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Biomedical subjects

J E Murphy

Publications and source records attributed to J E Murphy.

At least 19 recordsLinked to original sources
PubMed1999

Research experiences and research-related coursework in the education of doctors of pharmacy.

A study assessed coursework and experiential activities of students to determine the role of research in Doctor of Pharmacy education. Questionnaires were sent to all 78 (at that time) colleges and schools of pharmacy in the United States. Responses were received from 60 (76.9%), of which 57 were used, representing 139 Pharm.D. program types (entry-level, post-B.S., track-in, nontraditional). Most programs required coursework in research methodology, statistics, and drug information and literature evaluation, with research methodology required least. Although 41.0% of programs provided students the opportunity to conduct research as an elective, only 12.9% required an extensive project with data collection, analysis, and write-up. Another 6.5% required a project proposal only. Most colleges of pharmacy now offer the Pharm.D. degree, and the role of the pharmacist has also changed. Pharmacists must be able to disseminate evidence-based knowledge about drug products and drug therapy and use scientific knowledge and scholarly principles to solve problems.

Curriculum↗
PubMed1998

Evaluation of gentamicin pharmacokinetics and dosing protocols in 195 neonates.

Gentamicin pharmacokinetics and dosing protocols in neonates were studied. Demographic and pharmacokinetic data on 202 neonates treated with gentamicin at a 500-bed medical center were collected over a three-year period. Administered doses, gentamicin concentration measurements, and recorded times were used to calculate each patient's clearance, volume of distribution, elimination rate constant, and half-life. The performance of 15 dosing protocols, including 6 previously published ones and 9 developed on the basis of the study, was evaluated using the pharmacokinetic data. Of the 202 patients, 195 were included in the analysis. The mean +/- S.D. clearance, volume of distribution, elimination rate constant, and half-life were 0.047 +/- 0.015 L/hr/kg, 0.45 +/- 0.11 L/kg, 0.107 +/- 0.032 L/hr, and 7.19 +/- 2.64 hours, respectively. Weight, urine output, gestational age, and postconceptional age (PCA) had the highest correlation with the pharmacokinetic values. Blood urea nitrogen concentration (BUN) and Apgar score were poor predictors of the pharmacokinetic values. There were no significant differences among patient subsets based on race and BUN, but subset analysis based on PCA did indicate significant differences. In simulations, the protocols based on the study patients tended to perform better than the literature protocols, with all but three achieving therapeutic goals in 75% or more of the neonates. Of the published protocols, Murphy and Carter's produced the greatest percentage of neonates with peaks from 5 to 10 mg/L and troughs of <2 mg/L. The devised protocols tended to perform poorly in producing troughs between 1 and 2 mg/L, yet performed comparatively well in providing therapeutic peaks from 5 to 10 mg/L.

Body Weight↗
PubMed1998

A combinatorial approach to the discovery of efficient cationic peptoid reagents for gene delivery.

A family of N-substituted glycine oligomers (peptoids) of defined length and sequence are shown to condense plasmid DNA into small particles, protect it from nuclease degradation, and efficiently mediate the transfection of several cell lines. The oligomers were discovered by screening a combinatorial library of cationic peptoids that varied in length, density of charge, side-chain shape, and hydrophobicity. Transfection activity and peptoid-DNA complex formation are shown to be highly dependent on the peptoid structure. The most active peptoid is a 36-mer that contains 12 cationic aminoethyl side chains. This molecule can be synthesized efficiently from readily available building blocks. The peptoid condenses plasmid DNA into uniform particles 50-100 nm in diameter and mediates the transfection of a number of cell lines with efficiencies greater than or comparable to DMRIE-C, Lipofectin, and Lipofectamine. Unlike many cationic lipids, peptoids are capable of working in the presence of serum.

3T3 Cells↗
PubMed1998

Use of a recombinant murine cytomegalovirus expressing vesicular stomatitis virus G protein to pseudotype retroviral vectors.

A new method of producing vesicular stomatitis virus (VSV) G protein pseudotyped retroviral vectors is described. In this method, stocks of VSV-G pseudotyped vector were reproducibly obtained by infecting an env-, human, retroviral vector producer cell line with a recombinant murine cytomegalovirus (CMV) which expresses VSV-G protein. The recombinant murine CMV, RMCMVG, expressed VSV-G protein under transcriptional control of the human CMV immediate-early promoter. RMCMVG, like murine CMV, can infect human cells, but the infection is limited to the expression of the viral immediate-early genes; no productive replication of murine CMV occurs. Recombinant murine CMV vector infection of non-permissive cells may be useful in situations where high levels of gene expression are desired without concomitant viral vector replication.

3T3 Cells↗
PubMed1998

Lipitoids--novel cationic lipids for cellular delivery of plasmid DNA in vitro.

BACKGROUND: Although synthetic nonviral vectors hold promise for the delivery of plasmid DNA, their gene-transfer efficiencies are far from matching those of viruses. To systematically investigate the structure-activity relationship of cationic lipids, a small library of cationic lipid-peptoid conjugates (lipitoids) was synthesized. The compounds were evaluated for their ability to form complexes with plasmid DNA and to mediate DNA transfer in vitro. RESULTS: Lipid-peptoid conjugates were conveniently prepared in high yield using solid-phase synthesis. Several lipitoids condensed plasmid DNA into 100 nm spherical particles and protected the DNA and DNase digestion. A subset of lipitoids with a repeated (aminoethyl, neutral, neutral) sidechain trimer motif conjugated with dimyristoyl phosphatidyl-ethanolamine (DMPE) mediated DNA transfer with high efficiency. CONCLUSIONS: Automated solid-phase synthesis of cationic lipids allowed the rapid synthesis of a diverse set of transfection reagents. The most active compound DMPE-(Nae-Nmpe-Nmpe)3 (Nae, N-aminoethyl glycine; Nmpe, N-p-methoxyphenethyl-glycine) is more efficient than lipofectin or DMRIE-C (two commercial cationic lipid transfection reagents) and is active in the presence and absence of serum. The activity in the presence of serum suggests potential for applications in vivo.

3T3 Cells↗
PubMed1998

Adeno-associated virus-mediated delivery of erythropoietin leads to sustained elevation of hematocrit in nonhuman primates.

Recombinant adeno-associated virus encoding the monkey erythropoietin gene (rAAV-cm-Epo) was generated and tested for its potential to confer long-term expression of the gene product following intramuscular injection. A single intramuscular injection of 2 x 10(12) rAAV-cm-Epo particles into two baboons led to sustained high circulating Epo levels and a concomitant increase in hematocrit. The hematocrits reached 62 and 75% by week 10 (from pre-injection values of 38 and 40%, respectively) and remained elevated throughout the study period (28 weeks). Circulating Epo levels were also elevated throughout the study period. Our data demonstrate the potential for long-term gene expression in large animals by a single intramuscular injection of a recombinant adeno-associated virus (rAAV) vector.

Animals↗
PubMed1998

Forms and prevalence of intersexuality and effects of environmental contaminants on sexuality in cricket frogs (Acris crepitans).

Cricket frogs (Acris crepitans) from several different sites in Illinois were collected to assess the effects of environmental contamination on the prevalence of intersex gonads. Of 341 frogs collected in 1993, 1994, and 1995, 2.7% were intersex individuals. There was no statistically significant relationship between the chemical compounds detected and cricket frog intersexuality. However, there was an association approaching significance (p = 0.07) between the detection of atrazine and intersex individuals. A comparison of reference sites with sites that had point polychlorinated biphenyl (PCB) and polychlorinated dibenzofuran (PCDF) contamination revealed a significant relationship between sex-ratio reversal and contamination with PCBs and PCDFs. The sex ratio of juvenile frogs studied from three sites with PCB and PCDF point contamination favored males over females, which was the opposite of the sex ratio in control ponds (p = 0.0007). The statistically significant correlation between organochlorine contamination and sex-ratio reversal suggests PCBs and PCDFs can influence cricket frog sexual differentiation. The current study suggests that in cricket frogs, sex ratios and the prevalence of intersex gonads are altered by environmental contamination.

Aging↗
PubMed1997

Long-term correction of obesity and diabetes in genetically obese mice by a single intramuscular injection of recombinant adeno-associated virus encoding mouse leptin.

The ob/ob mouse is genetically deficient in leptin and exhibits a phenotype that includes obesity and non-insulin-dependent diabetes mellitus. This phenotype closely resembles the morbid obesity seen in humans. In this study, we demonstrate that a single intramuscular injection of a recombinant adeno-associated virus (AAV) vector encoding mouse leptin (rAAV-leptin) in ob/ob mice leads to prevention of obesity and diabetes. The treated animals show normalization of metabolic abnormalities including hyperglycemia, insulin resistance, impaired glucose tolerance, and lethargy. The effects of a single injection have lasted through the 6-month course of the study. At all time points measured the circulating levels of leptin in the serum were similar to age-matched control C57 mice. These results demonstrate that maintenance of normal levels of leptin (2-5 ng/ml) in the circulation can prevent both the onset of obesity and associated non-insulin-dependent diabetes. Thus a single injection of a rAAV vector expressing a therapeutic gene can lead to complete and long-term correction of a genetic disorder. Our study demonstrates the long-term correction of a disease caused by a genetic defect and proves the feasibility of using rAAV-based vectors for the treatment of chronic disorders like obesity.

Animals↗
PubMed1997

Intraperitoneal injection of genetically modified, human mesothelial cells for systemic gene therapy.

An ideal cell type for ex vivo gene therapy should be easy to biopsy, propagate, and genetically engineer in culture, should be transplantable using simple procedures, and should express therapeutic proteins at useful levels. The mesothelial cell appears to satisfy these criteria. Several thousand proliferative mesothelial cells were present in typical specimens of nonpathologic human peritoneal fluid obtained by needle aspiration. These divided rapidly in a specialized medium to yield pure cultures of approximately 10(7) cells within 2 weeks. The replicative lifespan of mesothelial cells cultured from adults was approximately 42-52 population doublings, permitting expansion and cryopreservation of a lifetime supply of autologous cells from one fluid sample. Cells transduced with a human growth hormone (hGH) adenoviral vector secreted 100-300 microg of hGH/10(6) cells per day for at least 6 weeks in culture when maintained at quiescence. Intraperitoneal injection of transduced cells into athymic mice resulted in rapid systemic delivery of hGH, with peak plasma levels of 0.1-1 microg/ml declining over 3 weeks to <1 ng/ml. Mice receiving a second injection of engineered cells displayed the same plasma hGH levels and duration as naive mice. Cells labeled with a beta-galactosidase vector were identifiable by in situ enzymatic staining as clusters attached to peritoneal surfaces at multiple sites for at least 19 days after injection. Cells serially passaged through about three-quarters of their lifespan before transduction and injection were as effective at hGH delivery as earlier-passage cells. These results indicate the clinical potential for ex vivo gene therapy using mesothelial cells.

Adenoviridae↗
PubMed1997

Satisfaction among residents in ASHP-accredited pharmacy residency programs.

The level of work satisfaction among pharmacists in ASHP-accredited residencies was studied. In March 1996 a questionnaire designed to measure residency satisfaction was mailed to 697 individuals in ASHP-accredited pharmacy practice and specialty practice residencies. Subjects responded to 16 statements relating to intrinsic and extrinsic determinants of work satisfaction on a scale of 1 to 5, where 1 = strongly disagree and 5 = strongly agree. Questionnaires were returned by 413 (59%) of the residents. The respondents were predominantly women (76%), and most (86%) had at least a Pharm. D. degree. Hospitals were the primary work setting (88%). Of the 413 residents, 305 were in pharmacy practice residencies and 108 were in specialized residencies. None of the mean scores indicated disagreement (scores < 3) with the positively worded statements or agreement (scores > 3) with the negatively worded statements. The median and mode were equal to 2 (disagree) for the three negatively worded items and 4 (agree) for all but three positively worded items. Only 8% of the residents indicated that they would not accept the residency again if given the chance. Specialized residents tended to rate positively worded statements higher and negatively worded statements lower than pharmacy practice residents. Female residents indicated greater satisfaction than male residents. Pay and benefits were rated slightly better than neutral. Pharmacy residents appeared generally satisfied with their residencies. Specialized pharmacy residents were more satisfied than pharmacy practice residents, and women were more satisfied than men.

Education, Pharmacy↗
PubMed1997

Trapping and visualization of a covalent enzyme-phosphate intermediate.

Using a mutant version of E. coli alkaline phosphatase, we succeeded in trapping and determining the structure of the phospho-enzyme intermediate. The X-ray structure also revealed the catalytic water molecule, bound to one of the active site zinc ions, positioned ideally for the apical attack necessary for the hydrolysis of the intermediate.

Alkaline Phosphatase↗
PubMed1996

National survey of hospital-based pharmacokinetic services.

The status of pharmacokinetic services in the nation's hospitals was studied. A questionnaire was mailed in February 1995 to all 252 respondents to ASHP's 1994 national survey of hospital-based pharmaceutical services who indicated the provision of pharmacokinetic services in their institution. Ninety-eight completed questionnaires were returned (40.2% response rate). The pharmacokinetic services provided required an average of 19.1 person-hours per week, tended to be provided by staff pharmacists, were managed by the pharmacy department, tended to be most focused on aminoglycosides and vancomycin, required an average of 60 notes in patient charts per month, and relied on both computers and calculators for deriving values. There was little contact with patients during the consultation process. Drug concentration measurements tended to be scheduled by service providers, but confidence in the accuracy of the timing of dose administration and blood sampling was limited. Respondents believed that the services tended to be supported by other hospital personnel and that they were successful. There was very little expectation that the workload for providing pharmacokinetic services would increase in the near future. A national survey of hospital-based pharmacokinetic services showed that it took 19 hours per week on average to provide the services, that the focus was on aminoglycosides and vancomycin, and that the services were perceived to be supported by other departments.

Drug Monitoring↗