Biomedical subjects

K R Barber

Publications and source records attributed to K R Barber.

At least 37 records · Page 2Linked to original sources

PubMed1997

Relationship between social support, self-esteem and codependency in the African American female.

Increasing numbers of minorities are seeking mental health assistance. Inclusion of cultural considerations is important for increasing sensitivity to those whose life experiences differ. For African Americans, therapy is better facilitated if one operates from a cultural specific frame of reference. African American women attending a women's support group were surveyed. Questionnaires querying dimensions on family relationships, self-esteem and dependency were utilized. Results indicated a relationship between social support, self-esteem and codependency in African American females. Social support and self-esteem were inversely associated with codependency. This study provides insight for mental health professionals in counseling African American females.

Adult↗

PubMed1996

Sphingolipid-derived signalling modulators: interaction with phosphatidylserine.

We previously described the synthesis of two deuterium-labelled sphingoid bases, which made it possible to perform NMR spectroscopy on this family of signalling modulators in membranes (Rigby, A.C, Barber, K.R and Grant, C.W.M. (1995) Biochim. Biophys. Acta 1240, 75-82). In the present work we sought to test the concept that such mediators may display altered physical behaviour through association with anionic lipids - as a possible mechanism of involvement in signal transduction. Lyso-dihydrogalactosylceramide with deuterium nuclei at C4 and C5 of the sphingosine backbone and at C'3 and C'4 of the galactose ring ([2H4]lyso-GalCer), and N,N-dimethylsphingosine with deuterated amino-methyl groups ([2H6]dimethylsphingosine), were assembled as minor components into unsonicated fluid bilayer membranes of 1-palmitoyl-2-oleoylphosphatidylcholine/cholesterol. The effect of (anionic) phosphatidylserine was considered in this zwitterionic host matrix. The results present a picture of rapidly reversible interaction. The (-) charged phosphatidylserine exerted readily-measurable control over the orientation of the carbohydrate residue of [2H4]lyso-GalCer. In contrast, surrounding (-) charges exerted little spectral influence at the level of C4 and C5 of the lyso-GalCer, membrane-inserted, backbone; or at the level of the amino group of dimethylsphingosine. It would appear that packing alterations induced by the phosphatidylserine/sphingoid base association can translate into sizeable spatial constraints in the neighbouring aqueous domain.

Cholesterol↗

PubMed1996

Transmembrane region of the epidermal growth factor receptor: behavior and interactions via 2H NMR.

The first wide-line 2H NMR investigation of a receptor tyrosine kinase is reported. Selectively deuterated peptides from the membrane-associated portion of the human epidermal growth factor (EGF) receptor were synthesized for examination in lipid bilayers mimicking certain natural membrane features. The peptide sequence included the 23-amino acid hydrophobic stretch thought to span the membrane (Ile622-Met644 of the EGF receptor), plus the first 10 amino acids of the receptor's cytoplasmic domain (Arg645-Thr654). Dispersion of the peptide with lipid in the lipomimetic solvent, trifluoroethanol (TFE), was found to be a very useful initial step for sample preparation. TFE readily dissolved all components and was then easily removed in vacuo to yield thin films which could be subsequently hydrated to produce bilayers incorporating homogeneously dispersed peptide. Samples extensively studied consisted of 6 mol % peptide in multilamellar liposomes of 1-palmitoyl-2-oleoylphosphatidylcholine and similar liposomes containing cholesterol. 2H NMR spectra of the resulting unsonicated model membranes indicated the existence of peptide monomers undergoing rapid axially symmetric diffusion. It was possible to examine structural and behavioral effects of events often suggested as pivotal in signaling mechanisms and to consider by wide-line NMR for the first time the effect of cholesterol on hydrophobic peptides. When it was incorporated into bilayers by an alternative method involving dialysis of aqueous solutions prepared using a cationic detergent, spectra suggested that the peptide existed primarily as irreversibly aggregated oligomers which were relatively immobile on a time scale of 10(-3)-10(-4) s. For liposomes prepared by hydration of thin films, deuterated methyl groups on the peptide at locations corresponding to Ala623, Met644, and Val650 of the human EGF receptor were individually distinguishable. In highly fluid matrices, spectra suggested the presence of peptide monomers, diffusing symmetrically about axes perpendicular to the membrane. Studied as a function of temperature, 2H NMR spectra of such samples permitted independent consideration of membrane/peptide relationships at separate locations in the receptor tyrosine kinase. None of the locations probed demonstrated significant conformational sensitivity to temperature over a wide range. Effects seen at Ala623 and Met644, at opposite ends of the putative membrane-spanning domain, suggested slight increases in motional order with decreasing temperature. Addition of 33% cholesterol to the membrane caused little apparent conformational change at Val650 or Met644. However, in the presence of the sterol, Met644 and Ala623 exhibited nonaxially symmetric motion at low temperatures, perhaps as a result of peptide oligomerization. Moreover, the presence of cholesterol led to considerable change in spatial arrangement or order at Ala623. There was little evidence to support transmission of conformational changes along the peptide segment probed.

Amino Acid Sequence↗

PubMed1996

Structural influence of cation binding to recombinant human brain S100b: evidence for calcium-induced exposure of a hydrophobic surface.

The dimeric calcium-binding protein S100b is proposed to undergo a calcium-induced structural change allowing it to interact, via a hydrophobic surface, with other proteins. Previously it has been suggested that calcium binding to S100b leads to the exposure of at least one phenylalanine residue (Mani et al., 1982, 1983). This effect appears to be "reversed" at higher ionic strength, leading to a possible reburying of phenylalanine residues (Mani et al., 1982, 1983). To study these effects, we monitored calcium binding to recombinant human S100b by NMR spectroscopy under different salt (KCI) conditions. 15N-Labeled glycine residues in S100b showed calcium-induced chemical shift changes similar to those reported for the related monomeric protein calbindin D9k, suggesting similar conformational changes are occurring in the calcium-binding loops of these two proteins. Calcium binding to S100b also resulted in a shifting and broadening of several 1H resonances from the Ca-S100b form only including those from the side chains of residues F14, F70, and F73 but not those of residue Y17. This broadening was enhanced with increased ionic strength (KCI). However, small additions ( < 15% v/v) of the hydrophobic solvent trifluoroethanol relieved this phenomenon, leading to narrower line widths. These observations are consistent with the calcium-induced exposure of at least one of these hydrophobic residues, resulting in self-association of the S100b dimer. Trifluoroethanol serves to dissociate these complexes back to the dimeric calcium species. We propose that this cluster of hydrophobic residues which include F14, F73, and F88 may be important for interactions with a target protein.

Base Sequence↗

PubMed1996

Minor influence of sialic acid on conformation of a membrane-bound oligosaccharide recognition site.

Wideline 2H NMR spectroscopy was used to assess the conformational and orientational effects of N-acetylneuraminic acid (NeuAc) (sialic acid) as a component of a particular oligosaccharide chain at a bilayer membrane surface. For this purpose, three glycosphingolipids, sharing a neutral core tetrasaccharide and differing only in the number of sialic acid residues, were compared. The starting compound was GD1A, which has terminal sialic acid attached to the second and fourth sugars of its neutral tetrasaccharide core. GD1A was probe-labeled in a non-perturbing fashion on both of these sialic acid residues and on its single GalNAc residue by replacement of -COCH3 with -COCD3 giving [(d3NeuAc)2,d3-GalNAc]GA1a. This represents the most complex glycolipid to have been studied by 2H NMR spectroscopy at a bilayer membrane surface. The sialic acid residue on the fourth sugar from the membrane was subsequently removed to produce the glycolipid [d3NeuAc,d3GalNAc]GM1, deuterated at the two remaining amino sugars. The neutral glycolipid [d3GalNAc]asialo-GM1 was then generated by removal of the second sialic acid residue, leaving an uncharged species deuterated at one (internal) oligosaccharide chain site (GalNAc). The effect of sialic acid was futher examined by selective deuteration of GM1 and asialo-GM1 at C6 of the terminal Gal residue, giving [d2Gal]GM1 and [d2Gal]asialo-GM1. Spectra of the three glycosphingolipids were compared at 7.7 mol % in unsoncicated fluid bilayers of 1-palmitoyl-2-oleoylphosphatidylcholine containing 23 mol % cholesterol. For liposomes suspend in buffered salt solutions with 2 mM Ca2+, 2H NMR spectra demonstrated the presence of well defined average conformation for each oligosaccharide chain. This preferred average conformation persisted over a wide temperature range, consistent with there being a single major oligosaccharide conformer in each case. Spectral features arising from both deuterated amino sugar (GalNAc) of asialo-GM1 could be identified, little changed, in spectra of GM1 and GD1A. Similarly, deuterons in the terminal Gal residue of asialo-Gm1 produced the same spectrum seen for this residue in GM1. Our findings indicate that certain major conformational and orientational features of this complex oligosaccharide recognition site are preserved, within maximum angular deviation + or -5 degrees or less upon addition or removal of a sialic acid residue.

Carbohydrate Conformation↗

PubMed1995

2H-NMR study of two probe-labelled glycosphingolipid-derived signalling modulators in bilayer membranes.

We describe here the first report of sphingoid bases bearing non-perturbing 2H probe nuclei. These were produced, by two different routes of partial synthesis, to permit direct assessment of their arrangement and behaviour as minor components in membrane systems. Wideline 2H-NMR spectra of N,N-dimethylsphingosine with deuterated amino-methyl groups ([2H6]dimethylsphingosine), and of lyso-dihydrogalactosylceramide (lyso-GalCer) with deuterium nuclei at C4,C5 of the sphingosine backbone and at C3,C4 of the galactose ring ([2H4]lyso-GalCer), were recorded in unsonicated, cholesterol-containing fluid bilayer membranes. The sphingolipid metabolites behaved as single populations of lipid amphiphiles dispersed uniformly in the membrane and undergoing rapid symmetric motion about their long molecular axes. This was the case throughout the pH ranges examined, which included values generally considered for the cell cytoplasm. Spectra of [2H6]dimethyl sphingosine indicated that the methyl groups are equivalent on the NMR timescale, and that the molecule's orientation and behaviour are largely unaffected by pH over the range, 6 to 10.5. There was no spectral evidence of deprotonation of the tertiary amine function in this range. Similarly, variation of pH between 6.4 and 8.9 had virtually no effect on the average conformation and orientational order of lyso-GalCer at the level of C4,C5 in the sphingosine backbone. pH did, however, exert significant control over the orientation of the galactose residue--the effect being most marked in the region of the sphingoid base pKa. The lyso-glycolipid showed some evidence of being less motionally ordered than the corresponding parent species, presumably as a result of removal of constraints imposed by the fatty acid.

Cell Membrane↗

PubMed1995

Structural influence of calcium on the heme cavity of cationic peanut peroxidase as determined by 1H-NMR spectroscopy.

The cationic isozyme of peanut peroxidase (CPRx) is one of many peroxidases which requires calcium for enzyme activity. It has been previously shown that it requires 2 mol calcium to coordinate to 1 mol CPRx, and its related peroxidases from the basidiomycete Phanerochaete chrysosporium (LiP) and isozyme C of horseradish (HRPc). X-ray crystallographic studies of LiP have shown that calcium is ligated near the C-terminus of helices proximal and distal to the heme, where it has been suggested to maintain the active site. To determine if such a mechanism was possible in CPRx, high resolution 1H-NMR spectroscopy was used to study the effect of calcium on the environment of its heme group and the coordinating histidine residues. The low-spin cyano complex of the enzyme (CPRxCN) was studied in order to assign the majority of the resonances arising from the protons in the heme pocket in both the presence and absence of bound calcium ions using two dimensional nuclear Overhauser effect spectroscopy (NOESY). The two calcium ions present in CPRxCN were removed by a non-denaturing method and a calcium titration was performed and monitored by 1H-NMR spectroscopy. These studies showed that the binding of both calcium ions in CPRx influenced the heme environment in a similar manner (Kd = 0.1 microM). In particular, calcium-dependent changes in several heme resonances and the proximal and distal histidine residues suggest that calcium binding to CPRx causes some reorientation of these residues with respect to the active site.

Arachis↗

PubMed1995

Human S100b protein: formation of a tetramer from synthetic calcium-binding site peptides.

Human brain S100b protein is a unique calcium-binding protein comprised of two identical 91-amino acid polypeptide chains that each contain two proposed helix-loop-helix (EF-hand) calcium-binding sites. In order to probe the assembly of the four calcium-binding sites in S100b, a peptide comprised of the N-terminal 46 residues of S100b protein was synthesized and studied by CD and 1H NMR spectroscopies as a function of concentration and temperature. At relatively high peptide concentrations and in the absence of calcium, the peptide exhibited a significant proportion of alpha-helix (45%). Decreasing the peptide concentration led to a loss of alpha-helix as monitored by CD spectroscopy and coincident changes in the 1H NMR spectrum. These changes were also observed by 1H NMR spectroscopy as a function of temperature where it was observed that the Tm of the peptide was lowered approximately 14 degrees C with a 17-fold decrease in peptide concentration. Sedimentation equilibrium studies were used to determine that the peptide formed a tetramer in solution in the absence of calcium. It is proposed that this tetrameric fold also occurs in S100b and is a result of the interaction of portions of all four calcium-binding sites.

Amino Acid Sequence↗

PubMed1995

Herbicide regulation: a case study of Michigan.

Lawn-care herbicides are a type of pesticide regulated under federal and state pesticide legislation. The Michigan Department of Agriculture implements herbicide regulation to protect the public's health and welfare. Yet, due to gaps that exist in all levels of government in the regulation of lawn-care herbicide application, the public is placed at risk. The federal pesticide legislation (Federal Insecticide, Fungicide, and Rodenticide Act) provides for a lower standard of safety in the classification of herbicides applied in the residential context as opposed to the agricultural context. Michigan legislation (The Pesticide Control Act) exempts from the law persons applying general herbicides on their own premises. The state does not require public notification of risks or safety precautions prior to commercial application of these herbicides. Furthermore, on-site inspections are not performed for residential application of herbicides and the state applicator certification program is not assessed for effectiveness.

2,4-Dichlorophenoxyacetic Acid↗

PubMed1994

Behaviour of complex oligosaccharides at a bilayer membrane surface: probed by 2H-NMR.

Deuterium wideline NMR was used in an attempt to directly assess oligosaccharide arrangement and motional characteristics of complex glycosphingolipids dispersed as minor components in phospholipid membranes. A convenient, general synthetic approach was developed which involved replacement of the acetate group of amido sugars with deuteroacetate (-COCD3). This provided excellent signal-to-noise when applied to the terminal GalNAc residue of globoside, and the terminal NANA residue of GM1. Simultaneously, globoside and GM1 fatty acids were replaced with stearic acid deuterated at C-2- a probe location sensitive to glycolipid hydrophobic backbone orientation and rigid body motion. Deuterated GM1 and globoside were studied by 2H-NMR in bilayers of 1-palmitoyl-2-oleoyl phosphatidylcholine, in the presence and absence of physiological quantities of cholesterol. The monoglycosyl glycosphingolipid, glucosyl ceramide, which is the common skeleton of many complex glycosphingolipids including those studied here, was also deuterated at fatty acid C-2 for comparative study in the same matrices. Correlation with spectra of the complex glycolipids demonstrated that, for a given temperature and membrane composition, ceramide backbone conformation was very similar amongst the species studied. Spectral features of GM1 deuterated on terminal NANA and assembled at a membrane surface, were found to be highly consistent with the oligosaccharide conformation determined in studies of GM1 in solution. In contrast, globoside deuterated in the terminal GalNAc residue gave spectra very different from those predicted on the basis of the conformation considered to exist in solution. It seems likely that this result reflects a combination of greater oligosaccharide chain flexibility relative to GM1, and the presence of the membrane environment. Interestingly, although there was highly significant spatial geometry associated with the complex oligosaccharide chains, and although temperature and the presence of cholesterol exert measurable effects on the membrane-inserted portion, these factors had very little impact on the measured spectral parameters associated with the NANA residue of GM1 or the terminal GalNAc residue of globoside. This seems to indicate lack of sensitivity of the complex oligosaccharide chains to conformation and internal motions of the hydrophobic chain segments in these fluid and semi-fluid membranes; and has important implications for mechanisms of crypticity.

Carbohydrate Sequence↗

PubMed1993

Baseline consideration of liposomal contrast agent. CNS transport by macrophages in experimental allergic encephalomyelitis.

The purpose of this study was to investigate a specialized liposomal contrast agent for magnetic resonance imaging (MRI), as part of a program to examine infiltrating immune cells in lesions of experimental allergic encephalomyelitis (EAE). A potent investigational liposomal contrast agent, phosphatidylethanolamine-DTPA-gadolinium, was chosen which has been shown to remain tightly liposomal-associated, with long persistence in vivo. Europium (Eu3+), a fluorescent paramagnetic metal, was also utilized in these experiments in place of gadolinium. This material is avidly taken up by monocytes in vivo. Thirty-four animals received some form of liposomal material either before or during the opening of the blood-brain barrier (BBB). Twenty-seven Hartley guinea pigs were inoculated for EAE with homogenized brain and Complete Freunds Adjuvant (CFA) and seven control animals received CFA alone. Eighty-two percent of the experimental animals exhibited degeneration of the BBB with inflammation and edema in the brain, while all control animals had normal brain scans. T1-weighted MRI, performed to detect the presence of liposomal contrast material in experimental animals, was not different from untreated animals. Fluorescent microscopy revealed no characteristic changes associated with Eu3+ presence in the brains of treated or control animals. Therefore, it would seem that insufficient material crosses the disrupted BBB, either in free form or subsequent to macrophage ingestion, to be detected by MRI or fluorescent microscopic examination.

Animals↗

PubMed1993

Clinical experience with multilamellar liposomal amphotericin B in patients with proven and suspected fungal infections.

Over a 3-year period, an unsonicated multilamellar vesicle preparation containing a low ratio of amphotericin B (5 mole %) was used as a routine alternative to amphotericin B-deoxycholate in treating 17 patients with a variety of systemic fungal infections representative of those commonly encountered on a tertiary care centre infectious disease service. Patient acceptability and convenience of administration were noteworthy. In 6/7 patients who had been given the liposomal drug after experiencing severe side effects (primarily hypokalemia and marked elevation of serum creatinine) on the non-liposomal form, the problems that had led to institution of the liposomal drug were reversed during treatment. However, multilamellar liposomal amphotericin B at conventional dosage was not without detectable toxicity in this patient population. Three transplant patients receiving cyclosporin at the same time as liposomal amphotericin B experienced a rise in serum creatinine, and 4 patients became hypokalemic during treatment: none of these effects was severe or required discontinuation of therapy. One or more liver enzymes rose measurably in 7 patients during treatment with liposomal amphotericin B, but remained unchanged or actually decreased in the remaining patients.

Adult↗

PubMed1992

Glycosphingolipids: 2H NMR study of the influence of ceramide fatty acid characteristics on the carbohydrate headgroup in phospholipid bilayers.

Galactosylceramides bearing a variety of different pure fatty acid chains were 2H labeled in the carbohydrate headgroup at C6 of the terminal galactose residue, for study by 2H NMR. Fatty acids investigated included the 24-carbon saturated lignoceric acid, 18-carbon saturated stearic acid, cis-9,10-unsaturated oleic acid, and D- and L-stereoisomers of alpha-hydroxystearic acid. Headgroup-deuterated glycolipids were incorporated at 10 mol % into unsonicated bilayers of 1-palmitoyl-2-oleoylphosphatidylcholine, and 2H NMR spectra were recorded at 65 and 40 degrees C. Under these experimental conditions, the membranes studied were primarily in the liquid-crystalline phase. At a given temperature, spectra for deuterated galactosylceramides dispersed in the fluid phase were remarkably similar, regardless of the nature of the fatty acid attached to the glycolipid sphingosine backbone. In each case, the spectrum consisted of a superposition of two quadrupolar powder patterns of approximately equal intensity. The spectra may be interpreted as arising from equal populations of two stereoisomers (pro-R and pro-S) of the deuterated galactose hydroxymethyl function, which is undergoing rapid (greater than 10(6) s-1) interconversion among the possible rotamers about the C5-C6 bond of the sugar ring. Within experimental error, the only fatty-acid-induced spectral difference detected among these glycosphingolipids deuterated in the carbohydrate headgroup was in the species with alpha-hydroxy-substituted fatty acids. At 65 degrees C, N-(D-alpha-hydroxy)stearoyl- and N-(L-alpha-hydroxy)stearoylgalactosylceramide gave rise to the same quadrupole splittings, but these differed marginally from the splittings observed for the other glycolipids studied.(ABSTRACT TRUNCATED AT 250 WORDS)

Fatty Acids↗

PubMed1991

Glycosphingolipids: 2H NMR study of the influence of carbohydrate headgroup structure on ceramide acyl chain behavior in glycolipid-phospholipid bilayers.

Galactosyl- and glucosylceramide, globoside, and dihydrolactosylceramide, bearing [2,2-2H2]stearic acid, have been studied at a concentration of 10 mol% in bilayers of dimyristoylphosphatidylcholine by 2H NMR. The quadrupolar splitting delta vQ of the C2 deuterons were measured at several temperatures in the range of 30-60 degrees C. Spin-lattice relaxation times T1 of C2 deuterons were determined in the same temperature range for all lipids but globoside. T1 values at 30 and 50 degrees C were unexpectedly short (6-8 ms), indicating reduced mobility of the ceramide acyl chains compared to that of the host phospholipid. At all temperatures, both delta vQ and T1 were essentially identical for the monoglycosylated species, GalCer and GlcCer, indicating that the order and dynamics of the upper portion of the fatty acyl chain are insensitive to this small change in the headgroup structure. In the case of globoside, where the glycolipid headgroup is equivalent to that of GlcCer extended by three sugar residues, values for the quadrupolar splittings associated with the acyl chain C2-position were very close to those obtained for Gal- and GlcCer. In contrast, the delta vQ values obtained for the diglycosyl species, LacCer, were significantly different at all temperatures. This different behavior of LacCer relative to that of the other glycolipids most likely originates from an orientational change of the acyl chain at the C2-position due to the absence of a 4,5 double bond in dihydrosphingosine. T1 values for the GlcCer and GalCer systems increased with temperature, indicating that the motions responsible for relaxation were in the short correlation time regime.(ABSTRACT TRUNCATED AT 250 WORDS)

Ceramides↗

PubMed1991

Phase behaviour of amphotericin B multilamellar vesicles.

Because side effect profiles and key physical properties of liposomal amphotericin B reflect the molecular nature of the hydrated preparations, effort has been directed toward understanding this nature. We describe here an examination by differential scanning calorimetry in the region of the main transition of the phase behaviour of amphotericin B multilamellar liposomes used investigationally for patient treatment. Liposomes were composed of 7:3 dimyristoylphosphatidylcholine/dimyristoylphosphatidylglycerol (7:3 DMPC/DMPG) containing up to 33 mol% drug. Preparations in which pure DMPC or pure 1-oleoyl-2-stearoylphosphatidylcholine (OSPC) was substituted for 7:3 DMPC/DMPG were subjected to the same measurements for comparison. The DSC-derived partial phase diagrams were similar to those previously recorded using EPR spectroscopy for unsonicated liposomes of 7:3 DMPC/DMPG containing amphotericin B, and for mixtures with different pure saturated and unsaturated phosphatidylcholines (Grant, C.W.M., et al. (1989) Biochim. Biophys. Acta 984, 11-20). Fluidization onset temperatures for liposome host matrices were relatively unaffected by drug compared to the temperatures of completion. This effect was particularly marked for the unsaturated phospholipid matrix. Partial phase diagrams were interpreted as demonstrating that amphotericin B has a tendency to separate into a rigid phase within the membrane. This is consistent with molecular modelling considerations which suggest that amphotericin B may exist as oligomers in a phospholipid matrix. Drug-induced alterations of DSC melting profiles for the phospholipid bilayers studied were less extensive than those reported for partially sonicated preparations of 7:3 DMPC/DMPG (Janoff, A.S., et al. (1989) Proc. Natl. Acad. Sci. USA 85, 6122-6126). Melting profiles obtained did not change upon further sample incubation, suggesting that the hydrated preparation represented a thermodynamically stable form.

Amphotericin B↗

PubMed1991

Comparative in vitro effects of liposomal amphotericin B, amphotericin B-deoxycholate, and free amphotericin B against fungal strains determined by using MIC and minimal lethal concentration susceptibility studies and time-kill curves.

Multilamellar liposomal amphotericin B (L-AmB) was generally less active in vitro against yeast strains than was amphotericin B-deoxycholate or free amphotericin B, although continual agitation of the broth disproportionately increased the activity of L-AmB. Time-kill studies also demonstrated a slower onset of action of L-AmB and supported the hypothesis that liposomes may act as reservoirs for free amphotericin B, which is the active moiety.

Amphotericin B↗

PubMed1991

Liposomal amphotericin B: an effective, nontoxic preparation for the treatment of urinary tract infections caused by Candida albicans.

Liposomal amphotericin B without prior administration of Fungizone was found to be an effective treatment in 4 patients with urinary tract infections caused by Candida albicans. Urine typically became culture negative after 1-4 days of dosing at 50 mg/day, demonstrating that therapeutic levels of amphotericin B were reached in the urine at conventional doses given in liposomal form. The low incidence of toxicity with this preparation was particularly useful in patients with impaired renal function, including renal transplant patients on cyclosporine immunosuppression.

Adult↗

PubMed1991

Enhanced biliary iron excretion with amphiphilic diethylenetriaminepentaacetic acid.

The elimination of toxic metal ions metabolically accumulated by patients remains a difficult clinical problem and a target of drug development. DTPA (diethylenetriaminepentaacetic acid) is a hydrophilic chelating agent with high affinity for divalent and trivalent metal ions including iron but with a limited ability to cross cell membranes for access to iron stores. In this study we have synthesized an amphiphilic form of this chelator-DTPA covalently linked to the phospholipid phosphatidylethanolamine (PE)--to produce a chelator that incorporates completely and stably into liposome membranes for efficient delivery to the liver and reticuloendothelial system. Biliary and urinary excretion of iron were studied in iron-loaded rats (n = 15) in association with a 2-hr intravenous infusion of sonicated liposomes of 1:1 amphiphilic phosphatidylethanolamine-DTPA/egg phosphatidylcholine (L-PE-DTPA) and compared with excretion obtained using equivalent amounts of water-soluble DTPA (alone or mixed with egg phosphatidylcholine liposomes [L-DTPA] as controls). For a 6-hr period, the administration of L-PE-DTPA resulted in approximately a 20-fold increase in biliary iron excretion (480 +/- 160 micrograms/6 hr, mean +/- S.D.) compared with that seen with DTPA (21.2 +/- 4.0 micrograms/6 hr) and L-DTPA (23.1 +/- 5.0 micrograms/6 hr) (p less than 0.05, analysis of variance). Urinary iron excretion was significantly decreased with L-PE-DTPA (41.5 +/- 38 micrograms/6 hr) compared with DTPA (154 +/- 110 micrograms/6 hr) and L-DTPA (86 +/- 17 micrograms/6 hr) (p less than 0.05). Combined biliary and urinary excretion of iron was three to four times greater with L-PE-DTPA.(ABSTRACT TRUNCATED AT 250 WORDS)

Analysis of Variance↗