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PubMed1997

Cloning and characterization of a complementary DNA for a thyroid hormone-responsive protein in mature rat cerebral tissue.

A gene responsive to thyroid hormone (TH) has been identified in the adult rat brain cerebral tissue. A cDNA probe differentially expressed in euthyroid, hypothyroid and hyperthyroid rat cerebral tissue, generated by reverse transcriptase-PCR differential display of mRNA, was used to screen the rat brain cDNA library. A 3.4 kb positive clone hybridized in Northern blots with a 3.8 kb mRNA that proved to be TH responsive (THR). The remaining coding sequence and a part of the 5' untranslated region of this cDNA were obtained by 5' rapid amplification of cDNA ends. The deduced amino acid sequence revealed that THR protein (THRP), a 68 kDa moiety, has 83% sequence similarity with c-Abl interactor protein (Abi-2), which is a substrate for tyrosine kinase activity of c-Abl. The extensive similarity between the two proteins suggests a potential role for THRP as a substrate for c-Abl. Northern analysis showed that the expression of THR mRNA in hyperthyroid rats is 6-fold that in euthyroid rats. There is also a 4-6-fold increase in the concentration of THRP, as analysed by Western analysis. Owing to the extensive similarity between rat THRP and human Abi-2, a polyclonal anti- (human Abi-2) antibody was successfully used for Western analysis of proteins from the rat tissues. The observed increase in both the mRNA and the protein did not decline after beta-adrenergic system blockade with propranolol, suggesting that the action of TH on the expression of this gene is not mediated through the beta-adrenergic system. Immunohistochemical studies revealed that neuronal cells were particularly rich in THRP. Both THR mRNA and THRP are rapidly induced in vivo after intravenous administration of thyroxine. Tissue distribution studies indicated that the cerebral tissue was particularly enriched with THR mRNA and 68 kDa THRP. A cDNA clone for a THR gene could provide a useful tool to study the molecular mechanisms of TH effects on cerebral tissue in adult animals.

Adaptor Proteins, Signal Transducing↗
PubMed2004

Evidence report on the treatment of pain in cancer patients.

Pain associated with cancer is of widespread concern. We conducted a systematic review to evaluate the best available evidence on the efficacy of treatments of cancer-related pain. The sources used were MEDLINE, CancerLit, and the Cochrane Library from 1966 through April 2001, as well as bibliographies of meta-analyses and review articles. We selected randomized controlled trials (RCTs) reporting on cancer pain treatment. We recorded the study characteristics, patient and disease characteristics, treatment comparisons, outcome measures, and results. The methodological quality, applicability, and magnitude of treatment effect for each study were graded. We screened 24 822 titles and selected 213 RCTs to address specific questions. RCTs of cancer pain control often enroll few subjects, have low methodological quality, offer little detail about pain characteristics and mechanisms, and involve heterogeneous interventions and outcomes. Nonsteroidal anti-inflammatory drugs (NSAIDs), opioids, selected adjuvant medications, bisphosphonates, radionuclides, external radiation, palliative chemotherapy, and neurolytic celiac plexus block are each efficacious in relieving cancer pain. However, the retrieved RCTs indicate no difference in the analgesic efficacies of NSAIDs versus other NSAIDs, NSAIDs plus opioids versus NSAIDs alone, or NSAIDs versus opioids. Studies of adjuvant medications and behavioral therapies are too few and varied to synthesize. RCTs of the analgesic effects of corticosteroids were not retrieved in our review, although we did conduct supplemental evidence reviews concerning pain control in oral mucositis, acute herpes zoster, or postherpetic neuralgia. RCTs confirm the efficacy of diverse interventions in relieving cancer pain. The optimal initial and subsequent sequence of choices among analgesic drug types cannot be inferred from the retrieved RCTs. Patient preferences, the relative efficacy of different routes of drug administration, the side effects of analgesics, and the relation of pain control to quality of life have not been studied comprehensively. The quantity and quality of scientific evidence on cancer pain relief compare unfavorably with evidence related to treatment of other high-impact conditions, including cancer itself. One contributor to this gap is the heterogeneity of outcomes instruments employed: of 218 retrieved trials, there were 125 distinct pain outcomes assessed. In the current era of patient-centered care, improving the quality and combinability of trials on cancer pain relief should be a high research priority.

Analgesics, Opioid↗
PubMed2001

A review of the chemistry, biological action, and clinical applications of anabolic-androgenic steroids.

BACKGROUND: Since its discovery in 1935, numerous derivatives of testosterone have been synthesized, with the goals of prolonging its biological activity in vivo, producing orally active androgens, and developing products, commonly referred to as anabolic-androgenic steroids (AAS), that are more anabolic and less androgenic than the parent molecule. OBJECTIVE: This article reviews the structure, biotransformation, and mechanism of action of testosterone and some of the most commonly used AAS. Clinical applications of the AAS are discussed, and guidelines and therapeutic maneuvers for minimizing their side effects are outlined. METHODS: Literature for inclusion in this review was identified using the libraries of the University of Wisconsin Medical School and School of Pharmacy, the author's files, and searches of MEDLINE, Science Citation Index, Biological Abstracts, and Chemical Abstracts. RESULTS: The myotrophic action of testosterone and its derivatives and their stimulatory effects on the brain have led to widespread use of AAS by athletes and "recreational" drug users. Consequently, all AAS were classified as class III controlled substances in 1991. Nonetheless, AAS have shown benefit in a variety of human disorders, including HIV-related muscle wasting and other catabolic conditions such as chronic obstructive pulmonary disease, severe burn injuries, and alcoholic hepatitis. Because of their diverse biological actions, AAS have been used to treat a variety of other conditions, including bone marrow failure syndromes, constitutional growth retardation in children, and hereditary angioedema. AAS therapy is associated with various side effects that are generally dose related; therefore, illicit use of megadoses of AAS for the purpose of bodybuilding and enhancement of athletic performance can lead to serious and irreversible organ damage. The most common side effects of AAS are some degree of masculinization in women and children, behavioral changes (eg, aggression), hepatotoxicity, and alteration of blood lipid levels and coagulation factors. CONCLUSIONS: To minimize or avoid serious toxicities with AAS therapy, close medical supervision and periodic monitoring are important, with dose adjustment as appropriate to achieve the minimum effective dose. Given the biological effects and potential adverse effects of AAS, administration of these agents should be avoided in pregnant women, women with breast cancer or hypercalcemia, men with carcinoma of the prostate or breast, and patients with nephrotic syndromes or significant liver dysfunction.

Anabolic Agents↗
PubMed2006

A nonadherent cell-based HTS assay for N-type calcium channel using calcium 3 dye.

The N-type calcium channel is a member of the voltage-sensitive calcium channel family and plays a major role in the regulation of neurotransmitter release in the central and peripheral nervous systems. Inhibition of the N-type calcium channel by intrathecal administration of the channel-specific blocker omega-conotoxin MVIIA (ziconotide) is efficacious in the treatment of severe chronic pain. While no orally active small molecules that block the N-type calcium channel are currently available, the discovery of such potentially valuable therapeutics would benefit from a reliable, high throughput assay. However, the assay of N-type calcium channel activity by measuring calcium influx using nonadherent cells in a high throughput fashion has not been achieved before, likely owing to a number of technical hurdles. For example, the measurement of calcium levels in nonadherent cells using conventional calcium indicators, such as Fluo-3 or Fluo-4, requires dyeloading the cells in suspension and subsequent removal of extracellular dye. This limits plate throughput and requires constant handling of the cells. To assay the N-type calcium channel activity using a nonadherent cell line in a high throughput manner, we investigated the application of no-wash calcium assay kits from Molecular Devices Corp. (Sunnyvale, CA): FLIPR Calcium, FLIPR Calcium Plus, and FLIPR Calcium 3. We show here that the FLIPR Calcium 3 assay kit can be used with nonadherent IMR-32 cells to measure potassium-evoked, omega-conotoxin MVIIA-reversible calcium flux with high throughput (15,000 data points/day), high quality (Z approximately 0.6), and minimal handling of the cells. Thus, this assay can be used to reliably and efficiently screen large compound libraries in the search for small molecule N-type calcium channel blockers.

Calcium↗
PubMed2006

Duration of treatment with vitamin K antagonists in symptomatic venous thromboembolism.

BACKGROUND: Currently, the most frequently used secondary treatment for patients with venous thromboembolism is vitamin K antagonists targeted at an INR of 2.5 (range 2.0 to 3.0). However, based on the continuing risk of bleeding and uncertainty regarding the risk of recurrent venous thromboembolism, there is discussion on the proper duration of treatment with vitamin K antagonists for these patients. Recently, several studies were published in which the risk and benefits of different durations of oral anticoagulants were compared in patients with venous thromboembolism. OBJECTIVES: The objective of this review was to evaluate efficacy and safety of different durations of treatment with vitamin K antagonists in patients with symptomatic venous thromboembolism. SEARCH STRATEGY: The Cochrane Peripheral Vascular Diseases Group searched their Specialised Register and the Cochrane Central Register of Controlled Trials (CENTRAL) in The Cochrane Library Issue 3, 2005). The Specialised Register is constructed from electronic searches of MEDLINE (from inception to October 2005) and EMBASE (inception to October 2005) and through handsearching relevant journals. In addition, we also contacted colleagues for details of trials. The last searches were carried out on 11 October 2005. SELECTION CRITERIA: Randomized controlled clinical trials comparing different durations of treatment with vitamin K antagonists in patients with symptomatic venous thromboembolism. DATA COLLECTION AND ANALYSIS: Two reviewers (BH and MP) extracted the data and assessed the quality of the trials independently. MAIN RESULTS: Eight studies with a total of 2994 patients were included. A consistent reduction in the risk of recurrent events was observed during prolonged treatment with vitamin K antagonists (OR 0.18; 95% CI 0.13 to 0.26) independent of the period elapsed since the index thrombotic event. A 'rebound' phenomenon, i.e. an excess of recurrences shortly after cessation of the prolonged treatment was not observed (OR 1.24; 95% CI 0.91 to 1.69). In addition, a substantial increase in bleeding complications was found during the entire period after randomization (OR 2.62; 95% CI 1.48 to 4.61). AUTHORS' CONCLUSIONS: In conclusion, this meta-analysis shows that treatment with vitamin K antagonists reduces the risk of recurrent venous thromboembolism for as long as it is used. However, the absolute risk of recurrent venous thromboembolism declines over time, while the risk for major bleeding remains. Thus, the efficacy of vitamin K antagonist administration decreases over time since the index event.

Anticoagulants↗
PubMed1995

Pharmacological characterization of PD 156707, an orally active ETA receptor antagonist.

We describe the pharmacological characteristics of PD 156707 (sodium 2-benzo[1,3]dioxol-5-yl-4-(4-methoxy-phenyl)-4-oxo-3-(3,4,5- trimethoxy-benzyl)-but-2-enoate), a potent, orally active, nonpeptide antagonist of the endothelin A (ETA) receptor subtype. PD 156707 was designed on the basis of a compound identified by screening the Parke-Davis chemical library. PD 156707 is highly selective for the ETA receptor (ETAR) and inhibits the binding of [125I]-ET-1 to cloned human ETAR and ETBR with Ki values of 0.17 and 133.8 nM, respectively. PD 156707 antagonizes ET-1-stimulated phosphoinositide hydrolysis in Ltk- cells expressing cloned human ETAR with an IC50 value of 2.4 nM. PD 156707 inhibits vasoconstriction in isolated blood vessels mediated by ETAR (rabbit femoral artery) and ETBR (rabbit pulmonary artery) with pA2 values of 7.5 and 4.7, respectively. PD 156707 administered orally to rats blocked subsequent ETAR-mediated pressor responses in vivo but had no effect on ETBR-mediated dilator responses. As a potent and orally active ETA-selective antagonist, PD 156707 will be useful in defining the physiological and pathological roles of ETAR.

Administration, Oral↗
PubMed1988

Liver (B-type) phosphofructokinase mRNA. Cloning, structure, and expression.

Mouse liver mRNA enriched in sequences coding for liver phosphofructokinase by polysome immunoadsorption was used as a template for the synthesis of cDNA. The double-stranded cDNA was inserted into the expression vector lambda gt11 and cloned. Preliminary identification of clones containing cDNA sequences for phosphofructokinase was made by screening the library with anti-rat liver phosphofructokinase serum and horseradish peroxidase-conjugated goat anti-rabbit IgG as second antibody. Subsequently, by selecting antibodies specific to fusion proteins expressed by putative clones and by reacting with Western blots of mouse liver proteins several clones were positively identified as containing liver phosphofructokinase sequences. A cDNA clone corresponding to 2708 nucleotides of liver phosphofructokinase mRNA was further characterized and sequenced. The liver phosphofructokinase mRNA has an open reading frame of 2343 nucleotides followed by a 3'-untranslated region of 303 nucleotides. The G/C-rich (76%) portion of the 5'-untranslated region precedes a characteristic translational start site of CCGCC(AUG). The mRNA coding sequence indicates that the liver phosphofructokinase subunit is composed of 780 amino acid residues and has a Mr of 85,000. Comparison of the deduced amino acid sequence of mouse liver phosphofructokinase with the known rabbit muscle phosphofructokinase shows 68% homology. The N-half of the liver phosphofructokinase has conserved substrate binding sites for ATP and fructose-6-P. The 25 C-terminal residues, which contain the ATP inhibitory site, are the least homologous (20%) but contain a putative phosphorylation site (Arg-Arg-X-X-Ser). The liver phosphofructokinase mRNA is under nutritional and hormonal regulation. The liver phosphofructokinase mRNA level increased 4-fold when previously starved mice were refed a high carbohydrate, fat-free diet. This increase in mRNA level was blocked by 50% by the administration of dibutyryl cAMP. The induction of liver phosphofructokinase mRNA by fasting/refeeding was also diminished in streptozotocin diabetic mice.

Amino Acid Sequence↗
PubMed2007

New beta-alanine derivatives are orally available glucagon receptor antagonists.

A weak human glucagon receptor antagonist with an IC50 of 7 microM was initially found by screening of libraries originally targeted to mimic the binding of the glucagon-like peptide (GLP-1) hormone to its receptor. Optimization of this hit for binding affinity for the glucagon receptor led to ligands with affinity in the nanomolar range. In addition to receptor binding, optimization efforts were made to stabilize the molecules against fast metabolic turnover. A potent antagonist of the human human glucagon receptor was obtained that had 17% oral availability in rats with a plasma half-life of 90 min. The major metabolites of this lead were identified and used to further optimize this series with respect to pharmacokinetic properties. This final optimization led to a potent glucagon antagonist that was orally available in rats and dogs and was efficacious in lowering blood glucose levels in a diabetic animal model.

Administration, Oral↗
PubMed2004

Oral antispastic drugs in nonprogressive neurologic diseases: a systematic review.

OBJECTIVE: To assess the efficacy of oral drugs in the treatment of spasticity in patients with nonprogressive neurologic disease (NPND). METHODS: Systematic review of double-blind randomized controlled trials of antispastic oral drugs in the treatment of spasticity in NPND. DATA SOURCES: Electronic MEDLINE, PubMed, Cochrane Library, and hand searches. RESULTS: Twelve studies (469 patients) were included (6 on stroke, 3 on spinal cord diseases, and 3 on cerebral palsy). Tizanidine was assessed in four trials (276 patients, 142 exposed), dantrolene in four (103, 93), baclofen in three (70, 55), diazepam in two (127, 76), and gabapentin in one (28, all exposed). Most trials were of small size, of short duration, and their methodologic quality was inadequate. Ten trials were controlled with placebo and only two were direct comparisons between drugs. Efficacy outcome variables were heterogeneous. Only four reports described the magnitude of the antispastic effect. The incidence of adverse drug effects (drowsiness, sedation, and muscle weakness) was high. CONCLUSION: Evidence on the efficacy of oral antispastic drugs in NPND is weak and does not include evaluation of patients' quality of life. If any, efficacy is marginal. Adverse drug reactions were common. Better methodologic instruments are needed for the evaluation of antispastic treatment.

Administration, Oral↗
PubMed2005

Antibiotic regimens for secondary peritonitis of gastrointestinal origin in adults.

BACKGROUND: Secondary peritonitis is associated with a high mortality rate and if not treated successfully leads to development of abscesses, severe sepsis and multi-organ failure. Source control and adjunctive antibiotics are the mainstay of treatment. However, no conclusive evidence suggest that one antibiotic regimen is better than any other but at the same time have a lower toxicity. OBJECTIVES: To ascertain the efficacy and adverse effects of different antibiotic regimens in treating intra-abdominal infections in adults. Outcomes were divided into primary (clinical success and effectiveness in reducing mortality) and secondary (microbiological success, preventing wound infection, intra-abdominal abscess, clinical sepsis, remote infection, superinfection, adverse reactions, duration of treatment required, effectiveness in reducing hospitalised stay, and time to defervescence). SEARCH STRATEGY: We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (Cochrane Library, Issue 4, 2004), MEDLINE (from 1966 to November 2004), EMBASE (from 1980 to November 2004) and Cochrane Colorectal Cancer Group specialised register SR-COLOCA. Bibliographies of identified studies were screened for further relevant trials. SELECTION CRITERIA: Randomised and quasi-randomised controlled trials comparing different antibiotic regimens in the treatment of secondary peritonitis in adults were selected. Trials reporting gynaecological or traumatic peritonitis were excluded from this review. Ambiguity regarding suitability of trials were discussed among the review team. DATA COLLECTION AND ANALYSIS: Six reviewers independently assessed trial quality and extracted data. Data collection was standardised using data collection form to ensure uniformity among reviewers. Statistical analyses were performed using the random effects model and the results expressed as odds ratio for dichotomous outcomes, or weight mean difference for continuous data with 95% confidence intervals. MAIN RESULTS: Fourty studies with 5094 patients met the inclusion criteria. Sixteen different comparative antibiotic regimens were reported. All antibiotics showed equivocal comparability in terms of clinical success. Mortality did not differ between the regimens. Despite the potential high toxicity profile of regimens using aminoglycosides, this was not demonstrated in this review. The reason for this could be the inherent bias within clinical trials in the form of patient selection and stringency in monitoring drug levels. AUTHORS' CONCLUSIONS: No specific recommendations can be made for the first line treatment of secondary peritonitis in adults with antibiotics, as all regimens showed equivocal efficacy. Other factors such as local guidelines and preferences, ease of administration, costs and availability must therefore be taken into consideration in deciding the antibiotic regimen of choice. Future trials should attempt to stratify patients and perform intention-to-treat analysis to allow better external validity.

Anti-Bacterial Agents↗
PubMed2001

Interferon-kappa, a novel type I interferon expressed in human keratinocytes.

High throughput cDNA sequencing has led to the identification of interferon-kappa, a novel subclass of type I interferon that displays approximately 30% homology to other family members. Interferon-kappa consists of 207 amino acids, including a 27-amino acid signal peptide and a series of cysteines conserved in type I interferons. The gene encoding interferon-kappa is located on the short arm of chromosome 9 adjacent to the type I interferon gene cluster and is selectively expressed in epidermal keratinocytes. Expression of interferon-kappa is significantly enhanced in keratinocytes upon viral infection, upon exposure to double-stranded RNA, or upon treatment with either interferon-gamma or interferon-beta. Administration of interferon-kappa recombinant protein imparts cellular protection against viral infection in a species-specific manner. Interferon-kappa activates the interferon-stimulated response element signaling pathway and a panel of genes similar to those regulated by other type I interferons including anti-viral mediators and transcriptional regulators. An antibody that neutralizes the type I interferon receptor completely blocks interferon-kappa signaling, demonstrating that interferon-kappa utilizes the same receptor as other type I interferons. Interferon-kappa therefore defines a novel subclass of type I interferon that is expressed in keratinocytes and expands the repertoire of known proteins mediating host defense.

Amino Acid Sequence↗
PubMed2006

Emergency department patient classification systems: A systematic review.

BACKGROUND: The emergency department is a dynamic environment with a high throughput of patients. The clinical stability of patients varies considerably. In order to provide optimal care for patients a responsive staffing pattern is required. There is a need for a valid and reliable, prospective, emergency department patient classification system to set adequate nurse staffing levels in the UK. AIMS AND OBJECTIVES: To conduct a systematic review of the literature and determine the validity, reliability, strengths and weaknesses of emergency department patient classification systems. METHODS: The following electronic databases were searched for years 1985-2004: MEDLINE; CINAHL; COCHRANE Library databases DARE, CDSR, CCTR, BioMedNet Reviews, National Research Register (NRR). Manual searches were also conducted and relevant references retrieved from those listed in key papers, reports, theses and dissertations. Studies were also retrieved by contacting researchers in the field. RESULTS: Twelve patient classification systems met all the inclusion criteria. Only three systems reported evidence of good validity and reliability: the ED Patient Needs Matrix developed in the US, the Conner's Tool (a modified version of the ED Patient Needs Matrix) developed in Australia and the Jones Dependency Tool developed in the UK. CONCLUSION: There are very few patient classification systems developed for use in the ED setting that have demonstrated good validity and reliability. The Jones Dependency Tool is a simple, easy to use prospective, patient classification system that has demonstrated good validity and reliability in the UK.

APACHE↗
PubMed2002

Identification of potent and novel alpha4beta1 antagonists using in silico screening.

The antigen alpha4beta1 (very late antigen-4, VLA-4) plays an important role in the migration of white blood cells to sites of inflammation. It has been implicated in the pathology of a variety of diseases including asthma, multiple sclerosis, and rheumatoid arthritis. We describe a series of potent inhibitors of alpha4beta1 that were discovered using computational screening for replacements of the peptide region of an existing tetrapeptide-based alpha4beta1 inhibitor (1; 4-[N'-(2-methylphenyl)ureido]phenylacetyl-Leu-Asp-Val) derived from fibronectin. The search query was constructed using a model of 1 that was based upon the X-ray conformation of the related integrin-binding region of vascular cell adhesion molecule-1 (VCAM-1). The 3D search query consisted of the N-terminal cap and the carboxyl side chain of 1 because, upon the basis of existing structure-activity data on this series, these were known to be critical for high-affinity binding to alpha4beta1. The computational screen identified 12 reagents from a virtual library of 8624 molecules as satisfying the model and our synthetic filters. All of the synthesized compounds tested inhibit alpha4beta1 association with VCAM-1, with the most potent compound having an IC(50) of 1 nM, comparable to the starting compound. Using CATALYST, a 3D QSAR was generated that rationalizes the variation in activities of these alpha4beta1 antagonists. The most potent compound was evaluated in a sheep model of asthma, and a 30 mg nebulized dose was able to inhibit early and late airway responses in allergic sheep following antigen challenge and prevented the development of nonspecific airway hyperresponsiveness to carbachol. Our results demonstrate that it is possible to rapidly identify nonpeptidic replacements of integrin peptide antagonists. This approach should be useful in identification of nonpeptidic alpha4beta1 inhibitors with improved pharmacokinetic properties relative to their peptidic counterparts.

Administration, Inhalation↗
PubMed2002

Heparin for prolonging peripheral intravenous catheter use in neonates.

BACKGROUND: Peripheral intravenous (PIV) catheters are widely used in modern medical practice. However, mechanical or infectious complications often necessitate their removal and/or replacement. Heparin has been shown to be effective in prolonging the patency of peripheral arterial catheters and central venous catheters, but may result in life threatening complications, especially in preterm neonates. OBJECTIVES: The primary objective was to determine the effectiveness of heparin versus placebo or no treatment on duration of PIV catheter patency, defined as number of hours of catheter use. The secondary objectives were to assess the effects of heparin on catheter blockage, phlebitis or thrombophlebitis, catheter related sepsis, and complications including abnormality of coagulation profile, allergic reactions to heparin, heparin induced thrombocytopenia, intraventricular/intracranial hemorrhage and mortality. SEARCH STRATEGY: A literature search was performed using the following databases: MEDLINE (1966-December 2001), EMBASE (1980-December 2001), CINAHL (1982-December 2001), Cochrane Controlled Trials Register (The Cochrane Library, Issue 4, 2001), and abstracts from the annual meetings of the Society for Pediatric Research, American Pediatric Society and Pediatric Academic Societies published in Pediatric Research (1991-2001). No language restrictions were applied. SELECTION CRITERIA: Randomized or quasi-randomized trials of heparin administered as flush or infusion versus placebo or no treatment were included. Studies which included a neonatal population and reported on at least one of the outcomes were included. DATA COLLECTION AND ANALYSIS: The methodological quality of the studies was assessed using criteria for blinding of randomization, blinding of intervention, completeness of follow-up and blinding of outcome assessment. Data on relevant outcomes were extracted and the effect size was estimated by calculating WMD (weighted mean difference, 95%CI), RR (relative risk, 95% CI) and RD (risk difference, 95% CI). MAIN RESULTS: Eight eligible studies were identified. Heparin was administered either as a flush solution or as an additive to the total parenteral nutrition solution. Five studies reported data on the duration of use of the first catheter. Two of these studies found no statistically significant effect of heparin; two studies showed a statistically significant increase and one study showed a statistically significant decrease in the duration of PIV catheter use in the heparin group. The results were not combined for meta-analysis due to significant heterogeneity of the treatment effect (p<0.01). In addition, there were marked differences between the studies in terms of the methodological quality, the dose, the timing, the route of administration of heparin and the outcomes reported. From a limited number of studies, there were no significant differences between the heparin and the placebo/no treatment groups in the risks of infiltration, phlebitis and intracranial hemorrhage. REVIEWER'S CONCLUSIONS IMPLICATIONS FOR PRACTICE: The effect of heparin on the duration of peripheral intravenous catheter use varied across the studies. Because of clinical heterogeneity and heterogeneity in treatment effect, recommendations for heparin use in neonates with PIV catheters cannot be made. IMPLICATIONS FOR RESEARCH: There are insufficient data concerning the effect of heparin for prolonging PIV catheter use in neonates. Further research on the effectiveness, the optimal dose, and the safety of heparin is required.

Anticoagulants↗
PubMed2005

Heparin for prolonging peripheral intravenous catheter use in neonates.

BACKGROUND: Peripheral intravenous (PIV) catheters are widely used in modern medical practice. However, mechanical or infectious complications often necessitate their removal and/or replacement. Heparin has been shown to be effective in prolonging the patency of peripheral arterial catheters and central venous catheters, but may result in life threatening complications, especially in preterm neonates. OBJECTIVES: The primary objective was to determine the effectiveness of heparin versus placebo or no treatment on duration of PIV catheter patency, defined as number of hours of catheter use. The secondary objectives were to assess the effects of heparin on catheter blockage, phlebitis or thrombophlebitis, catheter related sepsis, and complications including abnormality of coagulation profile, allergic reactions to heparin, heparin induced thrombocytopenia, intraventricular/intracranial hemorrhage and mortality. SEARCH STRATEGY: A literature search was performed using the following databases: MEDLINE (1966-February 2005), EMBASE (1980-February 2005), CINAHL (1982-February 2005), Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library, Issue 1, 2005), and abstracts from the annual meetings of the Society for Pediatric Research, American Pediatric Society and Pediatric Academic Societies published in Pediatric Research (1991-2004). No language restrictions were applied. SELECTION CRITERIA: Randomized or quasi-randomized trials of heparin administered as flush or infusion versus placebo or no treatment were included. Studies which included a neonatal population and reported on at least one of the outcomes were included. DATA COLLECTION AND ANALYSIS: The methodological quality of the studies was assessed using criteria for blinding of randomization, blinding of intervention, completeness of follow-up and blinding of outcome assessment. Data on relevant outcomes were extracted and the effect size was estimated by calculating WMD (weighted mean difference, 95%CI), RR (relative risk, 95% CI) and RD (risk difference, 95% CI). MAIN RESULTS: Ten eligible studies were identified. Heparin was administered either as a flush solution, or as an additive to the total parenteral nutrition solution. Five studies reported data on the duration of use of the first catheter. Two of these studies found no statistically significant effect of heparin; two studies showed a statistically significant increase and one study showed a statistically significant decrease in the duration of PIV catheter use in the heparin group. The results were not combined for meta-analysis due to significant heterogeneity of the treatment effect (p < 0.01). In addition, there were marked differences between the studies in terms of the methodological quality, the dose, the timing, the route of administration of heparin and the outcomes reported. From a limited number of studies, there were no significant differences between the heparin and the placebo/no treatment groups in the risks of infiltration, phlebitis and intracranial hemorrhage. AUTHORS' CONCLUSIONS IMPLICATIONS FOR PRACTICE: The effect of heparin on the duration of peripheral intravenous catheter use varied across the studies. Because of clinical heterogeneity and heterogeneity in treatment effect, recommendations for heparin use in neonates with PIV catheters cannot be made. IMPLICATIONS FOR RESEARCH: There are insufficient data concerning the effect of heparin for prolonging PIV catheter use in neonates. Further research on the effectiveness, the optimal dose, and the safety of heparin is required.

Anticoagulants↗
PubMed2002

[Effectiveness of inhaled corticosteroids in chronic obstructive lung disease: systematic review].

BACKGROUND: Inhaled corticosteroids are increasingly being used in patients with chronic obstructive lung disease (COPD), but their effectiveness is disputed. The aim of this study was to define the clinical effectiveness of inhaled corticosteroids in non-asthmatic COPD by a systematic review of the literature. MATERIAL AND METHOD: Literature searches were conducted in Medline, the Cochrane library and the Spanish Medical Index. Only placebo-controlled trials were included. All trials were reviewed by two authors and data were extracted in a pre-defined manner. Meta-analytic techniques were used to estimate global effects when data were comparable. RESULTS: No clinical trials on the role of inhaled corticosteroids during COPD exacerbations were found. Twelve studies on patients under a stable condition were identified and included in the review. Short-term studies showed that inhaled corticosteroids induced a small increase in FEV1 (average: 96 ml after 1-6 months). Longer term studies indicated that after 1-3 years of continued therapy, FEV1 was higher in treated than in control patients, but the difference was small (51 ml, CI 3-98). There were no consistent effects on symptom scores or the frequency of exacerbations. CONCLUSION: The results of this review do not support the systematic use of inhaled corticosteroids in patients with non-asthmatic COPD.

Administration, Inhalation↗
PubMed2005

[Portable coagulometers: a systematic review of the evidence on self-management of oral anticoagulant treatment].

BACKGROUND AND OBJECTIVE: We aimed to systematically review the scientific evidence about the use of portable coagulometers for patient's self-management of oral anticoagulant treatment. MATERIAL AND METHOD: Systematic review of scientific evidence available from MEDLINE'S, DARE's, HTA-Database's, NHS-EED's and The Cochrane Library' s bibliographic databases, from their origin to March 2003. Randomized control trials (RCT) and Quasi-Experimental trials were selected provided that they compared patients in self-management with patients under usual care. The quality of scientific evidence was elicited using the Scottish Intercollegiate Guideline Network (SIGN) recommendations, whilst efficacy and security were descriptively summarized. RESULTS: Twelve (7 RCT and 5 quasi-experimental trials) articles were found, and only two of them provided grade A recommendation. Patients under self-management remained the same or more time in the therapeutic range. The incidence of adverse effects in self-management patients was the same or less than that in patients under usual care. CONCLUSIONS: The quality of the scientific evidence is heterogeneous. For selected patients, patient's self-management is at least as effective and safe as usual care. New oral anticaogulants, which have shown promising results, should be scrutinized for future changes in service provision.

Administration, Oral↗
PubMed2005

A novel series of non-carboxylic acid, non-hydantoin inhibitors of aldose reductase with potent oral activity in diabetic rat models: 6-(5-chloro-3-methylbenzofuran-2-sulfonyl)-2H-pyridazin-3-one and congeners.

Discovery of a highly selective, potent, and safe non-carboxylic acid, non-hydantoin inhibitor of aldose reductase (AR) capable of potently blocking the excess glucose flux through the polyol pathway that prevails under diabetic conditions has been a long-standing challenge. In response, we did high-throughput screening of our internal libraries of compounds and identified 6-phenylsulfonylpyridazin-2H-3-one, 8, which showed modest inhibition of AR, both in vitro and in vivo. Initial structure-activity relationships concentrated on phenyl substituents and led to 6-(2,4-dichlorophenylsulfonyl)-2H-pyridazin-3-one, 8l, which was more potent than 8, both in vitro and in vivo. Incorporation of extant literature findings with other aldose reductase inhibitors, including zopolrestat, resulted in the title inhibitor, 19m, which is one of the most potent and highly selective non-carboxylic acid, non-hydantoin inhibitors of AR yet described (IC50, 1 nM; ED90 vs sciatic nerve sorbitol and fructose, respectively, 0.8 and 4.0 mg/kg). In rats, its oral bioavailability is 98% and it has a favorable plasma t(1/2) (26 +/- 3 h).

Administration, Oral↗