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PubMed2002

Screening, library-assisted identification and validated quantification of oral antidiabetics of the sulfonylurea-type in plasma by atmospheric pressure chemical ionization liquid chromatography-mass spectrometry.

An atmospheric pressure chemical ionization liquid chromatographic-mass spectrometric (APCI-LC-MS) LC-MS assay is presented for fast and reliable screening and identification as well as precise and sensitive quantification of oral antidiabetics of the sulfonylurea-type (OADs) in plasma. It allowed the specific diagnosis of an overdose situation or a Munchausen syndrome caused by ingestion of OADs. After liquid-liquid extraction, the OADs glibenclamide, glibornuride, gliclazide, glimepiride, glipizide, gliquidone, glisoxepide, tolazamide and tolbutamide were separated using fast gradient elution. After screening and identification in the scan mode using our new LC-MS library, the OADs were quantified in the selected-ion mode. The quantification assay was validated according to the criteria established by the Journal of Chromatography B. All validation data were inside the required limits. The assay is part of a general LC-MS procedure for fast screening, identification and quantification of different toxicologically relevant compounds in plasma and has proven to be appropriate for OADs.

Administration, Oral↗
PubMed1992

Regulation of basal and luminal cell-specific cytokeratin expression in rat accessory sex organs. Evidence for a new class of androgen-repressed genes and insight into their pairwise control.

Co-expression of cytokeratin (CK) pairs has been found to be associated with specific epithelial cell types whose expressions are developmentally regulated. In the prostate, CK 8 and 18 have been identified as luminal cell-specific markers, and CK 5 and 15 have been identified as basal cell-specific markers. In this study, we report the cloning and sequencing of a full-length CK 8 cDNA (1.9 kilobases) from a rat ventral prostate (VP) cDNA library. Although the open reading frame shares 90% homology with mouse CK 8 sequences, nucleotide comparison revealed that rat CK 8 cDNA comprises a species-specific sequence on both 5' and 3' ends. The steady-state levels of CK 8 mRNA were elevated in VP, seminal vesicle (SV), and liver of a castrated rat but not in the other organs such as the coagulating gland, bladder, and thymus. Unlike the other androgen-repressed genes, elevated CK 8 mRNA levels persisted even after the glandular involution was completed, indicating that CK 8 is a new class of androgen-repressed gene. The regression of CK 8 expression may be androgen receptor-mediated, since androgen but not estrogen administration to castrated hosts repressed the CK 8 mRNA levels, and this effect can be antagonized by the simultaneous administration of an antiandrogen (4-hydroxyflutamide). Immunohistochemical staining of prostatic tissues reveals that the CK 8 filamentous structure is shifted reversibly from a uniform distribution to a predominantly basal surface upon androgen deprivation. We noted that the steady-state levels of CK 8 protein remain rather constant throughout the various hormonal treatment, and the steady-state levels of CK 8 mRNA and the rate of CK 8 protein synthesis are consistently elevated. These results suggest that the turnover rate of CK 8 protein may be elevated in the prostatic epithelium from the castrated host. Similarly, the steady-state levels of CK 15 and 18 mRNA in VP and SV are also repressed in an androgen-dependent manner. These data, taken together, indicate that pairwise control of luminal (and possibly basal) specific cytokeratin gene expression remains intact in both VP and SV tissues and that the levels of CK mRNAs expression are negatively regulated by androgen.

Amino Acid Sequence↗
PubMed2004

Molecular properties that influence oral drug-like behavior.

Pharmaceutical companies are constantly racing to discover the next therapeutic blockbuster. The consensus in the industry is to focus on compounds that are by some measure drug-like, but in order to do this effectively a number of questions must be answered. For example, how should drug-like be defined and how might this definition be used to enhance drug discovery? Has the field moved beyond Lipinski's seminal 'rule-of-five' observations? This review offers a working definition of oral drug-likeness, describes various approaches used in its characterization and discusses its appropriate use. We will focus primarily on the use of computed molecular properties that attempt to predict the oral drug-like behavior of compounds and propose guidelines for the use of observations and trends established in existing datasets to support drug discovery efforts. In particular, this review will demonstrate how trends in simple properties of the data can be used prospectively to compare and prioritize groups of compounds, chemical libraries and different chemical series with greater reliability than for predicting drug-likeness of single compounds. It is the authors' belief, however, that properties or descriptors that will completely separate drug-like space from non-drug-like space are unlikely to be found; the focus should instead lie on overall distributions of drug-like and non-drug-like compounds in the property space that tend to overlap significantly.

Administration, Oral↗
PubMed1995

Iowa's National Laboratory for the study of Rural Telemedicine: a description of a work in progress.

As the federal administration advances the idea of the "information superhighway," many disciplines are being challenged to find ways to use advanced telecommunications to improve access to information, enhance learning opportunities, and achieve higher levels of international competitiveness. Telemedicine, the use of communications technology in the practice of medicine, may change the way rural health care is provided by improving access to medical information, diagnostic tools, and consultations. The information and health care services required by health care professionals are rapidly changing, and dissemination of this information to isolated practitioners has proven to be difficult. By providing support electronically from a central site, the most current information is more readily available. Using test-bed hospitals in rural and urban settings, the National Library of Medicine-funded National Laboratory for the Study of Rural Telemedicine at the University of Iowa is currently developing the necessary infrastructure to support targeted projects studying how telemedicine applications can be made more effective and readily available.

Clinical Laboratory Information Systems↗
PubMed2000

[The efficacy of corticosteroids in exacerbations of chronic obstructive pulmonary disease: meta-analysis of published studies].

BACKGROUND: Corticosteroids are frequently used in exacerbations of chronic obstructive pulmonary disease (COPD), but their efficacy is controversial. We have carried out a systematic review of the literature to clarify this issue. METHODS: We searched Medline, Cochrane Library and Indice Medico Español databases for articles about corticosteroids and COPD. Placebo-controlled studies were selected and reviewed independently by two investigators. RESULTS: We found no studies using inhaled corticosteroids. Six studies analysed the effect of systemic corticosteroids. They showed a significant improvement of FEV1 by three days (weighted mean difference between placebo and treated groups 89 ml; CI 25-153; 4 trials) and by 7-14 days (200 ml; CI 7-393; 3 trials). The duration of hospitalisation was also shorter in patients receiving corticosteroids (p = 0.03). There also was a non-statistically significant trend towards a lower failure rate in treated groups, without differences in mortality rate. At midterm, the differences in FEV1 disappeared. CONCLUSION: Corticosteroid administration by systemic route is associated with a clinically relevant short-term improvement in spyrometric values. Although there are no clear differences in prognostic variables, these data give support to the practice of using these drugs for short periods, not longer than two weeks.

Adrenal Cortex Hormones↗
PubMed1996

Quality assurance for abdominal CT: a rapid, computer-assisted technique.

OBJECTIVE: Maintaining high standards in a large CT imaging department with multiple scanners, a large technical and clerical staff, and a rotating staff of radiologists is an ongoing challenge. We undertook a project to design and implement a simple, rapidly performed computer-assisted system of quality assurance (QA) for use in abdominal CT. In our project, we also analyzed the results of that QA system. MATERIALS AND METHODS: We graded 1810 abdominal CT studies done in a 50-week period, using a three-point scale to indicate the quality of the following five parameters of technical quality: IV contrast enhancement, oral contrast opacification, window settings and artifacts, conformity to radiologists' protocol, and completeness and accuracy of header and scout data. In addition, a parameter reflecting performance of the film library and clerical staff was similarly graded. To provide a measure of peer review for radiologists, any disagreements with prior CT study reports were recorded when comparison studies were reviewed in the process of CT interpretation. A commercially available spreadsheet and database software program was tailored to allow rapid, easily performed data entry and analysis. Tables and graphs showing performance of technologists and film library and clerical staff were generated. This customized program was made available on the radiology department computer network. Results generated by the program were further analyzed with linear regression models. RESULTS: Our QA system was successfully integrated into the routine operation of the abdominal CT division. During the first 11.5 months of operation, the system reflected improvement in each of the technical parameters with a statistically significant improvement in the combined average technical score (from 1.15 to 1.68 on a scale of 0-2; p < .0001). The "Throughout Speed/Old Exams" parameter for performance of the film library and clerical staff, which was analyzed separately from the technical parameters, also improved significantly (from 1.3 to 1.8; p < .02). Improvements were statistically significant, even when we controlled for potential variations in quality among different CT scanners and variations among the radiologists who rated the quality of the examination. Thirty-eight disagreements with previous scan interpretations (5% of all scan comparisons) were recorded for evaluation at peer review conferences. CONCLUSION: The ability to monitor performance continuously using a rapid, computer-assisted system has effected measurable improvement in our CT service. Technologist and film library and clerical staff performance improved for all parameters studied. Deficiencies were revealed and trends demonstrated. The QA system allowed us to identify disagreements in interpretation of CT examinations for subsequent peer review by radiologists. Our QA software program has been made available on the Internet as freeware to licensed Excel users via anonymous file transfer protocol at Internet Protocol 134.192.6.110.

Administration, Oral↗
PubMed2001

Discovery of a non-peptide small molecule that selectively mimics the biological actions of calcitonin.

Calcitonin (CT), a 32-amino acid peptide hormone secreted mainly from the thyroid gland, plays an important role in maintaining bone homeostasis. To discover non-peptide small molecules with biological actions similar to those of CT, a cell-based screening of an in-house chemical library was performed and a pyridone derivative (SUN B8155) was identified. Like CT, it elevated cyclic AMP (cAMP) levels in T47D and UMR106-06 cells which endogenously express human and rat CT receptor, respectively. SUN B8155 also stimulated cAMP formation in cells expressing recombinant human CT receptor, but not in those expressing human parathyroid hormone/parathyroid hormone-related peptide receptor. Accumulation of cAMP in T47D cells was blocked by a selective antagonist of CT receptor, salmon CT(8-32), whereas SUN B8155 did not displace the specific binding of [(125)I]CT to the receptor. Our results suggested that the compound selectively interacts with the CT receptor by a mechanism similar to but probably different from that of CT itself. In rats, intraperitoneal administration of SUN B8155 significantly lowered serum calcium levels, like CT. Our results demonstrate, for the first time, that the biological activities of the newly identified small molecule can mimic that of CT, acting via the CT receptor.

Animals↗
PubMed2003

A comparison of physiochemical property profiles of development and marketed oral drugs.

The process of drug discovery applies rigorous selection pressures. Marketed oral drugs will generally possess favorable physiochemical properties with respect to absorption, metabolism, distribution, and clearance. This paper describes a study in which the distributions of physiochemical properties of oral drugs in different phases of clinical development are compared to those already marketed. The aim is to identify the trends in physiochemical properties that favor a drug's successful passage through clinical development and on to the market. Two libraries were created, one of current development oral drugs and one of marketed oral drugs. Statistical analysis of the two showed that the mean molecular weight of orally administered drugs in development decreases on passing through each of the different clinical phases and gradually converges toward the mean molecular weight of marketed oral drugs. It is also clear that the most lipophilic compounds are being discontinued from development.

Administration, Oral↗
PubMed1990

Tissue-specific expression and androgen regulation of different genes encoding rat prostatic 22-kilodalton glycoproteins homologous to human and rat cystatin.

22-Kilodalton (kDa) protein cDNA clones were isolated from a rat prostatic library. Nucleotide sequence analysis revealed three different cDNA sequences encoding two somewhat different open reading frames of 176 amino acids. The N-terminal 24 amino acids of these sequences show the typical characteristics of signal peptides of secretory proteins. The C-terminal end of the derived protein sequences displays sequence similarity to a number of cysteine proteinase inhibitors, called cystatins, suggesting a common physiological function. Upon Northern blotting with a labeled cDNA fragment, three different 22-kDa protein mRNAs, i.e. 950 nucleotides (nt), 920 nt and 860 nt, could be detected in the rat ventral prostate and the lacrymal gland. In both tissues these messengers were regulated by androgens showing the most rapid androgen response for the 950 nt mRNA form. Administration of cycloheximide nearly completely abolished the observed androgen effect suggesting that a short-living protein is required for the full induction of the 22-kDa protein genes. Hybridization experiments with specific oligonucleotides which distinguish between the mRNAs encoding both 22-kDa protein variants indicate that one protein form is less androgen dependent in the ventral prostate and not expressed in the lacrymal gland.

Amino Acid Sequence↗
PubMed1998

Cloning of rat dihydropyrimidine dehydrogenase and correlation of its mRNA increase in the rat liver with age.

Overlapping cDNAs encoding dihydropyrimidine dehydrogenase (DPD), the rate-limiting enzyme of pyrimidine degradation, were isolated from a rat liver cDNA library, and a 4,353 bp cDNA sequence with a 3,075 bp open reading frame encoding a polypeptide of 1,025 residues with a molecular mass of 111,458 Da was determined. Western blot analysis of COS-7 cells that were transfected with an RT-PCR-derived DPD cDNA showed that the product from the cDNA binds to an anti-serum for DPD. Northern blot analysis was performed by using a partial fragment of the cloned cDNA as a probe. The mRNA level, the protein level, and the activity of DPD in the rat liver increased to the adult level by 3 mo of age. The levels of DPD in the liver of adrenalectomized rats increased 48 h after glucocorticoid administration. The increase of DPD after birth may be caused by the increase in glucocorticoid level.

Aging↗
PubMed2001

Towards integration of clinical decision support in commercial hospital information systems using distributed, reusable software and knowledge components.

PROBLEM: Clinicians' acceptance of clinical decision support depends on its workflow-oriented, context-sensitive accessibility and availability at the point of care, integrated into the Electronic Patient Record (EPR). Commercially available Hospital Information Systems (HIS) often focus on administrative tasks and mostly do not provide additional knowledge based functionality. Their traditionally monolithic and closed software architecture encumbers integration of and interaction with external software modules. Our aim was to develop methods and interfaces to integrate knowledge sources into two different commercial hospital information systems to provide the best decision support possible within the context of available patient data. METHODS: An existing, proven standalone scoring system for acute abdominal pain was supplemented by a communication interface. In both HIS we defined data entry forms and developed individual and reusable mechanisms for data exchange with external software modules. We designed an additional knowledge support frontend which controls data exchange between HIS and the knowledge modules. Finally, we added guidelines and algorithms to the knowledge library. RESULTS: Despite some major drawbacks which resulted mainly from the HIS' closed software architectures we showed exemplary, how external knowledge support can be integrated almost seamlessly into different commercial HIS. This paper describes the prototypical design and current implementation and discusses our experiences.

Abdominal Pain↗
PubMed2003

"Understanding" medical school curriculum content using KnowledgeMap.

OBJECTIVE: To describe the development and evaluation of computational tools to identify concepts within medical curricular documents, using information derived from the National Library of Medicine's Unified Medical Language System (UMLS). The long-term goal of the KnowledgeMap (KM) project is to provide faculty and students with an improved ability to develop, review, and integrate components of the medical school curriculum. DESIGN: The KM concept identifier uses lexical resources partially derived from the UMLS (SPECIALIST lexicon and Metathesaurus), heuristic language processing techniques, and an empirical scoring algorithm. KM differentiates among potentially matching Metathesaurus concepts within a source document. The authors manually identified important "gold standard" biomedical concepts within selected medical school full-content lecture documents and used these documents to compare KM concept recognition with that of a known state-of-the-art "standard"-the National Library of Medicine's MetaMap program. MEASUREMENTS: The number of "gold standard" concepts in each lecture document identified by either KM or MetaMap, and the cause of each failure or relative success in a random subset of documents. RESULTS: For 4,281 "gold standard" concepts, MetaMap matched 78% and KM 82%. Precision for "gold standard" concepts was 85% for MetaMap and 89% for KM. The heuristics of KM accurately matched acronyms, concepts underspecified in the document, and ambiguous matches. The most frequent cause of matching failures was absence of target concepts from the UMLS Metathesaurus. CONCLUSION: The prototypic KM system provided an encouraging rate of concept extraction for representative medical curricular texts. Future versions of KM should be evaluated for their ability to allow administrators, lecturers, and students to navigate through the medical curriculum to locate redundancies, find interrelated information, and identify omissions. In addition, the ability of KM to meet specific, personal information needs should be assessed.

Abstracting and Indexing↗
PubMed1994

Efficacy of nonsteroidal anti-inflammatory drugs in the treatment of acute renal colic. A meta-analysis.

OBJECTIVE: To evaluate the efficacy of nonsteroidal anti-inflammatory drugs (NSAIDs) compared with placebo or analgesic agents in the treatment of acute renal colic. DATA SOURCES: The MEDLINE and EMBASE databases were searched using the following terms: anti-inflammatory agent, colic, kidney diseases, and ureteral diseases. The Family Medicine Library Index, references of retrieved articles, and documentation centers of pharmaceutical companies were also consulted. STUDY SELECTION: Among 60 retrieved articles, 19 were selected by consensus of a group of four physicians, based on the following criteria: randomized controlled trials, NSAID compared with placebo or analgesic agent in the treatment of acute renal colic, and articles written in either French or English. DATA EXTRACTION: Independent data extraction by four evaluators using a 20-item checklist. Final assessment was by group consensus. DATA SYNTHESIS: The 19 articles presented 20 studies, most comparing parenteral diclofenac or indomethacin (18 of 20) with placebo (n = 4) or analgesic agents (n = 16), most of which were narcotic agents. The results of pain relief 20 to 30 minutes after drug administration were pooled using the Mantel-Haenszel method for three distinct groups of studies: (1) NSAIDs vs placebo (n = 4): relative risk (RR), 2.34 (95% confidence interval [CI], 1.79 to 3.07); (2) NSAIDs vs analgesic agents, partial pain relief (n = 9): RR, 1.07 (95% CI, 1.02 to 1.12); and (3) NSAIDs vs analgesic agents, complete pain relief (n = 9): RR, 1.19 (95% CI, 1.03 to 1.37). CONCLUSIONS: Parenteral NSAIDs are more effective than placebo and as effective as analgesic agents in the treatment of acute renal colic.

Acute Disease↗
PubMed2006

Systemic antimicrobial prophylaxis for percutaneous endoscopic gastrostomy.

BACKGROUND: Percutaneous endoscopic gastrostomies (PEG) maintain nutrition in the short or long term. A PEG is a feeding tube, placed surgically through the anterior abdominal wall, which delivers a liquid diet, or medication, via a clean or sterile delivery system. Those undergoing PEG placement are often vulnerable to infection because of age, compromised nutritional intake, immunosuppression and underlying disease processes such as malignancy and diabetes mellitus. The increasing incidence of methicillin-resistant Staphylococcus aureus (MRSA) contributes both an additional risk to the placement procedure, and also to the debate surrounding antibiotic prophylaxis for PEG placement. The aim of surgical antimicrobial prophylaxis is to establish a bactericidal concentration of an antimicrobial drug in the patients serum and tissues, via a brief course of an appropriate agent, by the time of PEG placement. OBJECTIVES: The review seeks to establish whether prophylactic use of systemic antimicrobials reduces the risk of peristomal infection in people undergoing placement of percutaneous endoscopic gastrostomies. SEARCH STRATEGY: We searched the Cochrane Wounds Group Specialised Register (July 2006); The Cochrane Central Register of Controlled Trials (The Cochrane Library 2006, Issue 2); handsearched wound care journals relevant conference proceedings, and bibliographies of relevant publications identified by these strategies for further studies; and contacted manufacturers and distributors of PEG products. SELECTION CRITERIA: Randomised controlled trials (RCTs) evaluating the use of prophylactic antimicrobials for PEG placement, with no restrictions for language, date or publication status. DATA COLLECTION AND ANALYSIS: Both authors performed data extraction and assessment of study quality. Meta-analysis was performed where appropriate. MAIN RESULTS: We identified 10 eligible RCTs evaluating prophylactic antimicrobials in 1100 patients. All trials reported peristomal infection as an outcome, and a pooled analysis resulted in a statistically significant reduction in the incidence of peristomal infection with prophylactic antibiotics (pooled OR 0.31, 95% CI 0.22 to 0.44). AUTHORS' CONCLUSIONS: Administration of systemic prophylactic antibiotics for PEG placement reduces peristomal infection.

Anti-Infective Agents↗
PubMed1991

Cloning and expression of cDNA encoding 25-hydroxyvitamin D3 24-hydroxylase.

A cDNA encoding 25-hydroxyvitamin D3 24-hydroxylase (P450cc24) was isolated from a rat kidney cDNA library using specific antibodies to the enzyme. The isolated cDNA was 3.2 kbp long and contained a 1542-bp open reading frame encoding 514 amino acids. The deduced amino acid sequence contained a presequence typical of mitochondrial enzymes in the N-terminal region. The amino acid sequence shows less than 30% similarity to those of any other cytochrome P450s so far reported and, therefore, P450cc24 constitutes a novel family of P450. COS-7 cells transfected with the cDNA produced a protein that was reactive with the antibodies and catalyzed NADPH-dependent 24-hydroxylation of 25-hydroxyvitamin D3 in the presence of adrenodoxin and NADPH-adrenodoxin reductase. Using the cDNA as a probe we demonstrated that the increase of 24-hydroxylation activity caused by administration of vitamin D3 into rats was accompanied by an increase of the mRNA.

Amino Acid Sequence↗
PubMed2005

Uterine sensitization-associated gene-1 (USAG-1), a novel BMP antagonist expressed in the kidney, accelerates tubular injury.

Dialysis dependency is one of the leading causes of morbidity and mortality in the world, and once end-stage renal disease develops, it cannot be reversed by currently available therapy. Although administration of large doses of bone morphogenetic protein-7 (BMP-7) has been shown to repair established renal injury and improve renal function, the pathophysiological role of endogenous BMP-7 and regulatory mechanism of its activities remain elusive. Here we show that the product of uterine sensitization-associated gene-1 (USAG1), a novel BMP antagonist abundantly expressed in the kidney, is the central negative regulator of BMP function in the kidney and that mice lacking USAG-1 (USAG1 mice) are resistant to renal injury. USAG1 mice exhibited prolonged survival and preserved renal function in acute and chronic renal injury models. Renal BMP signaling, assessed by phosphorylation of Smad proteins, was significantly enhanced in USAG1 mice with renal injury, indicating that the preservation of renal function is attributable to enhancement of endogenous BMP signaling. Furthermore, the administration of neutralizing antibody against BMP-7 abolished renoprotection in USAG1 mice, indicating that USAG-1 plays a critical role in the modulation of renoprotective action of BMP and that inhibition of USAG-1 is a promising means of development of novel treatment for renal diseases.

Adaptor Proteins, Signal Transducing↗
PubMed1999

Systematic review of ondansetron for the prevention and treatment of postoperative nausea and vomiting in adults.

OBJECTIVES: To determine the efficacy and safety of ondansetron for the prevention and treatment of postoperative nausea and vomiting (PONV) in adults. DESIGN: Systematic review of published double-blind randomised controlled trials. DATA SOURCES: Twenty seven trials from 1990 to July 1998 retrieved from a systematic literature search (Medline, Cinahl, Embase, Cochrane Library, reference lists, hand searching of anaesthetic journals, & provided manufacturer information); restricted to English language. MAIN OUTCOME MEASURES: Estimation of efficacy (incidence of complete absence of nausea or other outcome measure as defined by the authors) at 24 hours. RESULTS: Seven double-blind randomised controlled trials with 1,623 patients studied intravenous ondansetron 1 mg, 4 mg, or 8 mg for the treatment of postoperative nausea and vomiting (PONV). Four mg, compared with metoclopramide 10 mg, produced higher patient satisfaction scores and an increased incidence of freedom from nausea at 24 hours. Further studies are required to compare the safety, efficacy and dose response with other anti-emetics at 24 hours. Twenty double-blind randomised controlled trials with 4,364 patients studied intravenous and oral administration of ondansetron 1 mg, 4 mg, and 8 mg for the prevention of postoperative nausea and vomiting. There appears to be no significant difference between droperidol (0.625 mg, 1 mg or 1.25 mg) i.v. and ondansetron 4 mg in efficacy and incidence of side effects. Compared with metoclopramide, ondansetron produced less nausea but the incidence of vomiting was the same at 24 hours. CONCLUSIONS: Further PONV could be prevented with ondansetron 4 mg compared with placebo and metoclopramide 10 mg. Further studies are required to compare ondansetron with other anti-emetics for the treatment of PONV. For prophylaxis of PONV ondansetron 4 mg appears to be equal to low dose droperidol in efficacy and the incidence of side effects, and superior to metoclopramide. Ondansetron should perhaps be limited to second line treatment in view of patient satisfaction, efficacy and cost when compared with droperidol.

Adult↗