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Biomedical subjects

J J Doyle

Publications and source records attributed to J J Doyle.

At least 55 records · Page 3Linked to original sources
PubMed1996

Full-cost determination of different levels of care in the intensive care unit. An activity-based costing approach.

We applied an activity-based costing methodology to determine the full cost of intensive care service at a community hospital, a university hospital and a health maintenance organisation (HMO)-affiliated hospital. A total of 5 patient care units were analysed: the intensive care unit (ICU) and surgical ICU (SICU) at the university setting, the ICU at the community setting, and the SICU and cardiac care unit at the HMO setting. The selection of the different ICU types was based on the types of critical care units that were found in each setting (e.g. the HMO did not have an ICU). Institution-specific cost data and clinical management parameters were collected through surveys and site visits from the 3 respective organisation types. The analysis revealed a marked increase in patient-minute cost associated with mechanical ventilation. Higher costs associated with prolonged neuromuscular blockade have important economic implications with respect to selection of an appropriate neuromuscular blocking agent.

Coronary Care Units↗
PubMed1996

Administration of recombinant human granulocyte-macrophage colony-stimulating factor after autologous bone marrow transplantation in children with acute myelogenous leukemia: a note of caution.

A series of 22 consecutive pediatric patients undergoing ABMT for treatment of primary AML was reviewed in an efficacy analysis of recombinant human granulocytemacrophage colony-stimulating factor (rhGM-CSF). Treatment with at least two cycles of chemotherapy and a standard conditioning regimen of busulfan and cyclophosphamide preceded the marrow infusion. Twelve patients who underwent transplants between 1992 and 1994 received 5.5 micrograms/kg/day rhGM-CSF as part of their transplant protocol. They were compared with 10 patients who underwent transplants between 1989 and 1991 but did not receive rhGM-CSF. Despite containing a significantly higher proportion of patients in first clinical remission at the time of the transplant, the rhGM-CSF-treated group had a significantly higher relapse and poorer overall survival rate after ABMT than the untreated group (36 vs 90%). The rhGM-CSF-treated group tended to have more rapid neutrophil engraftment and shorter hospital stays; however, neither of these trends was statistically significant. To properly determine the role of rhGM-CSF in the survival of pediatric patients undergoing ABMT for treatment of AML, a prospective randomized trial is desirable. Until these data are available, the current analysis suggests that particular caution is indicated with the use of this drug in this group of patients.

Acute Disease↗
PubMed1996

Building a computerized disease management operating system.

Under the increasing pressures of the marketplace, there has been a determined move in health care toward the development of disease management systems that improve efficiency, control costs, and ensure the best possible clinical outcome. Achieving these goals requires the ability to perform global analysis of complex and dynamic systems, beginning with point-of-care data collection and including the potential for multiple interfaces along the continuum of care. Our center has developed an integrated disease management system that enables the clinician to continuously monitor and assess relevant clinical and financial information flowing through the practice, providing robust and rigorous outcomes, health economic analysis, and pharmacoeconomic analysis of care at every step in the delivery process. This paper describes the results of pilot studies of the analytic capability of the system and includes an overview of the conceptual parameters employed in its development.

Costs and Cost Analysis↗
PubMed1996

A pharmacoeconomic evaluation of cisplatin in combination with either etoposide or etoposide phosphate in small cell lung cancer.

To compare etoposide and etoposide phosphate (Etopophos; Bristol-Myers Squibb Company, Princeton, NJ) in maximizing the cost efficiency of care for patients with small cell lung cancer (SCLC), we obtained pharmacoeconomic data from a phase II randomized study of these agents. This clinical investigation assessed the efficacy and toxicity of etoposide phosphate combined with cisplatin in treating SCLC. In the economic analysis, we identified resources expended during chemotherapy and related concomitant procedures and matched them with the current procedure terminology level of costs for the provider and the payor. The valuation process was conducted in the specific point-of-care (outpatient v inpatient) setting. The appropriate pharmacoeconomic analytic tool used when comparators are considered to achieve equivalent clinical outcomes is cost-minimization analysis. We provide the cost-minimization analysis from two oncology care perspectives: the provider and the payor. In addition, a payor/ provider cost reduction model was constructed to illustrate the potential economic effects achieved through more efficient use of the outpatient chemotherapy facility due to the ease of administration of etoposide phosphate. The provider's average cost per patient for treating an SCLC patient for six cycles in US dollars is $26,764.48 for etoposide versus $26,026.70 for etoposide phosphate. The payor's average treatment cost per patient for treating an SCLC patient for six cycles for the respective regimens was $34,270.65 and $34,320.70. When the time savings associated with the etoposide phosphate regimen are applied to the outpatient chemotherapy facility, the adjusted average treatment costs per patient for the payor are $2,797.29 less than the costs for using the standard etoposide intravenous formulation. Delivering an etoposide phosphate regimen accrued adjusted savings of $2,897.03 per patient. Based on these results, etoposide phosphate is a superior pharmacoeconomic alternative compared with standard etoposide chemotherapy in managing SCLC. The potential increase in patient volume conferred by the relative simplicity of etoposide phosphate administration would have a significant impact on operations in terms of scheduling patients and staff and increasing operational efficiencies, thereby facilitating cost reductions in excess of $2,700 per patient when an etoposide phosphate regimen is chosen over an etoposide regimen.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1995

Hypervariable microsatellites provide a general source of polymorphic DNA markers for the chloroplast genome.

BACKGROUND: The study of plant populations is greatly facilitated by the deployment of chloroplast DNA markers. Asymmetric inheritance, lower effective population sizes and perceived lower mutation rates indicate that the chloroplast genome may have different patterns of genetic diversity compared to nuclear genomes. Convenient assays that would allow intraspecific chloroplast variability to be detected are required. RESULTS: Eukaryote nuclear genomes contain ubiquitous simple sequence repeat (microsatellite) loci that are highly polymorphic in length; these polymorphisms can be rapidly typed by the polymerase chain reaction (PCR). Using primers flanking simple mononucleotide repeat motifs in the chloroplast DNA of annual and perennial soybean species, we demonstrate that microsatellites in the chloroplast genome also exhibit length variation, and that this polymorphism is due to changes in the repeat region. Furthermore, we have observed a nonrandom geographic distribution of variations at these loci, and have examined the number and location of such repeats within the chloroplast genomes of other species. CONCLUSIONS: PCR-based analysis of mononucleotide repeats may be used to detect both intraspecific and interspecific variability in the chloroplast genomes of seed plants. The analysis of polymorphic microsatellites thus provides an important experimental tool to examine a range of issues in plant genetics.

Base Sequence↗
PubMed1995

Pharmacoeconomic analysis of topical treatments for tinea infections.

The purpose of this study was to perform a government-perspective economic analysis of the most widely used topical creams [namely, ciclopirox (CIC), clotrimazole (CLO), ketoconazole (KET), miconazole (MIC), and terbinafine (TER)], for the treatment of 2 types of dermatophyte skin infections: dermatophytosis major (excluding onychomycosis) and dermatophytosis minor. A 3-phase approach was used. In phase I, experts were assembled to identify the standard approach for management of fungal infections and a decision tree was constructed to model the process; in phase II, meta-analysis was used to determine success, failure, and relapse rates; and in phase III, economic analyses were performed including cost of regimen, total expected cost and cost-effectiveness analysis. Sensitivity analyses (robustness analyses) were also performed in phase III. It was found that while TER was successful following 1 week of administration for minor infections and after 2 weeks for major infections, duration of drug treatment was usually twice that time. Other comparators (CIC, CLO, KET and MIC) took 4 weeks to achieve a successful outcome. In addition, an extra 2 weeks were often needed to clear both types of infections because the comparators are fungistatic, whereas TER is fungicidal. In the total expected cost analysis, TER had the lowest overall cost of treating patients for both infection categories. It was also responsible for the highest number of disease-free days and, consequently, the lowest cost per disease-free day. Sensitivity analyses confirmed that TER was the most cost-effective topical agent for treating dermatophytosis major (excluding onychomycosis) and dermatophytosis minor.

Administration, Topical↗
PubMed1995

Transient leukemia followed by megakaryoblastic leukemia in a child with mosaic Down syndrome.

A case is presented of a child with mosaic Down syndrome, who presented at birth with a transient leukemia and later progressed to megakaryoblastic leukemia. Evidence is presented that both leukemias were of megakaryoblastic lineage and evolved from a trisomic hematopoietic precursor. This case is unique in the poor course of the initial transient neonatal leukemia with improvement following chemotherapy. It also highlights the form of leukemia and associated myelodysplasia that occurs in children with Down syndrome. This form of leukemia and transient leukemia are interrelated and are unique to children with Down syndrome.

Adult↗
PubMed1995

A multifactorial approach to understanding anesthesia selection.

A full hospital cost accounting model to track the total costs of surgery and anesthesia for inpatients, from the perspective of a hospital CFO, utilizing time-allocation methodology is presented. This model was tested in a prospective multicenter economic clinical trial in three settings.

Accounting↗
PubMed1994

The reduced stability of a plant alcohol dehydrogenase is due to the substitution of serine for a highly conserved phenylalanine residue.

The zinc-binding long-chain alcohol dehydrogenases from plants and animals exhibit a considerable level of amino acid sequence conservation. While the functional importance of many of the conserved residues is known, the role of others has not yet been determined. We have identified a naturally occurring Adh-1 allele in the legume Phaseolus acutifolius with several unusual characteristics. Individuals homozygous for this allele, Adh-1 CN, possess a single isozyme starch gel electrophoretic pattern suggestive of a null allele, and exhibit ADH enzyme activity levels ca. 60% lower than the standard wild-type Adh-1F line. Interestingly, analysis of Adh-1CN homozygotes on an alternative gel system indicates that Adh-1CN does encode a polypeptide capable of forming functional homo- and heterodimers. However, the levels of ADH activity displayed by these isozymes are far lower than those observed for the corresponding wild type ADH-1F isozymes. Dialysis experiments indicate that isozymes containing the ADH-1CN polypeptide are inactivated by slightly acidic conditions, which may explain the apparent null phenotype on starch gels. Elevated temperatures cause a similar loss of enzyme activity. The deduced amino acid sequences of ADH-1CN and ADH-1F were obtained from their corresponding cDNA clones, and the only significant difference detected between the two is a single amino acid replacement substitution. Residue 144 is occupied by phenylalanine in the ADH-1F polypeptide, whereas serine occupies this position in the ADH-1CN polypeptide. The proximity of residue 144 to the catalytic zinc in the substrate-binding pocket, coupled with the fact that it is integral to a defined hydrophobic core of the ADH polypeptide, may explain the observed disruptive effect that the serine substitution has on both the activity and stability of the ADH-1CN polypeptide. It also provides an explanation for the maintenance of phenylalanine or the structurally similar tyrosine at this residue in Zn-binding long-chain ADHs.

Alcohol Dehydrogenase↗
PubMed1994

A novel anther-expressed adh-homologous gene in Lycopersicon esculentum.

Two novel tandemly-oriented open reading frames (ORFs) with homology to alcohol dehydrogenase (ADH) were isolated from tomato. The predicted amino acid composition for each of the two tandem adh genes indicates the presence of 22 and 21, respectively, of 22 amino acids conserved in ADH proteins from plants and animals. However, comparison to known plant adh genes reveals a significantly lower similarity indicating that they belong to a novel class of ADHs. According to mapping data, the adh-homologous ORFs do not represent either of the previously studied adh1 or adh2 genes of tomato. The tandem genes, termed adh3a and adh3b, mapped to a distal region of the long arm of chromosome 4, unlike adh1, which maps closer to the centromere. Adh3a and adh3b have over 90% similarity to each other at the nucleotide and putative peptide levels. The adh3a gene has ten exons and nine introns with the transcription initiation site 57 bp upstream of the translation start. A putative TATA box and polyadenylation site have been identified. Adh3a is transcribed and, according to cDNA sequence analysis, fully processed in the late stages of anther development. According to transformation analysis, tissue-specific regulatory elements reside within the -448 to +724 region. The termination codon of adh3a is separated from the putative adh3b translation start site by 789 bp of intervening sequence. The 5' untranscribed sequences of each gene contain a stretch of 68 bp with 78% similarity. Within this stretch are sequences which are homologous to sequences found in anaerobically-induced or pollen-expressed genes from various plant species.

Alcohol Dehydrogenase↗
PubMed1992

Highly potent, orally active diester macrocyclic human renin inhibitors.

Replacing one amide bond in macrocyclic renin inhibitors of the general structure 1 and 2 with an ester linkage gave glutamate-derived inhibitors 3 and serine-derived inhibitors 4. While this oxygen-for-nitrogen exchange had little effect on potency in the glutamate series, potency was dramatically increased in the serine series. In this series, the 14-membered ring compounds proved to be more potent than the corresponding 13-membered ring derivatives. Substitution of the ring at the position corresponding to P2' generally increased potency. The absolute configuration at this center was shown to be R for the 4-morpholinomethyl derivative (4o), both by asymmetric synthesis and X-ray crystallography. Replacing the "Boc-Phe" moiety of inhibitor 4o with a variety of substituents led to subnanomolar inhibitors, one of which (the "3(S)-quinuclidinyl-Phe" derivative 33) lowered blood pressure 20 mmHg and completely inhibited plasma renin activity for 6 h in sodium-depleted rhesus monkeys. This compound proved to have limited bioavailability (1% in rats) due to cleavage of the serine ester bond and rapid hepatic extraction.

Administration, Oral↗
PubMed1992

Chloroplast DNA inversions and the origin of the grass family (Poaceae).

The phylogenetic affinities of the grass family (Poaceae) have long been debated. The chloroplast genomes of at least some grasses have been known to possess three inversions relative to the typical gene arrangement found in most flowering plants. We have surveyed for the presence of these inversions in grasses and other monocots by polymerase chain reaction amplification with primers constructed from sequences flanking the inversion end points. Amplification phenotypes diagnostic for the largest inversion (28 kilobase pairs) were found in genera representing all grass subfamilies, and in the nongrass families Restionaceae, Ecdeiocoleaceae, and Joinvilleaceae, but not in any other monocots--notably, Flagellariaceae, Anarthriaceae, Cyperaceae, or Juncaceae. This finding is consistent with one of the two principal views of grass phylogeny in suggesting that Poaceae and Cyperaceae (sedges) are not closest relatives. A second (approximately 6 kilobases) inversion appears to occur in a subset of the families possessing the 28-kilobase inversion and links Joinvilleaceae and Poaceae, while the smallest inversion appears unique to grasses. These inversions thus provide a nested set of phylogenetic characters, indicating a hierarchy of relationships in the grasses and allies, with Joinvilleaceae identified as the likely sister group to the Poaceae.

Base Sequence↗
PubMed1992

Synthesis and use of 3-amino-4-phenyl-2-piperidones and 4-amino-2-benzazepin-3-ones as conformationally restricted phenylalanine isosteres in renin inhibitors.

The design of P2-P3 conformational restrictions in renin inhibitors by the use of a renin computer graphic model led to the synthesis of inhibitors containing N-Boc, N-acetyl, and N-phthalyl derivatives of 3(S)-amino-4(R,S)-2-piperidones and 4(S)-amino-2-benzazepinones in place of phenylalanine in the control compound N-acetyl-L-phenylalanyl-N-[4(S)-[(butylamino)carbonyl]-1(S)- (cyclohexylmethyl)-2(S)-hydroxy-5-methylhexyl]-L-norleuci namide (32). The piperidone inhibitors were prepared by utilization of the Evans chiral auxilliary to introduce the amino group with enantioselectivity and also to act as a leaving group in an intramolecular cyclization to the piperidone. The most potent inhibitor, 3(S)-(acetylamino)-alpha(S)-butyl-N-[4(S)- [(butylamino)carbonyl]-1(S)-(cyclohexylmethyl)-2(S)-hydroxy-5- methylhexyl]-2-oxo-4(R)-phenyl-1-piperidineacetamide (18, IC50 = 21 nM), was 25-fold less potent than the acyclic control 32. Considerable dependence of potency with the size of the P4 derivative was observed as had been expected based on the presynthetic modeling studies. Attempts to rationalize the observed potencies on the basis of further molecular modeling studies suggested that the loss in inhibitor potency was due to the conformational restrictions distorting the 3S center from the geometry present in the putative extended conformation present when the inhibitor is bound within the renin active site.

Benzazepines↗
PubMed1991

Renin inhibitors containing conformationally restricted P1-P1' dipeptide mimetics.

A series of renin inhibitors containing lactam-bridged P1-P1' dipeptide mimetics based on the ACHPA (4(S)-amino-5-cyclohexyl-3(S)-hydroxypentanoic acid) design was studied. The inhibitors were obtained by aldol addition of various lactams with N alpha-Boc-L-cyclohexylalaninal, followed by Boc group removal and acylation with Boc-Phe-His. The aldol diastereomer having the S configuration at the two newly generated stereogenic centers gave optimal enzyme inhibition. Potency was further enhanced in the gamma-lactam ring series by substitution with small hydrophobic groups to mimic the P1' side chain of the renin substrate. Thus, 2(S)-[(Boc-L-phenylalanyl-L-histidyl)amino]-3-cyclohexyl-1(S)-hydroxyl-1 - (1,5,5-trimethyl-2-oxopyrrolidin-3(S)-yl)propane (34) has an IC50 of 1.3 nM in the human plasma renin assay. A variety of substituents on the lactam nitrogen are tolerated and can be used to vary the physical properties of the inhibitor. By using a model of the human renin active site, the conformation of 34 in the enzyme-inhibitor complex is proposed. This modeled conformation is very similar to the solid-state conformation of 2(S)-[(Boc-L-phenylalanyl-L-histidyl)amino]-3-cyclohexyl-1(S)-hydroxyl- 1-(1-methyl-2-oxopyrrolidin-3(S)-yl)propane (36), the structure of which was determined by single-crystal X-ray diffraction analysis. The most potent ACH-PA-lactam renin inhibitors show good selectivity when assayed against other types of aspartic proteinases. By varying the lactam ring substituents, potent and selective inhibitors of cathepsin D and cathepsin E can be obtained.

Animals↗
PubMed1991

Design and synthesis of P2-P1'-linked macrocyclic human renin inhibitors.

Using a computer model of the active site of human renin developed at Merck, we designed a series of novel P2-P1'-linked, macrocyclic renin inhibitors 3-10. These unique inhibitors incorporate a transition-state isostere within a 13- or 14-membered ring. The three most active compounds in this family were 13-membered-ring glutamine-derived inhibitor 3, 14-membered-ring diaminopropionic acid derived inhibitor 6, and 13-membered-ring diol 9 (IC50 0.61, 0.59, 0.65 microM, respectively). Modification of inhibitor 3 at P4 led to 56 nM macrocyclic renin inhibitor 39. This study shows the viability of renin inhibitor designs which incorporate a scissile-bond replacement within a macrocycle.

Amino Acid Sequence↗