PubMed Health⌕ Search

Biomedical subjects

S Ong

Publications and source records attributed to S Ong.

At least 55 records · Page 3Linked to original sources
PubMed1995

Predicting drug-membrane interactions by HPLC: structural requirements of chromatographic surfaces.

Drug-membrane interactions have recently been studied by immobilized artificial membrane (IAM) chromatography (Pidgeon, C.; et al. J. Med. Chem. 1995, 38, 590-595. Ong, S.; et al. Anal. Chem. 1995, 67, 755-762), and the molecular recognition properties of IAM surfaces toward drug binding/partitioning appear to be remarkably close to the molecular recognition properties of fluid membranes. The structural requirements of chromatography surfaces to emulate biological partitioning are unknown. To begin to elucidate the surface structural requirements needed to predict drug partitioning into membranes, three bonded phases were prepared. The chromatography bonded phases were prepared by immobilizing (i) a single-chain analog containing the phosphocholine (PC) headgroup (IAM.PC.DD), (ii) a long-chain alcohol containing polar OH groups protruding from the surface (12-OH-silica), and (iii) a long-chain fatty acid containing OCH3 groups protruding from the surface (12-MO-silica). The 12-OH-silica surface can be considered as an immobilized "octanol" phase with OH groups protruding from the surface and is therefore a solid phase model of octanol/water partitioning systems. As expected, improved capability of predicting solute-membrane interactions as found for the chromatographic surface containing the PC polar head-group because the PC headgroup is also found in natural cell membranes. For instance, the IAM.PC.DD column predicted drug partitioning into dimyristoylphosphatidylcholine liposomes (r = 0.864) better than 12-OH-silica (r = 0.812), and 12-MO-silica (r = 0.817). IAM. PC.DD columns also predicted intestinal drug absorption (r = 0.788) better than 12-OH-silica (r = 0.590) and 12-MO-silica (r = 0.681); reversed phase octadecylsilica (ODS) columns could not predict intestinal absorption (r = 0.10). Collectively, these results suggest that chromatographic surfaces containing interfacial polar groups, i.e., PC, OH, and OCH3, model drug-membrane interactions, but surfaces lacking interfacial polar functional groups (e.g., ODS surface) are poor models. Most interestingly, drug partitioning into octanol/water systems does not correlate with drug binding to the immobilized octanol phase. However, drug partitioning into immobilized octanol correlates with drug partitioning into liposomes (r = 0.812).

Chromatography, High Pressure Liquid↗
PubMed1995

Thermodynamics of solute partitioning into immobilized artificial membranes.

The solute retention mechanism on immobilized artificial membranes (IAMs) was studied using three different IAM.PC phases. IAMs were prepared by immobilizing either single-chain or double-chain phosphatidylcholine (PC) ligands. Solute affinity for the single-chain IAM.PC columns (with a ligand density of 127 mumol of PC/g of IAM) was 3-fold lower compared to solute affinity on the double-chain IAM.PC column (with a ligand density of 98 mumol of PC/g of IAM). This suggests that the solute retention on IAMs is dominated by a solute partitioning mechanism. Temperature-dependent studies indicated that the thermodynamics of solute partitioning is similar on both the single-chain and double-chain IAM.PC surfaces. For a set of phenol derivatives, the partitioning into IAM.PC surfaces is both enthalpy and entropy driven. For beta-blockers, the partitioning into IAM.PC surfaces is entropy driven. The free energy of solute partitioning into IAMs correlates very well with the free energy of solute partitioning into liposomes.

Hydrocarbons↗
PubMed1995

IAM chromatography: an in vitro screen for predicting drug membrane permeability.

Fluid cell membranes are the main barrier to drug absorption when diffusion limits uptake. Immobilized artificial membranes (IAMs) are solid phase models of fluid membranes that predicted oral drug absorption in mice for a homologous set of cephalosporins. IAMs also predicted drug permeability through Caco-2 cells. Since drug permeability in Caco-2 cells is known to correlate with the oral absorption of drugs in humans, IAMs may also model drug absorption in humans. IAM analysis is experimentally simple, and large-volume screening of experimental compounds for drug absorption is possible.

Animals↗
PubMed1995

Membrane partition coefficients chromatographically measured using immobilized artificial membrane surfaces.

Immobilized artificial membranes (IAMs) are chromatographic surfaces prepared by covalently immobilizing cell membrane phospholipids. IAM surfaces mimic fluid cell membranes. Solute capacity factors (k'IAM) measured on IAM columns correlate very well with solute equilibrium partition coefficients (Km') measured in fluid liposome systems. For 23 structurally unrelated compounds, log-(k'IAM) correlates with log(Km') with a linear correlation coefficient r = 0.907. This indicates that solute partitioning between the IAM bonded phase and the aqueous mobile phase is similar to the solute partitioning between liposomes and the aqueous phase. Although both IAM chromatography and liposome partitioning can be used as in vitro methods to predict solute partitioning into cell membranes, IAM chromatography is experimentally convenient compared to liposome systems. To study the effect of lipid structure on drug binding to IAMs, IAMs were prepared from three different phosphatidylcholine ligands: (i) a diacylated phosphatidylcholine ligand, (ii) a single chain ether phosphatidylcholine ligand, and (iii) a single chain phosphatidylcholine ligand that lacks a glycerol backbone. Solute retention data were identical for all of these IAMs, and consequently, predictions of solute binding to fluid membranes were also identical. This indicates that the structure of the phosphatidylcholine ligand that is immobilized is not critical for the binding of solutes. Since the structure is not important, the binding of solutes to membranes is a bulk phase property, i.e., it is the interface created by the ligands that determines the solute binding properties, not the ligands themselves. Solute partitioning using octanol/water systems does not correlate with k'IAM unless a homologous series of hydrophobic solutes is being evaluated.

Binding Sites↗
PubMed1994

Preparation of mixed ligand immobilized artificial membranes for predicting drug binding to membranes.

Mixed ligand immobilized artificial membranes (IAMs) are surfaces that contain at least two immobilized membrane phospholipids which are designated as either the primary phospholipid or the secondary phospholipid. The primary immobilized phospholipid refers to the immobilized phospholipid that has the highest surface density. For this work, the primary immobilized phospholipid was a single-chain ether phosphatidylcholine (PC) analog. Four mixed-ligand IAMs were prepared by use of immobilized PC as the primary immobilized phospholipid. The secondary immobilized phospholipid ligand was either phosphatidylethanolamine, phosphatidylserine, phosphatidylglycerol, or phosphatidic acid. All of these secondary phospholipids are bonded at approximately 6-10 mol % relative to the molar amount of immobilized PC. Each secondary phospholipid contains functional groups in the polar head group region that require protecting groups during the immobilization process. The four-step synthetic strategy to prepare mixed-ligand IAMs involves (i) immobilization of the PC analog at high density to silica propylamine (SPA), (ii) immobilization of the second phospholipid (PL) analog at low density, (iii) end capping residual amines with a long-chain anhydride followed by end capping with a short-chain anhydride, and (iv) deprotection of the polar head group protecting groups. The surface density of the mixed PLs bonded to the silica support was approximately 130 mumol of PLs/g of SPA. High-performance liquid chromatography using these mixed lipid IAMs can be exploited to rapidly predict the membrane binding properties of drugs.

Adrenergic alpha-Agonists↗
PubMed1994

Phospholipid immobilization on solid surfaces.

Single chain ether phospholipids (PLs) containing omega-carboxyl groups in the alkyl chain were immobilized on silica propylamine (SPA) to form IAM chromatography packing material. The PL ligands are analogs of phosphatidylglycerol (PG), phosphatidylserine (PS), phosphatidylethanolamine (PE), and phosphatidic acid (PA). All of these PLs contain polar functional groups in the lipid head group that require protection prior to PL immobilization and then deprotection after immobilization. The IAM surface was prepared in four steps: (i) the omega-carboxyl group was activated with carbonyldiimidazole, (ii) the activated PL-imidazolide ligand was bonded to SPA, (iii) the surface was end capped with a long chain anhydride and then end-capped with a short chain anhydride, and (iv) protecting groups were removed to form the IAM surface. The extent of deblocking the protecting groups was typically > or = 90%. This immobilization strategy generated a phospholipid surface that was stable when solvated with all organic solvents and aqueous buffers between pH 2 and 8. Both FT-IR spectroscopy and elemental analysis indicated that the bonding densities were 64-83 mg of PL/g of SPA, which corresponds to an area per molecule of 66-104 A2. These bonding densities for the immobilized PLs are very close to the area per molecule of mobile phospholipids comprising liposome membrane. The similar areas per molecule of immobilized PLs and mobile phospholipid in liposomes indicate that the lipid environments are similar.

Liposomes↗
PubMed1988

Spectrum concept of neuroleptic malignant syndrome.

Although neuroleptic malignant syndrome (NMS) was initially thought to be a rare, idiosyncratic complication, the incidence estimates have been rising over the years. A part of this increase can be explained on the basis of an over-inclusive definition of NMS. The unitary concept of NMS has been challenged recently and a spectrum concept has been enunciated on the basis of findings of retrospective chart-reviews which have used too broad a definition of NMS. The authors describe three cases of neuroleptic-related toxicity with different clinical presentations which appeared in a manner apparently supporting the spectrum concept. They discuss this controversial concept critically, however, and caution against its overzealous use in routine clinical practice owing to its far-reaching clinical implications.

Adult↗
PubMed1980

Detection of prostaglandin induced antigen-stimulated changes in splenic AMP levels by immunofluorescence.

Antigen stimulated changes in cyclic AMP levels which are the result of increases in prostaglandin levels, were measured by immunofluorescence in frozen spleen sections. The results provide direct visual confirmation of previous reports in that an increase in the number of cells staining positively for cyclic AMP were detected. The increase in cyclic AMP levels occurs in approximately 40% of the cells in the cortical region of the spleen. No staining was observed in deeper regions. Using sRBC as a particulate antigen and DNP-BGG as a soluble antigen, it was possible to show that a slightly smaller increase in the number of cyclic AMP positive cells occurs using DNP-BGG compared to sRBC. These data mean that antigen stimulated changes in splenic AMP levels occurs in a much larger population than could be accounted for on the basis of antigenic specificity. Such a result is consistent with previous data showing the increase in cAMP is a result of a prior increase in prostaglandin. Thus, any cell bearing a prostaglandin receptor could respond by showing an elevated cAMP level.

Animals↗
PubMed1978

Effect on canine cerebral blood flow of two common pressor agents during prolonged halothane anesthesia.

Inasmuch as prolonged halothane anesthesia is often associated with hypotension, the effects of pressor agents possibly employed to adjust this hypotension on cerebral blood flow are of interest. In dogs, after prolonged halothane anesthesia, there was a marked difference in the effects of phenylephrine and angiotensin on cerebral blood flow at dosages which promote moderate rises in blood pressure. Phenylephrine had no effect whereas angiotensin had a significantly enhancing effect on cerebral blood flow.

Anesthesia, Inhalation↗
PubMedDate not supplied

Appropriateness of rabies postexposure prophylaxis treatment for animal exposures. Emergency ID Net Study Group.

CONTEXT: Rabies postexposure prophylaxis (RPEP) treatments and associated costs have increased in the United States. The extent to which RPEP use is consistent with guidelines is not well understood. OBJECTIVE: To characterize animal contacts and determine the frequency and factors associated with inappropriate RPEP use. DESIGN, SETTING, AND PATIENTS: Prospective case series study of patients presenting with an animal exposure-related complaint from July 1996 to September 1998 at 11 university-affiliated, urban emergency departments (the Emergency ID Net). MAIN OUTCOME MEASURES: Exposure type, circumstances, and RPEP use (appropriateness defined by local public health departments). RESULTS: Of 2030 exposures, 1635 (81%) were to dogs; 268 (13%) to cats; 88 (4%) to rodents/rabbits; 10 (0. 5%) to raccoons; 5 (0.2%) to bats; and 24 (1.2%) to other animals. Among those exposed, 136 (6.7%) received RPEP after dog (95), cat (21), raccoon (8), bat (4), or other animal (8) exposures. Use of RPEP varied by site (range, 0%-27.7% of exposures), with most frequent use reported at sites in the eastern United States. Management was considered appropriate in 1857 exposures (91.5%). Use of RPEP was considered inappropriate in 54 cases (40% of those in which it was given), owing to factors including animal availability for observation and exposure in a low-endemicity area. Rabies postexposure prophylaxis was considered inappropriately withheld from 119 cases (6.3% of those not receiving RPEP), often because a domestic animal was unavailable for observation or testing. CONCLUSION: These results suggest that use of RPEP is often inappropriate. Greater compliance with current guidelines would increase RPEP use. Physician education, improved coordination with public health officials, and clarification of RPEP guidelines could optimize use of this expensive resource. JAMA. 2000;284:1001-1007

Algorithms↗