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B D Anderson

Publications and source records attributed to B D Anderson.

126 records · Page 7Linked to original sources
PubMed1985

Hydrolysis and solvent-dependent 2'----5'and 3'----5' acyl migration in prodrugs of 9-beta-D-arabinofuranosyladenine.

As a prerequisite to quantitative in vivo studies to further explore the promising topical activity of the 2',3'-di-O-acetyl derivative of 9-beta-D-arabinofuranosyladenine (ara-A) against herpes virus infections, the kinetics of solution degradation of the 2',3'-di-O-acetyl derivative and the 2'-,3'-, and 5'-monoacetates were investigated. The rates of aqueous solution hydrolysis were found to be consistent with rank order predictions based on a consideration of substituent effects. Preliminary in vivo hydrolysis data, however, do not correlate with such predictions, indicating a need for more systemic studies of the effect of molecular structure on enzyme-catalyzed hydrolysis. An important reaction of the 2'-3'-diester and the 3'-monoester in aqueous solution, in addition to ester hydrolysis, is 3'----5' acyl migration. 2'----5' Acyl migration does not occur in water but is the predominant migration pathway in organic solvents, as verified by studies in acetonitrile. 1H NMR spectroscopy was employed to study the dependence of the conformation of the sugar ring on the solvent environment. Although a change in the equilibrium between the C(2')endo and C(3')endo conformational states does occur, it is not a dramatic change and cannot explain the solvent selectivity observed in the acyl migration kinetics.

Chemical Phenomena↗
PubMed1984

Carboxyl group catalysis of acyl transfer reactions in corticosteroid 17- and 21-monoesters.

Succinate esters, although frequently employed as water-soluble prodrugs of poorly soluble parent drugs, are not sufficiently stable to allow long-term storage in solution. Intramolecular catalysis of ester hydrolysis by the terminal succinate carboxyl group is a contributing factor to this instability. Methylprednisolone 21-succinate has recently been reported to undergo both hydrolysis and 21 in equilibrium 17 acyl migration in aqueous solutions. Intramolecular catalysis by the terminal carboxyl group is seen in both reactions, but the catalytic mechanisms are not well understood. While acyl migration can only be catalyzed via the carboxyl group acting as a general acid or general base, hydrolysis may undergo either nucleophilic or general acid-base catalysis. To gain further insight into the catalytic mechanism, hydrolysis of methylprednisolone 21-succinate was carried out in aniline buffers to trap any succinic anhydride (as the anilide) that would form if the catalysis were nucleophilic. The nucleophilic mechanism was shown to account for only 15-20% of the overall catalysis. Comparisons of the rates of the intramolecularly catalyzed reactions of methylprednisolone 21- and 17-succinate were made with the same reactions of methylprednisolone 21- and 17-acetate catalyzed intermolecularly by acetate ion. Interestingly, intramolecular catalysis appears to favor acyl migration over hydrolysis. Hence, the hydrolysis of methylprednisolone 21-succinate is faster in basic solutions (pH greater than 7.4), while acyl migration becomes the dominant reaction in the catalyzed region of the pH profile between pH 3.6 and 7.4. Arguments are presented to account for these differences in catalytic efficiency in terms of the transition-state structures for the two reactions.

Adrenal Cortex Hormones↗
PubMed1983

Influence of premicellar and micellar association on the reactivity of methylprednisolone 21-hemiesters in aqueous solution.

Self-association of drug molecules at formulation concentrations can have a major impact on formulation properties. In this study a homologous series of methylprednisolone 21-hemiesters were found to undergo self-association in aqueous solution. The effect of aggregate formation on the solution degradation of these compounds was examined. To determine the nature and extent of association of these steroidal esters, partition coefficients between butyronitrile and aqueous buffer (pH 8.5) were measured as a function of ester concentration. The partitioning data were found to be consistent with dimer formation at low concentration followed by true micelle formation at higher concentration. Chain length increases favored micelle formation, but appeared to have little effect on dimerization. The first-order rate constants for ester hydrolysis and 21 leads to 17 acyl migration in aqueous buffer (pH 8.5) were also found to be dependent on ester concentration. The kinetic data are consistent with a model which assumes stabilization by both dimer and micelle formation, the limiting factor at high concentration being the reactivity of the ester in the micelles. The degree of stabilization due to self-association was found to increase with chain length.

Colloids↗
PubMed1983

Neutron doses in negative pion radiotherapy.

Absorbed neutron doses in regions outside the treatment volume from negative pion radiotherapy are presented, based on neutron spectral measurements for pions stopping in a tissue-equivalent target. A Monte Carlo neutron transport computer code was developed and used to calculate the absorbed dose as a function of the distance from the centre of the treatment volume. The Monte Carlo code, which is a modification of a neutron detector efficiency code, follows neutrons and gamma rays as they interact with either hydrogen or oxygen nuclei in a phantom. The code includes neutron elastic scattering on both hydrogen and oxygen as well as five inelastic nuclear reactions on oxygen. The recoil charged particles which provide the absorbed dose are considered until the neutron escapes the phantom or its kinetic energy falls below 1 ke V. Calculations of absorbed dose are compared with earlier dose calculations and measurements. Measurements of the neutron spectrum from a tissue-equivalent target indicate that the total kinetic energy carried away by neutrons is about 76 MeV, which is a significantly higher value than that used in earlier estimates of the neutron dose. The calculations presented here suggest that the neutron dose outside large treatment volumes may limit the use of negative pions for some therapeutic applications.

Elementary Particles↗
PubMed1981

Initial rate studies of hydrolysis and acyl migration in methylprednisolone 21-hemisuccinate and 17-hemisuccinate.

The degradation of methylprednisolone 21-succinate in aqueous solution was examined as a function of pH at 25 degrees by monitoring the initial rates of product formation. In addition to hydrolysis, acyl migration fro the 21-hydroxyl group was found to be an important reaction. The 17-succinate was isolated, and its decomposition to the 21-succinate was followed by the initial rate method. Direct hydrolysis of the 17-ester was much slower than the 17 leads to 21 acyl migration under alkaline conditions. From the rate constants for the forward and reverse acyl migration, it may be concluded that the 21-ester is thermodynamically more stable, even though its alkaline hydrolysis is faster. The hydrolysis of the 21-ester and the reversible rearrangement are subject to intramolecular catalysis by the terminal carboxyl group, for which a kinetic pKa value of 4.5-4.6 was estimated.

Chemical Phenomena↗
PubMed1980

Prostaglandin prodrugs VI: structure-thermodynamic activity and structure-aqueous solubility relationships.

Solubilities in isoctane and water were determined for several C1-phenolic esters of prostaglandin F2 alpha and prostaglandin E2 and acetates having the same phenol moiety. Linear free energy relationships for solubility among the series were observed with slopes of approximately 1. These results suggest that the contributions of the phenyl substituent to the free energies of these processes are similar in the three series, even though the structure of the acyl moiety is varied. In addition, aqueous solubility was separated into two thermodynamic components, reflecting transfer from the solid phase to an inert solvent and transfer from the inert solvent to water, to evaluate the relative effects of various substituents on the escaping tendency of the drug from the solid phase and on solution interactions. It was found that polar, hydrogen-bonding functional groups in many cases do not bring about increased water solubility because of a corresponding increase in intermolecular interaction in the solid phase.

Prostaglandins↗
PubMed1980

Solubility of polar organic solutes in nonaqueous systems: role of specific interactions.

The changes in solubility of several polar organic solutes when polar organic solvents are added to a relatively inert solvent such as isooctane were determined. The relative changes in solubility predicted from regular solution theory using solubility parameters often did not agree with the observed results. However, the solubilities could be rationalized mathematically by assuming the formation of specific solute-solvent complexes. Agreement of the thermodynamic data reported here with such models provides further evidence that specific interactions, when they occur, are more important than the bulk properties of the pure components in determining drug solubilities in nonaqueous systems. Specific examples demonstrate the relationship between the solubility and molecular structure of the solute and solvent. For example, solubility can be related to the hydrogen-donating and hydrogen-accepting abilities of the solute and solvent. Steric factors also appear to play a role in solubility, while structural modifications in a solute or solvent molecule far removed from the interactive functional group have little influence on molar solubility changes with the added polar cosolvent.

Anthraquinones↗
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↗
PubMedDate not supplied

Production of neutrons from interactions of GCR-like particles.

In order to help assess the risk to astronauts due to the long-term exposure to the natural radiation environment in space, an understanding of how the primary radiation field is changed when passing through shielding and tissue materials must be obtained. One important aspect of the change in the primary radiation field after passing through shielding materials is the production of secondary particles from the breakup of the primary. Neutrons are an important component of the secondary particle field due to their relatively high biological weighting factors, and due to their relative abundance, especially behind thick shielding scenarios. Because of the complexity of the problem, the estimation of the risk from exposure to the secondary neutron field must be handled using calculational techniques. However, those calculations will need an extensive set of neutron cross section and thicktarget neutron yield data in order to make an accurate assessment of the risk. In this paper we briefly survey the existing neutron-production data sets that are applicable to the space radiation transport problem, and we point out how neutron production from protons is different than neutron production from heavy ions. We also make comparisons of one the heavy-ion data sets with Boltzmann-Uehling-Uhlenbeck (BUU) calculations.

Aerospace Medicine↗
PubMedDate not supplied

Diversion of 911 poisoning calls to a poison center.

OBJECTIVE: To determine the impact and safety of diverting poisoning calls from 911 to a regional poison center. METHODS: A prospective six-month review was performed of all calls transferred from 911 dispatchers to a regional poison center for management. Recommendations for management and transport were made by the poison center using existing protocols. Patients were followed with telephone contact by poison center staff until symptoms resolved or until hospital discharge. Medical outcomes were categorized using the American Association of Poison Control Center guidelines for medical outcome. RESULTS: A total of 262 cases were reviewed; four were excluded. The poison center was contacted prior to ambulance dispatch in 210 cases (81%). An ambulance was sent before the poison center was contacted 48 times (19%). The majority of patients originally calling 911 were managed at home (175/258; 68%). Patients experienced either no effect or minor effects in 254 cases (98%). Two patients developed moderate effects (0.8%), one developed a major effect (0.4%), and one died (0.04)%. No adverse effects or treatment delays resulted from diversion of calls to the poison center. CONCLUSIONS: Appropriate poisoning and toxic exposure cases may be diverted safely from emergency medical services dispatch to a regional poison center for management, reducing unnecessary responses, with substantial cost savings.

Adolescent↗
PubMedDate not supplied

Dose dependence in the plasma pharmacokinetics and uptake kinetics of 2',3'-dideoxyinosine into brain and cerebrospinal fluid of rats.

Dose dependence in the plasma pharmacokinetics of 2',3'-dideoxyinosine (ddI) was examined during and after 2-hr iv infusions in rats at infusion rates of 12.4, 32.7, and 125 mg/kg/hr. After termination of the infusions, the disappearance of ddI from plasma was distinctly biphasic, suggesting that the majority of ddI is eliminated before distribution equilibrium is achieved. The mean alpha t1/2 following the infusions was 2.7 min and was independent of dose. The mean terminal half-life (beta t1/2) was approximately 24 min and also independent of dose. Nonlinear pharmacokinetic behavior in plasma after infusions was manifested in a decreased clearance with increasing dose, as determined from steady state plasma concentrations of ddI during infusions. In parallel with the decreased clearance, the apparent volume of distribution of the central compartment, Vcapp, decreased with increasing dose. Nonlinearity in clearance with increasing dose could be accounted for using a model which includes rapid, saturable tissue binding. Dose dependence in the kinetics of uptake of ddI into brain tissue and cerebrospinal fluid (CSF) was also examined during and after iv infusions. Steady state concentrations of ddI in brain tissue and CSF varied linearly with steady state plasma concentrations over a plasma concentration range of greater than 30-fold. Mean tissue to plasma concentration ratios, expressed as percentages, were 2% in CSF, 5% in brain tissue, and 1-2% in brain parenchymal tissue (corrected for the contribution of the cerebral vascular space).

Animals↗