratios. There is a discrepancy between this constant for Na and the value, 370 mM, calculated from the single channel conductances and the assumption that a second ion cannot enter or affect an occupied pore. The dissociation constant for Rb is intermediate between those for K and Cs whereas tracer flux measurements (Schagina, Grinfeldt & Lev, 1983. J. Membrane Biol. 73: 203-216) have suggested that Rb interacts much more strongly with the channel than Cs.

Animals↗
PubMed1994

Cushing's disease: pituitary imaging.

Fourteen patients with adrenocorticotropic hormone (ACTH)-dependent hypercortisolism underwent pituitary scanning with computed axial tomography (CT) and magnetic resonance imaging (MRI). Computed tomography revealed pituitary macroadenomas in two patients, pituitary hyperplasia in one and a suspicion of pituitary microadenoma in one. Thirteen patients underwent MRI. One with a macroadenoma diagnosed on CT did not undergo MRI. The MRI revealed a pituitary macroadenoma in one, microadenoma in three and hyperplasia in two cases. Magnetic resonance imaging following gadolinium diethylene triamine penta acetic acid (gd-DTPA) enhancement revealed four more pituitary microadenomas. All patients who had pituitary adenomas (micro and macro) and hyperplasia underwent trans-sphenoidal pituitary surgery. One of the two patients, who had an enlarged pituitary on imaging but no demonstrable adenoma, was found to have a microadenoma at surgery. Patients with ACTH-dependent hypercortisolism should undergo MRI of the pituitary gland to identify/localize corticotroph pituitary adenomas. The study should include gd-DTPA enhancement in cases where the scan is normal.

Adenoma↗
PubMed1989

Mechanisms of water transport by epithelial cells.

Isosmotic transport of fluid across epithelial cell layers occurs by intraepithelial mechanisms that are not fully understood. Newer methods of measuring water flows across epithelia with higher resolution should now permit some key issues regarding solute-linked water transport to be clarified. Unstirred-layer effects are not likely to be serious sources of error in these measurements with judicious choice of experimental conditions. Progress in ultrastructural stereology has shown that in the proximal tubule most of the transporting membrane is located in the basal aspects of cells, making models based on a hyperosmolar lateral compartment less relevant. The current models of simple transcellular osmosis, though appealing for this simplicity, fail to account for some major experimental findings. Experimental design and methodological limitations have not yet achieved rigorous testing of whether or not epithelia can produce a perfectly isosmotic absorbate without any transepithelial driving forces. A better understanding of the mechanism of translocation of water through the lipid bilayer, the plasma membrane proteins, and special membrane structures like the tight junctions would significantly contribute to our knowledge of the mechanisms and intraepithelial routes by which water is transported by epithelia.

Animals↗
PubMed1988

Cell membrane water permeabilities and streaming currents in Ambystoma proximal tubule.

An electrophysiological approach is used to analyze the possible routes of osmotically driven water flow across the isolated perfused Ambystoma proximal tubule. The minimum hydraulic conductivities (Lp) of the cell membranes were estimated from the initial rate of change of intracellular activities of Na+ and K+ in response to a step gradient of 50 or 100 mosmol/kg sucrose. The Lp of the apical membrane is 1.30 X 10(-4) cm.s-1.osM-1 referred to the luminal epithelial surface and 2.45 X 10(-6) cm.s-1.osM-1 when corrected for amplification of the brush border (n = 8). The Lp of the basolateral membrane is 1.42 X 10(-4) cm.s-1.osM-1 referred to the basement membrane surface and 6.39 X 10(-6) cm.s-1.osM-1 when corrected for the amplification of the basal and lateral membranes (n = 5). Transepithelial water flows were generated in either direction by a unilateral step increase of osmolality with 100 mosmol sucrose. Bath-to-lumen flow increased paracellular transepithelial resistance (R3) by 48%; lumen-to-bath flow decreased R3 by only 3%. A bilateral increase in the osmolality of both solutions by 50 mosM had no significant effect on R3. Streaming potentials were observed during trans-epithelial water flow induced by unilateral gradients of sucrose; their polarity, magnitude, site of generation, and insensitivity to change of paracellular resistance are all indicative of water flow through paracellular structures, especially the lateral intercellular spaces. Contrary to earlier suggestions (J. M. Diamond, J. Membr. Biol. 51: 195-216, 1979), these potentials are not primarily diffusion potentials across anion-selective tight junctions resulting from solute polarization in the unstirred layers. Instead, a true electrokinetic basis for these streaming potentials is indicated by their continued presence after deletion of all Cl-. Thus water moves through both cellular and paracellular pathways in this epithelium.

Ambystoma↗
PubMed1987

Isolated perfused Ambystoma proximal tubule: hydrodynamics modulates ultrastructure.

A method using a pressure-sensing servo-pipette is described for measuring downstream transepithelial pressure within isolated renal tubules perfused at flow rates designed to keep luminal solution composition constant. The hydrodynamics of in vitro microperfusion of isolated proximal tubules of Ambystoma tigrinum was varied and different states of transepithelial hydrostatic pressure difference, axial tubule flow, and transepithelial transport were correlated with epithelial ultrastructure. Tubules analyzed by ultrastructural morphometry were as follows: unperfused with and without ouabain, perfused single-end cannulated with and without ouabain, and perfused double-end cannulated tubules incubated in substrate Ringer. The results indicate that proximal tubule fine structure is well preserved for more than 3 h in unperfused and perfused tubules. Small transepithelial hydrostatic pressure gradients (less than 162 Pa) increase tubule diameters and decrease cell height without changing volumes of the cells, lateral intercellular spaces (LIS), or the basal extracellular labyrinth (BEL). Pressure gradients of 271 Pa have no further effect on tubule diameters or cell height, but significantly reduce volumes of LIS and BEL. Transport inhibition and axial flow changes have minor structural effects. This study demonstrates a close dependence of tubule ultrastructure on hydrodynamic conditions and provides guidelines for optimizing the latter during perfusion of isolated renal tubules.

Ambystoma↗