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Biomedical subjects

M F Powell

Publications and source records attributed to M F Powell.

At least 37 records · Page 2Linked to original sources
PubMed1994

Immunogenicity and HIV-1 virus neutralization of MN recombinant glycoprotein 120/HIV-1 QS21 vaccine in baboons .

The effect of adjuvant and immunization schedule on the immunogenicity of HIV-1 envelope glycoprotein, MN rgp120, was optimized by using baboons. The novel adjuvant QS21 elicited earlier seroconversion than alum adjuvant, and the antibody titers to MN rgp120 for animals treated with QS21 were significantly greater than the titers obtained in animals treated with alum. The use of QS21 shifted the dose-response curve, resulting in less MN rgp120 required to achieve equivalent titers to those in the alum formulations. The in vitro virus neutralizing (VN) titers from animals treated with QS21 were 3- to 10-fold higher than with alum. The data presented herein point to the superiority of QS21 as adjuvant in primates for MN rgp120.

AIDS Vaccines↗
PubMed1994

Development of a single-shot subunit vaccine for HIV-1.

The successful development of an AIDS vaccine will require formulations that not only invoke the desired immunological response, but also are stable and easy to administer. A single shot MN rgp120 vaccine formulation comprised of MN rgp120 encapsulated in poly (lactic-coglycolic) acid (PLGA) microspheres was developed to provide an in vivo autoboost of antigen. These formulations were designed to yield an in vivo autoboost at 1, 2, 3 or 4-6 months. In addition, PLGA microspheres containing the adjuvant, QS21, were also prepared to provide an in vivo autoboost concomitant with antigen. In guinea pigs, these formulations yielded higher anti-MN rgp120 and anti-V3 loop antibody titers than alum formulations that were administered at higher antigen doses. Different doses of encapsulated MN rgp120 provided a clear and well-defined dose response curve for both anti-MN rgp120 and anti-V3 loop antibody titers. When soluble QS21 was mixed with the encapsulated MN rgp120, the antibody titers were increased by a factor of 5 over the titers with encapsulated MN rgp120 alone. An additional fivefold increase in antibody titers was observed for guinea pigs immunized with encapsulated MN rgp120 and QS21 on the same microspheres. These results suggest that the adjuvant properties of QS21 can be increased by microencapsulation in PLGA. Furthermore, antibodies induced by these preparations neutralized the MN strain of HIV-1. The neutralization titers for sera from animals immunized with MN rgp120-PLGA and soluble QS21 were greater than the titers obtained from guinea pigs that were treated with MN rgp120 and soluble QS21 at the same dose. Overall, these studies validate the in vivo autoboost concept, reveal a method for improving the adjuvant properties of QS21, and indicate the potential of future single shot vaccine formulations.

AIDS Vaccines↗
PubMed1993

HLA DR4w4-binding motifs illustrate the biochemical basis of degeneracy and specificity in peptide-DR interactions.

In the present study, we describe the definition of a DRB1*0401 (DR4w4)-specific motif. The strategy used entailed a three-step process: 1) screening a large set of unrelated peptide ligands to identify good MHC binders; 2) truncation analysis of several DR4w4 binding peptides of high affinity to identify the crucial core-binding regions; 3) the use of single amino acid substitutions of the DR4w4-binding peptide hemagglutinin (HA) 307-319 to elucidate the specific residues crucial for binding. The DR4w4 motif is characterized by the presence of a hydrophobic or aromatic (F, W, Y, L, I, V, M) anchor residue in position 1, and a second hydroxyl (S, T) or aliphatic (L, I, V, or M) anchor residue in position 6. Furthermore, positive charges (R, K) are not allowed in positions 4, 7, and 9, and negative charges (D, E) are not allowed in position 9. This motif was present in 92% of good (IC50 < or = 100 nM) DR4w4-binding peptides, but less than 25% of the negative (IC50 > 45 microM) binders, indicating that the presence of the motif is necessary, but not sufficient for good DR4w4 binding capacity. The results of the present study are discussed in relation to previous work defining binding motifs and rules for other DR alleles, illustrating how different DR alleles bind variations on a similar structural theme. Finally, using two different peptide ligands [tetanus toxoid 830-843 and HA 307-319] as model systems, it is demonstrated how the fine allelic specificity of the DR binders can be predictably modulated by introducing subtle changes in the primary amino acid sequence.

Amino Acid Sequence↗
PubMed1993

Peptide stability in drug development. II. Effect of single amino acid substitution and glycosylation on peptide reactivity in human serum.

The determination of peptide stability in human serum (HS) or plasma constitutes a powerful screening assay for eliminating unstable peptides from further development. Herein we report on the stability in HS of several major histocompatibility complex (MHC)-binding peptides. Some of these peptides are in development for the novel treatment of selected autoimmune disorders such as rheumatoid arthritis and insulin-dependent diabetes. For most of the l-amino acid peptides studied, the predominant degradation mechanism is exopeptidase-catalyzed cleavage. Peptides that were protected by d-amino acids at both termini were found to be more stable than predicted, based on additivity of single substitutions. In addition, N-acetylglucosamine glycopeptides were significantly stabilized, even when the glycosylation site was several amino acids from the predominant site(s) of cleavage. This indicates that long-range stabilization is possible, and likely due to altered peptide conformation. Finally, the effect of single amino acid substitutions on peptide stability in HS was determined using a model set of poly-Ala peptides which were protected from exopeptidase cleavage, allowing the study of endopeptidase cleavage pathways.

Acetylglucosamine↗
PubMed1993

The development of stable protein formulations: a close look at protein aggregation, deamidation, and oxidation.

The biochemical literature has been surveyed to present an overview of the three most common protein degradation pathways: protein aggregation, deamidation, and oxidation. The mechanisms for each of these degradation routes are discussed with particular attention given to the effect of formulation conditions such as pH, ionic strength, temperature, and buffer composition. Strategies to reduce protein degradation are also discussed. These strategies are based on an understanding of the degradation mechanisms and the effect of changes in the storage conditions and formulation components on the degradation. The effects of each of the degradation routes on pharmaceutically relevant properties such as biological activity, metabolic half-life, and immunogenicity are summarized. Predicting a priori the alteration of pharmaceutical properties caused by the three degradation routes is difficult, and must be determined on a case-by-case basis for each protein. The difficulty in predicting the effect of degradation and analyzing the temperature dependence of reaction rates in proteins results in longer development times for protein formulations than for small molecule formulations. Although the use of accelerated stability to predict protein shelf life is difficult, conditions are discussed whereby the Arrhenius equation can be used to shorten formulation development time.

Amides↗
PubMed1992

Peptide stability in drug development: a comparison of peptide reactivity in different biological media.

Degradation kinetics for several peptides that bind to the major histocompatibility complex on antigen-presenting cells were determined in both human serum (HS; 25%) and synovial fluid (SF; 25%) from patients with rheumatoid arthritis to test whether therapeutic intervention of rheumatoid arthritis by direct intrasynovial injection is feasible (at least in terms of peptide stability). Controls consisted of enzymatically immature 10% fetal calf serum and peptidase-rich 5% liver homogenate (all diluted with RPMI-1040 tissue culture medium). Peptide half-lives ranged from approximately 4 to greater than 10,000 min, with most peptides showing half-lives of approximately 10-100 min. These studies show that, even though the populations of inflammatory and other cell types in SF and HS are different (and may, therefore, generate different peptidase profiles), the observed peptide stabilities in SF and HS are similar. This finding indicates that the effect of SF on peptide stability is similar to that of HS.

Amino Acid Sequence↗
PubMed1992

Justification for a pediatric satellite pharmacy at a tertiary-care institution.

The justification for a pediatric satellite pharmacy is described. Of the 742 inpatient beds in a tertiary-care medical center, 150 are dedicated to pediatric patients. The pharmacy department provides services to both adult and pediatric patients from a central pharmacy. However, unit dose drug distribution services are not provided to the nurseries. Furthermore, the department lacks a core of pharmacists specializing in pediatric practice. As a result, the ability of the pharmacy to support pediatric drug use has been compromised, and medication errors and infection control problems have occurred that can be attributed to this situation. A pediatric satellite pharmacy was proposed to improve the quality of pediatric care. Service objectives were established, and benefits were identified. A financial analysis was included in the proposal that documented a total gain attributable to a pediatric satellite pharmacy of approximately $285,000 over five years. The satellite pharmacy was approved by hospital administration. The pharmacy department's quality assurance committee will monitor the satellite's impact. The justification for a proposed pediatric satellite pharmacy included indications that the satellite could correct medication-related problems and improve pediatric care and that implementation would have a positive effect on finances.

Child, Preschool↗
PubMed1991

Chemical and enzymatic degradation of ganciclovir prodrugs: enhanced stability of the diadamantoate prodrug under acid conditions.

We report the chemical and enzymatic hydrolysis of two hydrophobic prodrugs of ganciclovir (3 = dipropionate ester; 4 = diadamantoate ester). Both prodrugs undergo hydrolysis showing a pH dependence of kobs = kH+aH+ + ko + kHO-aHO- and a pH of maximum stability near pH 5. Only 4 exhibited a shelf life (t90) greater than 2 years. Compound 4 reacts significantly slower than ganciclovir in acidic media, even though the adamantyl esters provide additional reaction sites (which would be expected to increase the rate of degradation) that are distally removed from the guanine ring system, offering negligible steric or electronic substituent effects. Both 3 and 4 hydrolyzed in tissue homogenate, where kobs followed liver greater than intestine much greater than skin. Based on these findings of chemical stability, lipophilicity, and acceptable rate of enzymatic cleavage by skin esterases, 4 meets several of the criteria required for the topical sustained delivery of ganciclovir.

Animals↗
PubMed1991

Parenteral peptide formulations: chemical and physical properties of native luteinizing hormone-releasing hormone (LHRH) and hydrophobic analogues in aqueous solution.

The degradation of native LHRH in aqueous buffers of pH approximately 1-10 obeyed the rate equation, kobs = kH + alpha H+ + ko + kHO-(alpha HO-)x, where x at 60-100 degrees C was approximately 0.64 and temperature independent. Extrapolation to 25 degrees C using the Arrhenius equation and secondary rate constants showed that native LHRH is reasonably stable at pH 5.4, giving a shelf life (t90) of approximately 5 years. Regarding physical properties, hydrophobic LHRH analogues nafarelin and detirelix were found to be surface active as demonstrated by a decrease in apparent surface tension with increased peptide concentration. The CMC for detirelix at pH 7.4 was determined to be 5.3 x 10(-4) M (0.88 mg/ml), and that for nafarelin, greater than 2 mg/ml. At higher concentrations (approximately 4-8 mg/ml), nafarelin and detirelix formed nematic liquid crystals of undulose extinction (birefringence, less than 0.001). The thermodynamic stability of these peptide liquid crystals was probed by determining their melting points (Tcm) in the presence of propylene glycol, a solvent which proved to be efficacious at suppressing gelation and at destabilizing liquid crystals as measured by a reduction in Tcm.

Chemical Phenomena↗
PubMed1991

A survey of current operations and future plans for ambulatory pharmacy services.

Survey results indicate that the number of hospital-based ambulatory pharmacies in the survey area is increasing substantially. By the end of 1989, there would have been a 71 percent increase in the number of hospitals providing ambulatory pharmacy services in this region. This assumes that those hospitals in the planning stages of developing ambulatory pharmacy services completed their plans. While the number of hospital-based ambulatory pharmacies is on the rise, there has been a concurrent increase in the number of services provided by the pharmacies already in operation. There has been a 38 percent increase in the number of services provided by these pharmacies since the inception of DRGs. The services that have been added are primarily specialized services including home TPN compounding, intravenous antibiotic compounding, intravenous chemotherapy compounding, medical supplies, and durable medical equipment. It is likely that these services will continue to increase in the coming years as home therapies continue to become more advanced. The study also indicates that most hospital-based ambulatory pharmacies in this region are operated as nonprofit entities. A trend toward for-profit pharmacy operations was anticipated, and this is still anticipated as more ambulatory pharmacy operations become separate entities from inpatient services. Future studies of this type should monitor this possible trend. Most hospital-based ambulatory pharmacies are owned by the hospital or a hospital affiliate. More than half of respondents reported their ambulatory pharmacies are located within the inpatient pharmacy of the hospital. As the trend toward separate ambulatory pharmacy operations increases, it would not be unusual for the pharmacies to be operated by for-profit affiliates of the hospital or outside contractors. Barker predicts that hospital-based ambulatory pharmacies could become units of major drug store chains in the future. This is another area that is worthy of future studies of hospital-based ambulatory pharmacy operations. Overall, the results of this study indicate that hospitals in this region have not remained static since the inception of DRGs. There seems to be a dynamic period of change evolving in the delivery of health care services in this region. The demographic section of this study reveals that the majority (more than 70 percent) of the hospitals surveyed are operating fewer numbers of beds for inpatient services since ther inception of DRGs. The length of time that patients remain in the hospital for inpatient services is decreasing, resulting in decreased demand for inpatient beds.(ABSTRACT TRUNCATED AT 400 WORDS)

Ambulatory Care↗
PubMed1990

The use of peptide analogs with improved stability and MHC binding capacity to inhibit antigen presentation in vitro and in vivo.

The identification of a core region for OVA 323-339, which is critical in determining binding to IAd, has enabled us to generate a series of analog peptides in which this core region was extended at both the N and C termini with different amino acid residues. When assessed for binding capacity, several peptides were shown to have increased affinity for IAd compared with the parent sequence, and in addition, some peptides had acquired binding specificities for class II MHC haplotypes not present for OVA 323-339. These peptides were next examined for their ability to inhibit T cell responses in vitro and in vivo. The correlation between binding and the ability to inhibit T cell activation in vitro was good. However, when assessed in vivo, it was clear that high Ia binding was not sufficient in itself to define the inhibitory capacity of a given peptide. That this discrepancy was due to differences in degradation of the core-extended peptides was suggested by 1) results from an inhibition of Ag presentation assay, in which the pulse period with Ag and inhibitor was extended to 20 h; and 2) direct analysis of peptide stability by using reverse phase HPLC. Finally, by protecting the peptide from degradation with N- and C-terminal substitutions of D-amino acids, the inhibitory capacity of an unstable core-extended peptide in vitro could be greatly enhanced. These data indicate that the core extension approach may be one method by which antagonists for MHC class II molecules may be generated.

Animals↗
PubMed1989

Labor standard development for a decentralized mobile cart unit dose drug distribution system.

A project to develop labor standards for a decentralized mobile cart unit dose drug distribution system was performed. First, the tasks associated with the drug distribution system were defined. Then a predetermined number of observations were made using a modified self-reporting and work sampling technique to document activities of the floor pharmacists and pharmacists in the unit dose room. Stop-watch time studies were performed to evaluate computer entry tasks. From the data collected, average times for completion of each task defined were calculated. For each calculated average time, an adjusted average was calculated based upon other productive and personal time observed as part of the work study. The calculated labor standards are compared with other labor standards reported in the literature.

Centralized Hospital Services↗
PubMed1989

An analysis of 1986 drug procurement practices in hospitals within the United States.

The purpose of this study was to statistically answer a set of predefined objectives concerning pharmaceutical procurement. The key indicators were assumed to be cost per patient day and turnover rate. Of the 5,911 surveys mailed, 709 surveys were returned for a 12% response rate. The following statements were based on attempts to answer the six predetermined objectives. Pharmaceutical purchasing is controlled by pharmacy departments to the extent that comparisons to pharmaceutical purchasing by materials management departments was not possible. Prime vendor purchasing is the procurement method of choice. Competitive bidding through a group process is so popular that a valid comparison to nongroup bidding could not be accomplished with the results of this survey. Certain variables of group purchasing such as group age, contract adherence, and volume commitment, do not appear to be correlated to purchasing outcomes in this study. When comparing government to private hospitals, the private sector seems to have an advantage in managing turnover rates. Cost per patient day results were less conclusive. As single and multiple hospital systems were compared for purchasing outcomes, the results were not totally conclusive. Although, multiple hospital systems had a significantly higher turnover rate. Finally, a comparison based on the use, or lack of use, of prime vendor arrangements demonstrated interesting results. The duration of contract did not significantly affect the purchasing outcomes. Other hospital variables such as size, type, ownership, and organization, demonstrated notable trends. The importance of examining hospitals based on case mix and mission seems to be most important. Also, the ability to relate purchasing outcomes with formulary management strategies needs further study before conclusive statements can be adopted.

Contract Services↗
PubMed1988

Formulation of vaccine adjuvant muramyldipeptides (MDP). 2. The thermal reactivity and pH of maximum stability of MDP compounds in aqueous solution.

The degradation of muramyldipeptides (MDPs) in aqueous solution obeys the rate law kobs = kH+aH+ + ko + kHO-aHO- and the Arrhenius equation. For example, the rate constants for degradation of N-acetylmuramyl-L-threonyl-D-isoglutamine, 3, at 25 degrees C are kH+ = 2.3 X 10(-6) M-1 sec-1, ko = 8.2 X 10(-10) sec-1, and kHO- = 0.19 M-1 sec-1. The degradation rates are dependent on the side-chain substituents; it is predicted that sterically hindered MDP compounds will show an extended shelf life in aqueous solution. Product studies in the weakly acid pH region (where the pH of maximum stability occurs) show that MDP compounds degrade largely by hydrolysis of the dipeptide side chain. These data show that MDP 3 exhibits a shelf life (t90) of greater than 2 years in aqueous solutions of pH 4-4.5, the pH of maximum stability.

Acetylmuramyl-Alanyl-Isoglutamine↗
PubMed1988

Stability of prostacyclin analogues: an unusual lack of reactivity in acid-catalyzed alkene hydration.

Prostacyclin analogue 5 undergoes specific acid-catalyzed hydration (kH+ = 1.9 x 10(-7)M-1 sec-1 at 25 degrees C) and a pH-independent oxidation reaction (k0 = 1.2 x 10(-10) sec-1 at 25 degrees C) above pH approximately 5. The hydration reaction for 5 is much slower than for other structurally similar exocyclic alkenes, even though the rate-determining step is proton transfer. This slowness of reaction and an analysis of the pH-rate profile show that 5 does not exhibit significant intramolecular general acid catalysis, as does prostacyclin.

Acids↗
PubMed1988

Using the business plan to propose revenue-generating pharmacy services.

The business plan is a document that may be used to initiate administrative action on revenue generating business ventures. It has proven to be a powerful tool in the financial business community for a number of years. The article discusses the components of a business plan in detail. It also provides some general examples of how a business plan may be used in pharmacy.

Capital Expenditures↗