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Biomedical subjects

B D Anderson

Publications and source records attributed to B D Anderson.

At least 19 recordsLinked to original sources
PubMed1992

Synthesis and anti-HIV activity of isonucleosides.

A series of isomeric 2',3'-dideoxynucleosides which contains a modified carbohydrate moiety has been prepared. This class of compounds was designed to mimic the activity of known anti-HIV dideoxynucleosides, while imparting enhanced chemical and enzymatic stability. Isonucleosides containing the standard heterocyclic bases (A, C, G, T) were synthesized via nucleophilic addition of the base to an isomeric sugar unit. Modified derivatives were generated by manipulation of the intact isonucleoside. Two of the compound prepared, iso-ddA (1) and iso-ddG (6), exhibit significant and selective anti-HIV activity, as well as beneficial hydrolytic stability.

Antiviral Agents↗
PubMed1992

Transport methods for probing the barrier domain of lipid bilayer membranes.

Two experimental techniques have been utilized to explore the barrier properties of lecithin/decane bilayer membranes with the aim of determining the contributions of various domains within the bilayer to the overall barrier. The thickness of lecithin/decane bilayers was systematically varied by modulating the chemical potential of decane in the annulus surrounding the bilayer using different mole fractions of squalene in decane. The dependence of permeability of a model permeant (acetamide) on the thickness of the solvent-filled region of the bilayer was assessed in these bilayers to determine the contribution of this region to the overall barrier. The flux of acetamide was found to vary linearly with bilayer area with Pm = (2.9 +/- 0.3) x 10(-4) cm s-1, after correcting for diffusion through unstirred water layers. The ratio between the overall membrane permeability coefficient and that calculated for diffusion through the hydrocarbon core in membranes having maximum thickness was 0.24, suggesting that the solvent domain contributes only slightly to the overall barrier properties. Consistent with these results, the permeability of acetamide was found to be independent of bilayer thickness. The relative contributions of the bilayer interface and ordered hydrocarbon regions to the transport barrier may be evaluated qualitatively by exploring the effective chemical nature of the barrier microenvironment. This may be probed by comparing functional group contributions to transport with those obtained for partitioning between water and various model bulk solvents ranging in polarity or hydrogen-bonding potential. A novel approach is described for obtaining group contributions to transport using ionizable permeants and pH adjustment. Using this approach, bilayer permeability coefficients of p-toluic acid and p-hydroxymethyl benzoic acid were determined to be 1.1 +/- 0.2 cm s-1 and (1.6 +/- 0.4) x 10(-3) cm s-1, respectively. From these values, the -OH group contribution to bilayer transport [delta(delta G0-OH)] was found to be 3.9 kcal/mol. This result suggests that the barrier region of the bilayer does not resemble the hydrogen-bonding environment found in octanol, but is somewhat less selective (more polar) than a hydrocarbon solvent.

Acetamides↗
PubMed1992

Central nervous system targeting of 2',3'-dideoxyinosine via adenosine deaminase-activated 6-halo-dideoxypurine prodrugs.

AIDS dementia complex is a neurologic disorder, characterized by increasingly severe cognitive, behavioral, and motor impairment, which is associated with human immunodeficiency virus (HIV) infection in the central nervous system (CNS). Many of the dideoxynucleosides effective systemically in the treatment of HIV infections, such as 2',3'-dideoxyinosine (ddI), exhibit limited penetration into the CNS and limited or variable effectiveness in reversing the symptoms of AIDS dementia. Thus, approaches for increasing the CNS uptake of ddI and other dideoxynucleosides are needed. The CNS uptake of a series of 6-halo-2',3'-dideoxypurine ribofuranosides (6-halo-ddPs) previously shown to be active against HIV because of their conversion to ddI through the action of adenosine deaminase was examined in rats. In vitro studies in rat blood and brain tissue homogenate suggested a favorable selectivity for bioconversion in brain tissue, but with bioconversion half-lives varying widely within the series. In vivo infusions of 6-chloro-ddP (6-Cl-ddP), 6-bromo-ddP (6-Br-ddP), and 6-iodo-ddP (6-I-ddP) resulted in significant increases (20- to 34-fold) in the ddI concentration ratios in brain parenchyma/plasma when compared with those after an infusion of ddI alone. Absolute concentrations of ddI in brain parenchyma were increased 10- and 4-fold, respectively, following 30-min infusions of 6-Cl-ddP or 6-Br-ddP, but were 2.4-fold lower after an infusion of 6-I-ddP relative to that after a control infusion of ddI. Detailed studies of the plasma pharmacokinetics, CNS uptake kinetics, and bioconversion of 6-Cl-ddP were conducted to compare in vivo transport and bioconversion parameters with those predicted from in vitro measurements and to rationalize the efficiency of CNS delivery of ddI from 6-Cl-ddP. The results show that increased lipophilicity alone does not ensure that a given prodrug will deliver higher levels of a parent compound to the CNS. Both the selectivity and absolute rate of bioconversion in the brain are important factors.

Animals↗
PubMed1991

Probenecid enhances central nervous system uptake of 2',3'-dideoxyinosine by inhibiting cerebrospinal fluid efflux.

The effects of probenecid on the pharmacokinetics of 2',3'-dideoxyinosine (ddl) and on the distribution of ddl to cerebrospinal fluid (CSF) and brain tissue were determined in rats during and after a 2-hr i.v. infusion of ddl, 125 mg/kg/hr. Probenecid-treated rats received a loading dose of probenecid followed by an i.v. infusion of probenecid initiated 1 hr before and continued during and for 2 hr after termination of the ddl infusion. Plasma concentrations of probenecid averaged 221 +/- 34 micrograms/ml upon termination of the ddl infusion and 258 +/- 34 micrograms/ml (mean +/- S.D., n = 4) 1 hr later. In the probenecid-treated animals, ddl concentrations were higher in plasma (1.5-fold), brain (1.5-fold) and CSF (5.4-fold) at the termination of the ddl infusion and postinfusion concentrations declined more slowly compared to controls. Postinfusion, the CSF/plasma and brain/plasma ratios steadily increased to a greater extent in the probenecid-treated rats compared to control animals. The time course of plasma, CSF and brain tissue concentrations were analyzed by nonlinear least-squares regression using two different compartmental models, one which neglected the direct exchange of drug between the CSF and brain parenchyma, whereas the other allowed for such exchange to occur and neglected direct vascular transfer of drug to brain tissue. Allowing exchange between the CSF and brain tissue gave slightly improved fitting of the data from both probenecid-treated and control rats.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1990

Physicochemical properties of carbovir, a potential anti-HIV agent.

(+-)-Carbovir [(+-)-9-[4 alpha-(hydroxymethyl)-cyclopent-2-ene-1 alpha-yl]guanine; NSC 614846] is a novel carbocyclic nucleoside analogue which has been shown to be a potent and selective inhibitor of HIV in vitro. As part of an effort to develop a parenteral formulation for subsequent clinical and toxicological evaluation of this compound, the aqueous solution stability of carbovir as a function of pH and temperature and various physicochemical properties of carbovir including its pKa, solubility versus pH and solvent composition, and octanol-water partition coefficient have been examined. Ultraviolet spectrophotometry indicated that carbovir has pKa values of 3.15 and 9.68, respectively, at 25 degrees C and 0.01 ionic strength. The aqueous solubility of carbovir over the pH range 7-10.5 was consistent with that expected of a weak acid with a pKa of 9.65 and an intrinsic solubility of 1.24 mg/mL. Due to the limited solubility of carbovir at physiological pH, methods for solubilizing carbovir in aqueous solution were explored, including propylene glycol-water cosolvents and complexation with hydroxypropyl-beta-cyclodextrin. As expected for carbovir, a semipolar compound with an octanol-water partition coefficient of 0.29, propylene glycol:water cosolvents were not highly effective in enhancing solubility. Complex formation between carbovir and 2-hydroxypropyl-beta-cyclodextrin was found to be more effective, with a K1:1 of 105 M-1 for the complexation. The pH profiles generated at 50, 70, and 90 degrees C were accounted for by acid-catalyzed degradation at low pH leading to the formation of guanine and a neutral degradation pathway which dominates above pH 4. Prototype lyophilized formulations containing (after reconstitution) 10 mg/mL of carbovir at a pH of 10.6 were developed and evaluated.

2-Hydroxypropyl-beta-cyclodextrin↗
PubMed1990

Brain and cerebrospinal fluid uptake of zidovudine (AZT) in rats after intravenous injection.

Uptake kinetics of zidovudine into cerebrospinal fluid (CSF) and brain tissue were determined in adult Sprague Dawley male rats after single intravenous injection of 6.7 mg/kg (25 mumol/kg). The drug kinetics in plasma followed biexponential disposition with an initial distribution half-life of approximately 11 minutes and an elimination half-life of 40 minutes. Over the plasma concentration range of 0.2 to 10 micrograms/ml, the cerebrospinal fluid to plasma ratio averaged 14.8 +/- 1.9% whereas the mean brain tissue to plasma ratio was 8.2 +/- 1.2% (uncorrected) or 2.3 +/- 1.8% (corrected) for the brain vascular space contribution. Simultaneous nonlinear regression analysis of brain, CSF and plasma concentration data indicate that the overall rate constant for efflux of drug from brain is approximately 75-fold higher and from CSF is 8-fold higher than the respective rate constants for influx. Thus, the ratio of the efflux to influx appears to be the predominant factor in determining the net accumulation of drug into CSF and brain parenchymal tissue.

Animals↗
PubMed1990

Uptake kinetics of 2',3'-dideoxyinosine into brain and cerebrospinal fluid of rats: intravenous infusion studies.

The pharmacokinetics of 2',3'-dideoxyinosine (ddl) and its distribution to plasma, brain tissue and cerebrospinal fluid (CSF) were determined during and after 2-hr i.v. infusions of ddl (125 mg/kg/hr) in rats to define its specific pharmacokinetic parameters for subsequent studies of prodrugs designed to target this compound to the brain. Steady-state plasma concentrations of 50 micrograms/ml were obtained within 30 min after the start of infusions corresponding to a total clearance of 2.4 l/kg/hr. Postinfusion, ddl concentrations declined biphasically from plasma with alpha T1/2 = 3 min and beta T1/2 = 35 min. STeady-state concentrations of ddl in brain tissue and CSF were 2.6 micrograms/g in tissue and 0.81 microgram/ml in CSF, respectively. These values represent 4.7 and 1.5%, respectively, of the simultaneously determined plasma concentration. The estimated brain vascular space contribution to the observed brain uptake was 4.1%, obtained by least squares fitting of a compartmental pharmacokinetic model to the uptake data. Postinfusion, the elimination of ddl from the brain and CSF was significantly slower than from plasma, resulting in increased brain/plasma and CSF/plasma ratios after the infusions. The low steady-state brain/plasma or CSF/plasma ratios suggest rapid disappearance of ddl from the CNS relative to its rate of entry. These data indicate that ddl penetrates poorly into the brain. Thus, prodrugs with enhanced blood-brain barrier transport may improve the delivery of ddl to the brain.

Animals↗
PubMed1989

Fatty acid synthetase in control, starved and refed Richardson's ground squirrels.

1. Starvation for 6 days reduced whole body mass and total body lipids to 76 and 71%, respectively, of pre-starvation levels in weight-gain phase ground squirrels. After 4 days of refeeding, body mass increased to 86% of pre-starvation level but total body lipids had not changed from starvation levels. 2. Compared to the fed state, fatty acid synthetase (FAS) activity in white adipose tissue (WAT) was 15 and 31% in starved and refed 4-day animals, respectively, and in liver was 26 and 21% in starved and refed 4-day animals, respectively. Lipids depleted by starvation during prehibernatory fattening were not rapidly restored in Richardson's ground squirrels. 3. Changes in these parameters with starvation and refeeding were similar in weight-loss phase animals. 4. In control animals of both phases, WAT accounted for at least 90% of total FAS activity and liver nearly all of the remainder.

Adipose Tissue↗
PubMed1989

Dehydration kinetics of prostaglandin E1 in a lipid emulsion.

The overall dehydration kinetics of prostaglandin E1 (PGE1) in a lipid emulsion at 35 degrees C were found to fit a model whereby the kapparent measured at each pH is simply the sum of the product of the fraction of the PGE1 at the interface, fi, and the rate constant at the interface, ki, plus the product of the fraction of the PGE1 in the aqueous phase, faq, and the rate constant in the aqueous phase, kaq. The values for fi and faq were reported earlier as a function of pH at 35 degrees C. The kaq and kapparent were experimentally determined as a function of pH at 35 degrees C. The ki was indirectly determined from the stability data in the emulsion. Microscopic rate constants for dehydration of PGE1 in the aqueous phase and interface at 35 degrees C were estimated from the experimental data. Based on the kinetic evaluation performed, it appears that the dehydration kinetics might be manipulated by the addition of charged surface active agents.

Alprostadil↗
PubMed1989

Solute structure-permeability relationships in human stratum corneum.

The permeability coefficients (kp) of a series of methyl-substituted p-cresols were determined in human stratum corneum along with their partition coefficients (PC) between water and untreated stratum corneum, delipidized stratum corneum, octanol, and heptane. The PC values were identical in untreated and delipidized stratum corneum, suggesting that the stratum corneum/water PC data reflect the protein domain rather than the lipids. Although uptake into human stratum corneum was relatively insensitive to solute lipophilicity, reflecting the predominant role of proteins in the uptake, permeability coefficients were found to be more sensitive to lipophilicity, suggesting that transport is by a lipid pathway. A log-log plot of kp versus stratum corneum/water PC within the phenol series is linear, but with a slope of 3.6, indicating that kp is not directly proportional to PC. Functional group contributions to the free energy of the transfer process reflected in permeability or partitioning experiments were compared with group contribution data generated previously for the same substituents attached to the chain terminus of 21-esters of hydrocortisone. Within experimental error, a given functional group altered permeability by the same factor in either series of compounds. Group contributions of polar, hydrogen bonding substituents obtained from kp data were similar to those from octanol/water PC data, suggesting that the barrier microenvironment resembles that of a hydrogen bonding organic solvent. Comparison of the kp values of substituted p-cresols with those of hydrocortisone esters having similar lipophilicities also indicated a steep dependence of kp on molecular weight (log kp = constant + psi log PC - n log MW, n = 4.6) similar to the dependence observed in other biomembranes and isolated lipid bilayers.

Chemical Phenomena↗
PubMed1988

The role of protein and lipid domains in the uptake of solutes by human stratum corneum.

The uptake of a series of hydrocortisone esters varying in lipophilicity from water into untreated and delipidized human stratum corneum has been determined. The partition coefficients of solutes into fully hydrated stratum corneum are postulated to represent the separate contributions of three structurally distinct domains--the extractable lipids, protein, and the solvent domain. The solvent domain was assumed to have the properties of bulk water. The relative affinities of the protein and lipid domains of stratum corneum for solutes varying in structure were determined by comparing solute uptake in untreated and delipidized stratum corneum. Partitioning into the extracted lipids was also examined. Solute uptake into stratum corneum may be governed by the protein domain, the lipid domain, or a combination of the two, depending on solute lipophilicity. Due to differences in the selectivity of the two domains, a change in uptake mechanism occurs with increasing solute lipophilicity from protein-dominated uptake for hydrophilic solutes to lipid domain-dominated uptake for lipophilic solutes. The stratum corneum lipid content, which varies dramatically from individual to individual (3-46% in this study), is an important determinant of the affinity of the stratum corneum for highly lipophilic solutes but has no effect on the uptake of hydrophilic solutes.

Chromatography, Liquid↗
PubMed1988

Determination of the pH-dependent phase distribution of prostaglandin E1 in a lipid emulsion by ultrafiltration.

The distribution of prostaglandin E1 (PGE1) in a lipid emulsion has been shown to be consistent with a three-phase model which assumes that solute may reside in the bulk aqueous and oil phases and at the oil/water interface. Calculations suggest that, in a lipid emulsion having an average particle size of 0.11 micron, it is theoretically possible for a surface active species such as PGE1 to exist predominantly at the interface. Aqueous phase concentrations of PGE1 versus pH were measured in an emulsion having an oil/water phase volume ratio of 0.1 by the use of an ultrafiltration technique in order to estimate the relative percentages of PGE1 in each phase. From bulk oil/water partition coefficient determinations, the amount of PGE1 present in the bulk oil phase of the emulsion was concluded to be insignificant. At emulsion pH values less than 5, PGE1 resides preferentially (greater than 97%) at the interface. With increasing pH's, the percentage of PGE1 in the aqueous phase increases, reaching 51% at high pH's. A model which assumes that both the nonionized and the ionized PGE1 species may be present at the interface, depending on the pH, was shown to be consistent with the data. Estimates were made of the distribution coefficients of the ionized and nonionized PGE1 between the interface and the aqueous phase and their concentration dependence. The apparent pKa of PGE1 at the interface derived from these data was 6.8. The distribution coefficients were used to generate a distribution profile of the various PGE1 species as a function of the pH. This distribution profile will be useful in explaining kinetic data of PGE1 in the emulsion as a function of pH.

Alprostadil↗
PubMed1988

Heterogeneity effects on permeability-partition coefficient relationships in human stratum corneum.

The relationship between the permeability of solutes undergoing transport via the lipid pathway of the stratum corneum and the degree to which the same solutes partition into the stratum corneum has been explored by measuring the permeability coefficients and stratum corneum/water partition coefficients of a series of hydrocortisone esters varying in lipophilicity. Isolated human stratum corneum, used in both the permeability and the uptake experiments, was shown to resemble full-thickness skin in its overall resistance and selectivity to solute structure. As with full-thickness skin, delipidization destroys the barrier properties of isolated stratum corneum. Although a linear relationship is frequently assumed to exist between permeability coefficients and membrane/water partition coefficients, a log-log plot of permeability coefficients versus the intrinsic stratum corneum/water partition coefficients for the series of hydrocortisone esters studied is distinctly nonlinear. This nonlinearity arises from the fact that the transport of these solutes is rate limited by a lipid pathway in the stratum corneum, while uptake reflects both lipid and protein domains. From the relative permeability coefficients of 21-esters of hydrocortisone varying in acyl-chain structure, group contributions to the free energy of transfer of solute into the rate-limiting barrier microenvironment of the stratum corneum lipid pathway are calculate for a variety of functional groups including the -CH2-, -CONH2, -CON(CH3)2, -COOCH3, -COOH, and -OH groups.(ABSTRACT TRUNCATED AT 250 WORDS)

Biological Transport↗
PubMed1988

The aerobic cost of saltatory locomotion in the fowler's toad (Bufo woodhousei fowleri).

Studies of kangaroos suggest that hopping provides energy savings during locomotion at high speeds, although studies of small mammals suggest that hopping is no more economical than running. To obtain comparative data on anurans, we exercised Fowler's toads (Bufo woodhousei fowleri, 25.8 g) on treadmills at speeds ranging from 0.09 to 0.63 km h-1 while measuring oxygen consumption (VO2), endurance or hop kinematics. The toads walked at slow speeds and hopped at fast speeds. Steady-state VO2 (VO2,ss) increased linearly with speed to a maximum (VO2, max) of 1.17 ml O2 g-1 h-1 at 0.27 km h-1 and was nine times the average pre-exercise VO2. The maximum rate of oxygen consumption during treadmill exercise was comparable to VO2,max previously reported for less natural exercise regimes. At speeds greater than or equal to 0.27 km h-1, VO2,ss was independent of speed. At speeds less than or equal to 0.36 km h-1, toads moved for over 1h, but endurance decreased sharply at higher speeds. Hop rate, hop length, hop height and angle of take-off increased with speed. Hopping in B.w. fowleri was not less costly than running in other animals of similar body size and was inefficient at converting metabolic to mechanical energy. The present study suggests that hopping in toads, as in small mammals, is not economical during sustained locomotion and is most important during short bursts of high-intensity activity.

Animals↗
PubMed1975

Multiple extraction patterns in severe discrepancy cases.

Thirty-five cases have been collected from colleagues which illustrate that removal of additional maxillary teeth, following first bicuspid extractions, can allow the successful resolution of difficult discrepancy and anchorage cases. Charts 1 and 2 describe the amounts of space that might be expected by removal of additional upper bicuspids, upper first molars, and upper second molars. The findings on upper second molars are admittedly limited. Anchorage values as expressed by an efficiency percentage were approximately what would be expected from a study of anchorage values of the roots of teeth. The removal of upper second bicuspids has a better anchorage efficiency potential than the upper first molar, but this may be overcome somewhat by the greater size of the molar. Clear guidance cannot be given as to which teeth to remove in a specific case, but it is the observation of the author that for cases that are still in full Class II following four bicuspid space closure, upper second bicuspid removal would be more helpful from an anchorage perspective, whereas for cases that are in end-to-end molar relationship or require only a few millimeters to move into Class I, the upper first molar might be the tooth of choice. Also, the supper first molar removal allows for a more "normal" appearing arch assuming normal alignment and size of the upper second and third molars. The comparison with the nonextraction control group showed an enormous difference in the amount of incisor retraction that extractions provide when related to the maxilla. The nonextraction control group, though experiencing dramatic correction of Class II relationships, showed no incisor movement within the maxilla. Some problems which appeared in the sample were described. Removal of upper teeth in addition to the four first bicuspids can be a solution to an occasional anchorage, skeletal, growth or cooperation problem.

Adolescent↗