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PubMed2002

Serotonergic dysregulation in bipolar disorders: a literature review of serotonergic challenge studies.

OBJECTIVES: Serotonin (5-hydroxytryptamine; 5-HT) and endocrine abnormalities have been repeatedly reported in bipolar disorders (BD). Useful methods to investigate 5-HT responsivity, and the interaction with neuroendocrine functioning, are provided by acute 5-HT challenge and depletion paradigms. In this review 5-HT challenges are limited to paradigms that stimulate 5-HT activity in BD. METHODS: Literature was searched for in electronic libraries: MEDLINE and PSYCHLIT, period 1966-2001. Papers describing effects of an acute 5-HT challenge on neuroendocrine functioning in BD patients were selected. RESULTS: Review of the literature revealed 15 studies: five papers described the effects of 5-HT challenges in manic BD patients, four papers in euthymic BD and seven in depressed BD patients. The reviewed 5-HT challenge paradigms are acute administration of oral and intravenous (i.v.) dosage of d,l-fenfluramine, tryptophan, 5-hydroxytryptophan, ipsapirone and buspirone. There were no papers which investigated neuroendocrine effects of m-chlorophenylpiperazine, clomipramine and citalopram in BD patients and were therefore not reviewed. CONCLUSIONS: The literature on 5-HT challenge procedures in BD shows evidence for a blunted prolactin (PRL) in mania and depression as well as a blunted cortisol in euthymic BD patients. This suggests that in both mania and depression similar changes in the 5-HT system are involved. It is speculated that blunting of cortisol responses in euthymic BD patients may be a result of chronically altered 5-HT functioning, whereas changes in PRL release following 5-HT challenges reflect more state-dependent changes in 5-HT activity. The 5-HT responsivity in BD patients has also been associated with pharmacological treatment, suicidal behaviour, weight loss and age. Recommendations for future research are given.

Bipolar Disorder↗
PubMedDate not supplied

Recommendations for responsible monitoring and regulation of clinical software systems. American Medical Informatics Association, Computer-based Patient Record Institute, Medical Library Association, Association of Academic Health Science Libraries, American Health Information Management Association, American Nurses Association.

In mid-1996, the FDA called for discussions on regulation of clinical software programs as medical devices. In response, a consortium of organizations dedicated to improving health care through information technology has developed recommendations for the responsible regulation and monitoring of clinical software systems by users, vendors, and regulatory agencies. Organizations assisting in development of recommendations, or endorsing the consortium position include the American Medical Informatics Association, the Computer-based Patient Record Institute, the Medical Library Association, the Association of Academic Health Sciences Libraries, the American Health Information Management Association, the American Nurses Association, the Center for Healthcare Information Management, and the American College of Physicians. The consortium proposes four categories of clinical system risks and four classes of measured monitoring and regulatory actions that can be applied strategically based on the level of risk in a given setting. The consortium recommends local oversight of clinical software systems, and adoption by healthcare information system developers of a code of good business practices. Budgetary and other constraints limit the type and number of systems that the FDA can regulate effectively. FDA regulation should exempt most clinical software systems and focus on those systems posing highest clinical risk, with limited opportunities for competent human intervention.

Clinical Medicine↗
PubMed2022

Identification of Novel Retinal Pericyte-Targeting rAAV Vectors Through Directed Evolution.

PURPOSE: Retinal pericytes play a vital role in maintaining retinal homeostasis, and their dysfunction underlies pathogenesis in such vascular eye diseases as diabetic retinopathy and wet age-related macular degeneration. Consequently, retinal pericytes are attractive therapeutic targets for gene therapy, but effectively targeting pericytes with recombinant adeno-associated virus (rAAV) vectors remains a challenge. METHODS: We introduced genetic modifications into the surface-exposed variable regions of the rAAV2/2 capsid to generate a complex library (>1 × 107) of capsid mutants that were then screened for preferential tropism toward retinal pericytes. Using the Tg(Cspg4-DsRed.T1)1Akik/J reporter mouse model, which has red fluorescent pericytes that can be isolated via flow cytometry in order to recover vector genomes, we performed three rounds of screening and identified seven putative mutants capable of transducing retinal pericytes. RESULTS: Following intravitreal administration of mutant vectors packaging ubiquitously expressing green fluorescent protein reporters and postmortem flow cytometry of enzymatically digested retinae, two mutants in particular, Peri-E and Peri-G, demonstrated significantly greater transduction of retinal pericytes than unmodified rAAV2/2 (1.4-fold and 2.8-fold, respectively). CONCLUSIONS: Although difficult to characterize the effect of each point mutation in the context of multiple amino acid variations from the wild-type AAV2 sequence, we identified several point mutations that may play critical roles in limiting HSPG binding, evading neutralization by murine A20 monoclonal antibodies, modulating antigenicity, and evading ubiquitination to ultimately improve transduction efficiency of retinal pericytes. TRANSLATIONAL RELEVANCE: Identification of novel retinal pericyte targeting rAAV vectors enables the development of new, long-lasting gene therapies for retinal diseases such as diabetic retinopathy and wet age-related macular degeneration.

Animals↗
PubMed2003

Optimized expression and specific activity of IL-12 by directed molecular evolution.

DNA delivery of IL-12 has shown promise in reducing the toxic side effects associated with administration of recombinant human (h)IL-12 protein while maintaining the ability to inhibit tumor growth and abolish tumor metastases in animal models. We have developed a more potent version of IL-12 by using DNA shuffling and screening to improve its expression in human cells and specific activity on human T cells. The most improved evolved IL-12 (EvIL-12) derived from seven mammalian genes encoding both the p35 and p40 subunits of IL-12 showed a 128-fold improvement in human T cell proliferation compared with native hIL-12 during the initial screening of supernatants from transected cells. When purified hIL-12 and EvIL-12 proteins were compared in vitro in human T cell proliferation and Th1 differentiation assays, it was demonstrated that EvIL-12 exhibited a concomitant 10-fold increase in the specific activity of the protein compared with hIL-12. Furthermore, DNA shuffling improved the level of expression and homogeneity of the heterodimer synthesized by 293 human embryonic kidney cells transfected with EvIL-12 by at least 10-fold. Molecular analysis of the variant revealed strategic placement of amino acid substitutions that potentially may facilitate heterodimer formation and product expression. The enhanced expression and biological activity of EvIL-12 may improve the effectiveness of IL-12 gene-based vaccines and therapeutics without the toxic side effects sometimes associated with hIL-12 protein administration.

Amino Acid Sequence↗
PubMed2000

Androgen-regulated expression of a novel member of the aldo-keto reductase superfamily in regrowing rat prostate.

The rat prostate is dependent on androgen for normal growth and differentiation. In addition, the organ undergoes rapid cell death upon withdrawal of androgen on castration, and the atrophied tissue is capable of regrowth after androgen replacement in adult animals. In our search for novel factor(s) that participate in this androgen-induced proliferation of adult rat prostate cells, we have generated a complementary DNA (cDNA) library enriched in cDNAs transiently up-regulated after androgen stimulation in castrated rat ventral prostate using a PCR-based subtractive hybridization technique. Sequence analysis of about one hundred clones in the library showed that approximately 70% of them are identical or closely related to genes of known function, the remaining ones showing no or very low similarity to any genes characterized previously. Among the former a new member of the rat aldo-keto reductase superfamily that is closely related to aflatoxin, B1 aldehyde reductase has been identified. The newly identified protein (androgen-inducible aldehyde reductase, AIAR) and rat aflatoxin B1 aldehyde reductase (AFAR) exhibit 80% amino acid sequence homology. The enzymatic activity toward 4-nitrobenzaldehyde of recombinant AIAR expressed in Escherichia coli was about 16% of that of rat AFAR. Northern blot analysis revealed AIAR expression in various adult rat tissues in addition to the ventral and dorsolateral prostates, which differs from the highly restricted expression of AFAR in the kidney and liver. The AIAR messenger RNA (mRNA) content of the ventral prostate was low in normal and castrated rats, transiently increased after androgen administration to castrated rats, attaining a peak 12-24 h after the treatment. Although the physiological substrate(s) of AIAR has not been identified, the current results suggest that AIAR expression is associated with some growth-related processes in regrowing rat prostate.

Aflatoxin B1↗
PubMed1999

Dual regulation of promoter II- and promoter 1f-derived cytochrome P450 aromatase transcripts in equine granulosa cells during human chorionic gonadotropin-induced ovulation: a novel model for the study of aromatase promoter switching.

Estradiol biosynthesis is a key biochemical trait of developing follicles. To study its regulation in equine follicles, the objectives of this study were to clone and determine the structure of equine cytochrome P450 aromatase (P450AROM), and characterize the regulation of P450AROM and P450 17alpha-hydroxylase/C17-20 lyase (P45017alpha) messenger RNAs (mRNAs) in vivo in equine preovulatory follicles isolated during hCG-induced ovulation. Two distinct P450AROM complementary DNAs (cDNAs) were isolated from an equine preovulatory follicle cDNA library. One clone was 2682 bp in length and included 115 bp of 5'-untranslated region (UTR), 1509 bp of open reading frame encoding a well conserved 503-amino acid protein, and 1058 bp of 3'-UTR. Its 5'-most region represented the equine homolog of exon 1f, previously designated brain specific. The other cDNA clone encoded a truncated protein and contained a distinct 5'-UTR characteristic of transcripts derived from promoter II, previously identified as the predominant ovarian mRNA. Northern blot analyses were performed using preovulatory follicles obtained during estrus between 0-39 h after the administration of hCG and with corpora lutea isolated on day 8 of the estrous cycle (day 0 = day of ovulation). The results showed a biphasic regulation of P450AROM mRNA expression: levels were highest in follicles at 0 h post-hCG, decreased significantly during the ovulatory process at 12 and 24 h (P < 0.05), and increased again between 30-39 h post-hCG and in corpora lutea. When oligonucleotides specific for P450AROM mRNA variants were used as probes, a novel switching phenomenon was observed. Promoter II-derived transcripts accounted for the message present in follicles at 0 h post-hCG and in corpora lutea, whereas promoter 1f-derived mRNA was expressed exclusively during the ovulatory process (30-39 h post-hCG). Levels of P45017alpha mRNA were high in follicles at 0 h, but significantly decreased after hCG treatment (P < 0.05), with lowest levels in follicles at 36 and 39 h post-hCG and in corpora lutea. Northern blots performed on isolated cellular preparations revealed that P450AROM and P45017alpha transcripts were localized exclusively in granulosa cells and theca interna, respectively. Equine aromatase promoters II and 1f were cloned from a genomic library, and putative transcription start sites were characterized by primer extension assays. Sequence analyses identified distinct potential regulatory elements in each promoter. Thus, this study identifies a novel aromatase promoter-switching phenomenon in equine granulosa cells during follicular luteinization and provides a new model in which aromatase promoter switching is induced in vivo.

Amino Acid Sequence↗
PubMed2000

Early administration of inhaled corticosteroids for preventing chronic lung disease in ventilated very low birth weight preterm neonates.

BACKGROUND: Chronic lung disease remains a common complication amongst preterm infants. There is increasing evidence that inflammation play an important role in the pathogenesis of CLD. Due to their strong anti-inflammatory properties corticosteroids is an attractive intervention strategy. However, there are growing concerns regarding short and long term effects of systemic corticosteroids. Theoretically, administration of inhaled corticosteroids may allow for beneficial effects on the pulmonary system with a lower risk of undesirable systemic side effects. OBJECTIVES: To determine the impact of inhaled corticosteroids administered to ventilated very low birth weight preterm neonates in the first two weeks of life for the prevention of chronic lung disease(CLD). SEARCH STRATEGY: Systematic search in accordance with Cochrane Neonatal Review Group. Randomized and quasi-randomized trials were identified by searching MEDLINE, Embase, CINAHL, the Cochrane Library, reference lists of published trials and abstracts published in Pediatric Research. SELECTION CRITERIA: Randomized controlled trials of inhaled corticosteroid therapy initiated within the first 2 weeks of life in ventilated preterm infants with birth weight 1500 grams or less were included in this review. DATA COLLECTION AND ANALYSIS: Data regarding clinical outcomes including chronic lung disease at 28 days or 36 weeks corrected gestational age (CGA), mortality, combined outcome of death or CLD at 28 days of age and at 36 weeks CGA, the need for systemic corticosteroids, failure to extubate within 14 days and adverse effects of corticosteroids were evaluated. All data were analyzed using Revman 3.1. When possible, meta-analysis was performed using relative risk (RR), risk difference (RD), along with their 95% confidence intervals (CI). If RD was significant, number needed to treat (NNT) was calculated. MAIN RESULTS: Eight trials assessing the impact of inhaled corticosteroid for the prevention of CLD were identified. The study by Kovacs 1998 was excluded as investigators evaluated the impact of a combination of systemic and inhaled corticosteroid for prevention of CLD. Seven trials qualified for inclusion in this review but data from two of these studies are awaiting assessment. Thus, the present review includes data analyses based on five qualifying trials. There was no statistically significant effect of inhaled steroids on CLD either at 28 days or at 36 weeks CGA, when analyzed either for all randomized infants or amongst survivors. No statistically significant differences were noted for mortality or for the combined outcome of mortality and CLD either at 28 days of age or at 36 weeks CGA. The meta-analysis supports a reduction in the need for systemic steroids, RR 0.78 (95% CI 0.62, 0.99), RD -0. 097 (95% CI -0.187, -0.008); however statistical heterogeneity was noted. The number needed to treat (NNT) to reduce the need for systemic steroid was 10 (95% CI 5.3, 125). There were no statistically significant differences in adverse events between groups. REVIEWER'S CONCLUSIONS: There is no evidence from the trials reviewed that early administration (in the first 2 weeks of life) of inhaled steroids to ventilated preterm neonates was effective in reducing the incidence of CLD. There was a reduction in the need for systemic steroids. Although this difference was statistically significant, there was significant heterogeneity between studies and the upper limit of the 95% CI for this outcome was very close to no effect. Currently, use of inhaled steroids in this population cannot be recommended. Studies are needed to identify the risk/benefit ratio of different delivery techniques and dosing schedules for the administration of these medications. Studies need to address both the short-term and long-term benefits and adverse effects of inhaled steroids with particular attention to neurodevelopmental outcome.

Administration, Inhalation↗
PubMed2001

Single-dose dipyrone for acute postoperative pain.

BACKGROUND: The use of dipyrone as an analgesic is controversial. It is used most commonly to treat postoperative pain, colic pain, cancer pain and migraine, and in many countries, eg, Russia, Spain, Brazil, and in many parts of South-America and Africa, it is the most popular non opioid first line analgesic. In others it has been banned (e.g. USA, UK) because of its association with potentially life-threatening blood dyscrasias such as agranulocytosis. Dipyrone is currently available in Austria, Belgium, France, Germany, Italy, The Netherlands, Spain, Switzerland, South Africa, Latin America, Russia, Israel and India. OBJECTIVES: To assess quantitatively the analgesic efficacy and adverse effects of single-dose dipyrone in randomised trials in moderate to severe postoperative pain. To compare the relative efficacy of dipyrone with other drugs assessed in the same way. SEARCH STRATEGY: Published reports were identified from Medline, Embase, the Cochrane Library (Issue 3 1999), LILACs and the Oxford Pain Relief Database. Additional studies were identified from bibliographies of retrieved reports. Date of the most recent search: December 1999. SELECTION CRITERIA: The following inclusion criteria were used: full journal publication, clinical trial, random allocation of patients to treatment groups, double-blind design, adult patients, pain of moderate to severe intensity at the baseline assessment, postoperative administration of study drugs, treatment arms which included dipyrone and placebo or active control and oral, rectal, intramuscular or intravenous administration of study drugs. DATA COLLECTION AND ANALYSIS: Summed pain intensity and pain relief data over 4-6 hours were extracted and converted into dichotomous information to yield the number of patients who obtained at least 50% pain relief. This was used to calculate the proportion of patients with, and number-needed-to-treat for, at least 50% pain relief over 4-6 hours. Single-dose adverse effect data were collected. MAIN RESULTS: Fifteen studies were included; eight used placebo and seven used an active control (oral dexketoprofen 12.5 mg or 25 mg, oral ketorolac 10 mg, intramuscular pethidine 100 mg or ketorolac 30 mg, intravenous tramadol 100 mg or rectal suprofen 300 mg). In five trials (288 patients) the mean response rate (proportion of patients with at least 50% pain relief) for single dose oral dipyrone 500 mg was 73% (range 54% to 87%) and with placebo it was 32% (19% to 41%) in moderate to severe postoperative pain over 4-6 hours. In two studies (113 patients) the response rate with oral dipyrone 1 g was 69% (61% and 77%) and with placebo it was 20% (11% and 25%). In one study (70 patients) the response rate with intramuscular dipyrone 2 g was 74% and with placebo it was 46%. No analyses could be conducted for adverse effects. The response rates in the active controlled trials were similar to those reported in the placebo controlled trials. REVIEWER'S CONCLUSIONS: Single-dose dipyrone appears to be of similar efficacy to ibuprofen 400 mg and other analgesics frequently used in the treatment of moderate to severe postoperative pain. The commonest adverse effects were somnolence, gastric discomfort and nausea.

Acute Disease↗
PubMed2003

Ketamine as an adjuvant to opioids for cancer pain.

BACKGROUND: Ketamine is a commonly used anaesthetic agent, and in subanaesthetic doses is also given as an adjuvant to opioids for the treatment of cancer pain, particularly when opioids alone prove to be ineffective. Ketamine is known to have hallucinogenic side effects. To date no systematic review of the benefits and harms of adjuvant ketamine for cancer pain has been undertaken. OBJECTIVES: To determine the effectiveness and adverse effects of ketamine as an adjuvant to opioids in the treatment of cancer pain. SEARCH STRATEGY: Studies were identified from MEDLINE (1966-2001), EMBASE (1980-2001), CancerLit (1966-2001), the Cochrane Library (Issue 1, 2001); by handsearching reference lists from review articles, trials, and chapters from standard textbooks on pain and palliative care. The manufacturer of ketamine (Pfizer Parke-Davis) provided search results from their in-house database, PARDLARS. SELECTION CRITERIA: RCTs of adult patients with cancer and pain being treated with an opioid, and receiving either ketamine (any dose and any route of administration) or placebo or an active control. DATA COLLECTION AND ANALYSIS: Two independent reviewers identified four RCTs for possible inclusion in the review, and 32 case studies/case series reports. Quality and validity assessment was performed by three independent reviewers, and two RCTs were excluded because of inappropriate study design. Patient reported pain intensity and pain relief was assessed using visual analog scales, verbal rating scales or other validated scales, and adverse effects data were collated. MAIN RESULTS: Two trials were eligible for inclusion in the review and both concluded that ketamine improves the effectiveness of morphine in the treatment of cancer pain. However, pooling of the data was not appropriate because of the small total number of patients (30), and the presence of clinical heterogeneity. Some patients experienced hallucinations on both ketamine plus morphine and morphine alone and were treated successfully with diazepam. No other serious adverse effects were reported. REVIEWER'S CONCLUSIONS: Current evidence is insufficient to assess the benefits and harms of ketamine as an adjuvant to opioids for the relief of cancer pain. More randomized controlled trials are needed.

Adult↗
PubMed1984

Molecular cloning of hormone-responsive genes from the yeast Saccharomyces cerevisiae.

A method for identifying yeast genes whose transcription is differentially regulated was developed. The technique is based on incorporation of the analog 4-thiouridine into nascent RNAs, which allows their purification. The purified RNAs are used to prepare cDNA copies for screening of genomic DNA libraries by hybridization. Using this procedure, several cloned yeast DNA segments were found whose transcription in MATa haploids in vivo is apparently modulated in dramatic fashion within 10-15 min after exposure to the mating pheromone, alpha factor. Subsequent analysis indicated that these sequences fall into three major classes: (i) genes expressed in vegetatively growing cells that are no longer transcribed after alpha-factor administration ("turn-off" genes); (ii) genes whose expression is increased 10- to 20-fold after exposure of the MATa cells to alpha factor ("turn-up" genes); and (iii) genes that are expressed only after alpha-factor treatment ("turn-on" genes). The first class may encode products required for cell cycle progression; the third class may code for products uniquely involved in the mating process.

Animals↗
PubMed2007

Meta-analysis of risk of malignancy with immunosuppressive drugs in inflammatory bowel disease.

BACKGROUND: There is a concern as to whether long-term administration of immunosuppressants in patients with inflammatory bowel disease (IBD) would increase the risk of malignancy. OBJECTIVE: To compare the risks of developing malignancy between patients with IBD treated with immunosuppressive agents and patients with IBD not receiving these agents. METHODS: A systematic literature review was conducted, and a meta-analysis was performed on data retrieved from cohort studies that followed patients with IBD who received immunosuppressive agents for more than a year and documented the incidence of newly developed malignancy. An electronic search was conducted using MEDLINE (1966-September 2006), the Cochrane Library (issue 3, 2006), and Japana Centra Revuo Medicina (1981-September 2006). Medical subject headings used in the searches were azathioprine, 6-mercaptopurine, cyclosporine, methotrexate, tacrolimus, inflammatory bowel disease, and neoplasms. We imposed no language limitation in the searches. Additionally, a manual search of reference listings from all articles retrieved from the electronic databases was performed. Using data obtained from control groups or population-based studies, the incidence of newly developed malignancy in patients with IBD treated with immunosuppressive agents was compared with that of patients with IBD who were not receiving immunosuppressive agents. Statistical analysis for the change in risk of developing malignancy was performed using the weighted mean difference (WMD) normalized to per person-year and its 95% confidence interval. RESULTS: Nine cohort studies met the inclusion criteria for this meta-analysis. Analysis of these studies showed no discernible difference (WMD -0.3 x 10(-3)/person-year; 95% CI -1.2 x 10(-3) to 0.7 x 10(-3)) in the incidence of any kind of malignancy in patients with IBD who received immunosuppressants compared with those who did not receive immunosuppressants. No significant difference in WMD was observed when the data from patients with either Crohn's disease (CD) or ulcerative colitis (UC) were analyzed separately. CONCLUSIONS: Our findings suggest that the administration of immunosuppressive agents in patients with either CD or UC probably does not confer a significantly increased risk of malignancy compared with patients with IBD who are not receiving these agents.

Cohort Studies↗
PubMed2002

Rabbit epididymal secretory proteins. III. Molecular cloning and characterization of the complementary DNA for REP38.

REP38 is a rabbit epididymal secretory protein of 38 kDa that has recently been shown to interact with spermatozoa. A rabbit epididymal cDNA expression library was screened with a polyclonal antibody raised against REP38. A single clone (REP38-c1) with an open reading frame encoding a polypeptide of 666 amino acids was obtained. Cleavage of a 22-amino acid N-terminal signal peptide revealed a mature protein with a theoretical molecular mass of 74.5 kDa. Northern blot analysis revealed the presence of two cross-hybridizing transcripts of approximately 1.3 and 2.5 kilobases that appear to result from alternative mRNA splicing. This finding may explain the discrepancies between the observed (38 kDa) and deduced molecular mass of REP38. Expression of both transcripts was epididymis specific and was detected only in regions 2-6. During development, the expression of REP38-c1 mRNA was initiated between 1 and 2 mo postnatum and therefore precedes the appearance of sperm within the lumen of the epididymis. These findings are in agreement with the immunohistochemical localization of the REP38 protein. Androgen deprivation induced by orchidectomy reduced REP38-c1 mRNA levels below the limit of detection, an effect that was reversed by administration of exogenous testosterone. Although REP38-c1 mRNA was detected only in the rabbit epididymis, database searches indicated homology with two rat testis specific cDNAs, KTT4 and odf2, which encode sperm outer dense fiber proteins.

Amino Acid Sequence↗
PubMed1999

Use of Caco-2 cells and LC/MS/MS to screen a peptide combinatorial library for permeable structures.

The transepithelial transport of a synthetic peptide combinatorial library containing 375,000 individual peptides was assessed using Caco-2 cell monolayers in order to screen for permeability and deliverability. A series of 150 pools, each containing 2500 tripeptide sequences, were applied to the apical side of Caco-2 monolayers. Basolateral side samples were collected after 4 h and screened by capillary high-pressure liquid chromatography. The majority of pools showed no permeable species, due to low solubility, limited permeability and extensive metabolism. Several pools contained permeable structure, and transport proved reproducible with passage number and time. Permeable structures were identified by liquid chromatography/mass spectrometry/mass spectrometry (LC/MS/MS). To discriminate between isobaric structures, several tripeptides were resynthesized and tested as discrete compounds. For example, 1-2% D-Phe-D-Ala-D-Ser-OH was transported across the Caco-2 cell monolayer with a Papp value of 0.35-0.69 x 10(-6) cm/s, which is comparable with the permeability of amino acids (Leu, Papp = 0.30 x 10(-6) cm/s) and dipeptides (L-Val-L-Val, Papp = 0.18 x 10(-6) cm/s) (Lennernas, H., Palm, K., Fagerholm, U., Artursson, P., 1996. Comparison between active and passive drug transport in human intestinal epithelial (Caco-2) cells in vitro and human jejunum in vivo. Int. J. Pharm. 127, 103-107; Tamura, K., Bhatnagar, P.K., Takata, J.S., Lee, C.P., Smith, P.L., Borchardt, R.T., 1996. Metabolism, uptake, and transepithelial transport of the diastereomers of Val-Val in the human intestinal cell line Caco-2. Pharm. Res. 13, 1213-1218). These studies demonstrate the techniques used to screen combinatorial libraries for permeability across Caco-2 cells and structurally identify the resulting compounds. Such methodology can be of importance in the achievement of structure-permeability relationships, useful in the design of pharmaceutically bioavailable drugs.

Administration, Oral↗
PubMed1999

Recognizing molecules with drug-like properties.

A variety of successful approaches to the problem of recognizing 'drug-like' molecules have been employed. These range from simple counting schemes such as the Lipinski 'rule of five' to the analysis of the multidimensional 'chemistry space' occupied by drugs, to neural network learning systems. With this variety of tools, it now appears possible to design libraries that are enriched in compounds which have desirable or 'drug-like' properties. Verifying the robustness of these methods, and extending them, will form the basis of research in this field during the next few years.

Administration, Oral↗
PubMed1999

The Brigham integrated computing system (BICS): advanced clinical systems in an academic hospital environment.

The Brigham integrated computing system (BICS) provides nearly all clinical, administrative, and financial computing services to Brigham and Women's Hospital, an academic tertiary-care hospital in Boston. The BICS clinical information system includes a very wide range of data and applications, including results review, longitudinal medical records, provider order entry, critical pathway management, operating-room dynamic scheduling, critical-event detection and altering, dynamic coverage lists, automated inpatient summaries, and an online reference library. BICS design emphasizes direct physician interaction and extensive clinical decision support. Impact studies have demonstrated significant value of the system in preventing adverse events and in saving costs, particularly for medications.

Computer Security↗
PubMed2007

Challenges to macromolecular drug delivery.

The use of macromolecules, particularly monoclonal antibodies, as therapeutic agents has come to the forefront in recent years. The biodistribution and delivery issues for protein drugs are shared to a substantial degree with other emerging therapeutic approaches including pharmacologically active nucleic acids and nanoparticles. A generalized approach to these issues involves consideration of the multiple biological barriers that stand between the macromolecular drug or nanoparticle at its site of administration and its ultimate biological target. Considerations of size, stability, non-specific versus specific associations and potency versus toxicity all play a role. The creation of delivery approaches that combine high specificity for the target cell or tissue, high therapeutic payload and modest toxicity remains a challenge, although some very promising examples have emerged recently. A variety of sophisticated targeting strategies, based primarily on combinatorial library methods, when used in combination with new technologies to identify cell-surface receptor 'signatures' of specific tissues, will facilitate advances in targeted delivery of macromolecules and nanoparticles. The challenges to contemporary macromolecule drug delivery are complex, thus new research paradigms are emerging that combine the talents of physical and biological scientists to address this key issue for modern pharmacology and therapeutics.

Antibodies, Monoclonal↗
PubMed1998

Identification of the integral membrane protein RM3/1 on human monocytes as a glucocorticoid-inducible member of the scavenger receptor cysteine-rich family (CD163).

The RM3/1 Ag is a membrane glycoprotein restricted to human monocytes and macrophages that evolve in the late phase of inflammation. Peptide sequence analysis of the RM3/1 protein revealed similarity to CD163, a member of the scavenger receptor cysteine-rich family. Using specific Abs (RM3/1, Ki-M8), we demonstrate an identical cellular regulation for the RM3/1 and the CD163 protein. Most notably, we show for the first time that CD163 is significantly up-regulated by glucocorticoids. In contrast, the protein is down-regulated by the immunosuppressant cyclosporin A and by phorbol esters, while the inflammatory mediator LPS has no significant influence on the expression. We describe the first isolation of a full-length cDNA of CD163 and expression of the corresponding protein. Several splice variants of CD163 exist, and we elucidated the kinetics of induction of three major mRNA splice variants by fluticasone propionate; another splice variant was proved to be unresponsive to this glucocorticoid. Taken together with a previous result showing an involvement of RM3/1 in adhesion of monocytes to the activated endothelium, we discuss that CD163 might play an important role in inflammatory processes.

Administration, Topical↗
PubMed2006

One dose per day compared to multiple doses per day of gentamicin for treatment of suspected or proven sepsis in neonates.

BACKGROUND: Gentamicin is widely used in the treatment of suspected or proven neonatal sepsis. Animal studies and systematic reviews from trials in older children and adults suggest that a one dose per day regimen is superior to a multiple doses per day regimen. Pharmacokinetic studies and retrospective audits in neonatal population also favour once a day administration of gentamicin. However, there is no consensus regarding the dose interval regimen in the neonatal population. OBJECTIVES: To compare the efficacy and safety of one dose per day compared to multiple doses per day of gentamicin in suspected or proven sepsis in neonates. SEARCH STRATEGY: Eligible studies were identified by searching MEDLINE (March 2005), EMBASE 1980 - 2004, Oxford Database of Perinatal Trials, Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library, Issue 2, 2005) and CINAHL (December 1982 - March 2005). Abstracts of the Society for Pediatric Research were hand searched from 1980 to 2004 inclusive. No language restrictions were applied. SELECTION CRITERIA: All randomised or quasi randomised controlled trials comparing one dose per day ( 'once a day') compared to multiple doses per day ( 'multiple doses a day') of gentamicin to newborn infants < 28 days of life. DATA COLLECTION AND ANALYSIS: Methodological quality of eligible studies was assessed according to allocation concealment, blinding of intervention, blinding of outcome assessment and completeness of follow up. Data were sought regarding effects on clinical efficacy, pharmacokinetic efficacy, ototoxicity and nephrotoxicity of the two regimens. When appropriate, meta-analysis was conducted to provide a pooled estimate of effect. For categorical data, the typical relative risk (RR), typical risk difference (RD) and number needed to treat (NNT) with 95% confidence intervals (CI) were calculated. Continuous data were analysed using weighted mean difference (WMD). MAIN RESULTS: Twenty four studies were initially identified. Thirteen were excluded and eleven studies (N = 574) included. All studies compared the effectiveness and safety of 'once a day' versus 'multiple doses a day' regimen of gentamicin in newborn infants. Only one study enrolled infants less than 32 weeks gestation. All except one trial used intravenous infusion. One trial used gentamicin as a bolus dose over one minute. Two trials used intramuscular gentamicin in some of their study infants. For the primary outcome of 'clearance of sepsis', all infants in both 'once a day' as well as 'multiple doses a day' regimen showed adequate clearance of sepsis [Typical RD 0.00 (95% CI - 0.19, 0.19); 3 trials; N = 36]. For the other primary outcome measures relating to gentamicin pharmacokinetics, 'once a day dosing' of gentamicin was superior. 'Once a day' gentamicin regimen is associated with less failures to attain peak level of at least 5 microg/ml [Typical RR 0.22 (95% CI 0.11, 0.47); Typical RD -0.13 (95% CI -0.19, -0.08); 9 trials; N = 422]; less failures to achieve trough levels of < 2 microg/ml [Typical RR 0.38 (95% CI 0.27, 0.55); Typical RD -0.22 (95% CI -0.29, -0.15); 11 trials N = 503]; higher peak levels [WMD 2.58 (95% CI 2.26, 2.89); 10 trials; N = 440] and lower trough levels [WMD -0.57 (95% CI -0.69, -0.44); 10 trials; N = 440] compared to 'multiple doses a day' regimen. Ototoxicity and nephrotoxicity were not noted with either of the treatment regimens. Significant heterogeneity was noted for some of the outcomes measured. Hence the results need to be interpreted with caution. Possible reasons for heterogeneity are different gestational ages of study infants and the timing of collection of blood samples in relation to a particular dose and the day of therapy on which the samples were collected. AUTHORS' CONCLUSIONS: There is insufficient evidence from the currently available RCTs to conclude whether 'once a day' or 'multiple doses a day' regimen of gentamicin is superior in treating proven neonatal sepsis. However data suggests that pharmacokinetic properties of 'once a day' gentamicin regimen are superior to 'multiple doses a day' regimen in that it achieves higher peak levels while avoiding toxic trough levels. There is no change in nephrotoxicity or auditory toxicity. Based on this assessment of pharmacokinetics, 'once a day regimen' may be superior in treating neonatal sepsis in neonates more than 32 weeks gestation.

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