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Biomedical subjects

B D Anderson

Publications and source records attributed to B D Anderson.

At least 109 records · Page 6Linked to original sources
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↗
PubMed1985

Strategies in the design of solution-stable, water-soluble prodrugs I: a physical-organic approach to pro-moiety selection for 21-esters of corticosteroids.

The ideal water-soluble prodrug should exhibit sufficient aqueous solution stability to allow long-term storage of its solutions (i.e., 2 years at room temperature) and yet should be converted rapidly in vivo to the active parent drug--two severe and seemingly conflicting demands which limit the utility of many common solubilizing pro-moieties. For example, succinate esters, which are commonly utilized as water-soluble prodrugs, are unstable in solution and may undergo slow and incomplete bioconversion in vivo. In this study, the solution stability problems associated with 21-esters of corticosteroids are reviewed. It is concluded that the most important reaction limiting shelf life is ester hydrolysis. From a consideration of the influence of molecular structure on ester reactivity, a strategy for the design of solution-stable, water-soluble prodrugs of corticosteroids has been developed. Two key requirements for dilute solution stability are high solubility at the pH of optimum stability and appropriate design of the pH-rate profile. Several 21-esters of methylprednisolone have been synthesized, and the rates of their aqueous solution hydrolysis have been determined to test the strategy. Compounds exhibiting estimated shelf lives in dilute solution of greater than 2 years at 25 degrees C have been identified.

Adrenal Cortex Hormones↗
PubMed1985

Strategies in the design of solution-stable, water-soluble prodrugs II: properties of micellar prodrugs of methylprednisolone.

In a previous study, a physical-organic approach to the design of solution-stable, water-soluble prodrugs of the corticosteroid methylprednisolone was outlined, and several 21-esters were synthesized to test the approach. Compounds exhibiting dilute solution stabilities approaching 2 years at 25 degrees C were reported. A complicating factor in more concentrated aqueous solutions of water-soluble prodrugs, however, is the limited extent to which hydrolysis can occur before the solution becomes saturated with respect to the relatively insoluble parent drug. In this study the advantages of micellar prodrugs as water-soluble delivery systems for parenteral administration of relatively insoluble parent drugs are explored. Micellar prodrugs, besides being highly water soluble, have additional advantages in that their micelles solubilize poorly soluble degradation products which may otherwise precipitate and may act as a self-stabilizing influence due to protection of the hydrolytically labile prodrug linkage within the micelle interior. Two 21-esters of methylprednisolone previously identified as having promising dilute solution stability have now been shown to self-associate in aqueous solution at higher concentrations, as determined by solubility, kinetic, and light-scattering measurements. One consequence of self-association is that free methylprednisolone, the product of prodrug hydrolysis, is solubilized in concentrated prodrug formulations. In addition, acid- and base-catalyzed hydrolysis rate constants are altered in the micelles, resulting in further prolongation of shelf life in concentrated solutions. Due to the added benefits of self-micellization, the water-soluble 21-esters investigated exhibit shelf lives exceeding 2 years at 30 degrees C, the upper limit of the controlled room temperature range.

Chemistry, Pharmaceutical↗
PubMed1985

Strategies in the design of solution-stable, water-soluble prodrugs III: influence of the pro-moiety on the bioconversion of 21-esters of corticosteroids.

Succinate esters and many other carboxylic acid esters utilized as water-soluble prodrugs have limited utility due to their aqueous solution instability. In an earlier study, a strategy for the design of solution-stable 21-carboxylic acid esters of corticosteroids was developed from a consideration of various physical organic factors which influence ester hydrolysis. Several 21-esters of methylprednisolone were synthesized, and their stability in aqueous solution was monitored to demonstrate the feasibility of the approach. In this study, the bioconversion of representative examples of 21-esters of methylprednisolone exhibiting shelf lives of greater than or equal to 2 years at 25 degrees C was monitored to evaluate their utility as prodrugs in comparison to a commercially marketed sodium succinate ester. Ester hydrolysis studies conducted in human and rhesus monkey serum suggest that derivatives having an anionic solubilizing moiety (sulfonate or carboxylate) are not hydrolyzed in serum, while compounds having a cationic (tertiary amino) solubilizing moiety are hydrolyzed rapidly by serum esterases. In vivo pharmacokinetic studies in rhesus monkeys were also conducted to compare the bioconversion rates and overall bioavailability of several solution-stable prodrugs with the 21-succinate ester. Derivatives having solution stability exceeding 2 years at 25 degrees C with a faster bioconversion rate and an overall bioavailability equal to or higher than that of the succinate ester have been identified. Relative bioavailability appears to be highly sensitive to the charge of the solubilizing pro-moiety and pro-moiety chain length.

Adrenal Cortex Hormones↗
PubMed1985

Evaluation of lincomycin as a cholesterol gallstone dissolution rate accelerator.

These studies were undertaken to test the hypothesis that interfacial resistance may be an important rate-limiting factor in cholesterol gallstone dissolution. The addition of lincomycin hydrochloride to the gallbladder bile of dogs in an in vitro bath system resulted in an acceleration in the rate of dissolution of a compressed cholesterol monohydrate pellet incubating in the bile. However, the constant infusion of lincomycin for 13 d directly into the gallbladders of conscious, unrestrained dogs, which resulted in biliary lincomycin concentrations comparable to that of the in vitro tests, did not alter the dissolution rate of a compressed cholesterol monohydrate pellet which had been surgically placed into the gallbladder. We therefore conclude that the interfacial resistance between the cholesterol monohydrate pellet and the bile may be reduced by the addition of lincomycin to the gallbladder bile which, in the in vitro environment, results in an acceleration in the rate of dissolution of compressed cholesterol pellets. However, the ineffectiveness of lincomycin in accelerating the dissolution of cholesterol pellets in vivo suggests that interfacial resistance is not the only rate-limiting factor in gallstone dissolution. Other factors, such as mixing, may also be critical.

Animals↗
PubMed1985

Predictive relationships in the water solubility of salts of a nonsteroidal anti-inflammatory drug.

A number of metal and amine salts of the nonsteroidal anti-inflammatory drug 2-(2-fluoro-4-biphenylyl)propionic acid (flurbiprofen) (1) were synthesized, and the water solubilities of these materials were investigated. The solubility of flurbiprofen versus pH is in excellent agreement with the theoretical profile which assumes an intrinsic solubility of 5.0 X 10(-5) M for the free acid and a pKa of 4.22. The solubility determination of 1:1 amine salts of slightly soluble carboxylic acids is complicated by possible precipitation of the free acid when the salt is dissolved in water. The lower than expected apparent salt solubility seen when this phenomenon occurs is referred to as the "stoichiometric solubility." A theoretical treatment delineating three distinct regions in the phase solubility diagram for the tromethamine salt of flurbiprofen illustrates the care which must be taken in characterizing the system for salt solubility determinations. A multiple linear regression analysis was carried out to determine the relationship between the log Ksp of six amine salts and their melting points and cation hydrophilicities. While a strong dependence of Ksp on melting point was found, there was not a significant correlation between Ksp and amine cation hydrophilicity.

Anti-Inflammatory Agents↗