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PubMed2003

Single-chain antibody and its derivatives directed against vascular endothelial growth factor: application for antiangiogenic gene therapy.

Single-chain antibodies (scFv) have an enormous potential for clinical application. However, rapid blood clearance and difficulties in large-scale production of active scFvs have limited the practical use of these antibody fragments. Recently, an anti-vascular endothelial growth factor (VEGF) scFv (scFv V65) was selected in our laboratory from a human antibody phage-display library. This antibody was able to reduce tumor growth in mice by approximately 50%. Here, we employ a gene therapy strategy for sustained in vivo expression of scFv V65 and its derivatives. scFv fusion proteins containing parts of the constant IgG1 region were generated (minibody and scFv V65-Fc) to increase the serum half-life of the scFv V65. Systemic administration of recombinant adenovirus encoding scFv V65 resulted in substantial tumor inhibition. This effect could be improved by multiple virus injections. We found that the efficacy of different scFv V65 formats was dependent on the mode of administration: whereas scFv V65-Fc was the most efficient when expressed locally, scFv V65 was superior when delivered systemically. Our results show that therapeutic levels of scFv V65 can be obtained by systemic injection of recombinant adenoviruses. Therefore, therapeutic gene delivery of scFv is a feasible strategy that overcomes several limitations of conventional antibody therapy.

Adenoviridae↗

PubMed1982

cDNA cloning and analysis of chick-embryo-liver cytochrome P-450 mRNA induced by porphyrinogenic drugs.

Hepatic microsomal cytochrome P-450 was elevated in 17-day chick embryos by combined administration of the porphyrinogenic drugs 2-allyl-2-isopropylacetamide and 3,5-diethoxycarbonyl-1,4-dihydrocollidine. Increased apoprotein levels were the result of de novo protein synthesis; in vitro obtained translation data suggested that cytochrome P-450 mRNA levels were elevated. A 1000-base cDNA sequence for the drug-induced cytochrome P-450 mRNA was isolated from a chick embryo cDNA 'library' and this was used as a specific probe to investigate drug-mediated induction of cytochrome P-450 mRNA. RNA-DNA 'dot' hybridisation studies demonstrated that drug treatment led to a 3-5-fold increase in the level of this mRNA and that the mRNA was predominantly associated with membrane-bound polyribosomes. Treatment of embryos with the drugs individually demonstrated that both of them induced synthesis of the same mRNA. These studies show directly that treatment of chick embryos with 2-allyl-2-isopropylacetamide or 3,5-diethoxycarbonyl-1,4-dihydrocollidine caused increased levels of cytochrome P-450 mRNA and suggest that this involved increased transcription of the gene.

Acetamides↗

PubMed2001

Hematopoietic growth factor mimetics.

Hematopoietic growth factors are glycoproteins of 15-70 kDa. Although much clinical success has been obtained using recombinant proteins produced in mammalian cell lines and in microbial fermentation processes, the full-length polypeptides necessarily are expensive to produce, require parenteral administration, and in some cases have provoked detrimental immune responses. With the availability of high throughput biological function and receptor binding assays it has become possible to screen millions, if not billions, of randomly produced organic compounds and relatively short peptides to identify lead compounds for the development of small molecular mimetics of hematopoietic growth factors. Herein the strategies used to screen libraries of small molecules and peptides and the successes in finding mimetics and antagonists for/to erythropoietin, granulocyte colony-stimulating factor, and thrombopoietin are reviewed. Finally, the structural study of mimetic-receptor complexes has provided us with many molecular details of growth factor-induced receptor activation and is likely to yield new insights into the molecular basis of hematopoietic signal transduction.

Amino Acid Sequence↗

PubMed2004

Model system for high-throughput screening of novel human immunodeficiency virus protease inhibitors in Escherichia coli.

Novel human immunodeficiency virus (HIV) protease inhibitors are urgently needed for combating the drug-resistance problem in the fight against AIDS. To facilitate lead discovery of HIV protease inhibitors, we have developed a safe, convenient, and cost-effective Escherichia coli-based assay system. This E. coli-based system involves coexpression of an engineered beta-galactosidase as an HIV protease substrate and the HIV protease precursor comprising the transframe region and the protease domain. Autoprocessing of the HIV protease precursor releases the mature HIV protease. Subsequently, the HIV protease cleaves beta-galactosidase, resulting in a loss of the beta-galactosidase activity, which can be detected in high-throughput screens. Using Food and Drug Administration-approved HIV protease inhibitors, this E. coli-based system is validated as a surrogate screening system for identifying inhibitors that not only possess inhibitory activity against HIV protease but also have solubility and permeability for in vivo activity. The usefulness of the E. coli-based system was demonstrated with the identification of a novel HIV protease inhibitor from a library of compounds that were prepared by an amide-forming reaction with transition-state analog cores. A novel inhibitor with a sulfonamide core of amprenavir, E2, has shown good correlation with the in vitro enzymatic assay and in vivo E. coli-based system. This system can also be used to generate drug resistance profiles that could be used to suggest therapeutic uses of HIV protease inhibitors to treat the drug-resistant HIV strains. This simple yet efficient E. coli system not only represents a screening platform for high-throughput identification of leads targeting the HIV proteases but also can be adapted to all other classes of proteases.

Amides↗

PubMed1990

Isolation from adult human serum of four insulin-like growth factor (IGF) binding proteins and molecular cloning of one of them that is increased by IGF I administration and in extrapancreatic tumor hypoglycemia.

We have isolated four insulin-like growth factor binding proteins (IGFBPs) from adult human serum by insulin-like growth factor (IGF) I affinity chromatography and high performance liquid chromatography. A 36-kDa binding protein (BP), not digestible with N-glycanase, is increased in patients with extrapancreatic tumor hypoglycemia and during IGF I administration in healthy adults. Its 38 NH2-terminal amino acids are identical to those of an IGFBP sequence derived from a human cDNA that cross-hybridizes with the rat IGFBP-2 cDNA. With probes encoding a NH2-terminal, COOH-terminal, and a middle region of this protein we have obtained three cDNA clones from a Hep G2 cDNA library; one encodes human IGFBP-2, and the other two presumably represent unspliced heteronuclear and alternatively spliced mRNA, respectively. A 28-30-kDa IGFBP represents a novel BP species in human serum. Its 30 NH2-terminal amino acids are not homologous to IGFBP-1, -2, or -3. It is not digestible with N-glycanase and does not bind 125I-IGF I. The NH2-terminal sequences of a 42/45- and a 31-kDa IGFBP are identical to that of human IGFBP-3. The 42/45-kDa proteins are two glycosylation variants of BP-3. The 31-kDa protein presumably is a degradation product of BP-3 that lacks the COOH terminus. It is likely that the different IGFBPs modulate auto-/paracrine and endocrine effects of IGFs on growth and metabolism in a different and specific manner.

Adult↗

PubMed2004

Identifying and communicating the contributions of library and information services in hospitals and academic health sciences centers.

OBJECTIVE: This article introduces a systematic approach to identifying and communicating the value of library and information services (LIS) from the perspective of their contributions to achieving organizational goals. METHODS: The contributions of library and information services (CLIS) approach for identifying and communicating the value of LIS draws on findings from a multimethod study of hospitals and academic health sciences centers. RESULTS: The CLIS approach is based on the concept that an individual unit's value to an organization can be demonstrated by identifying and measuring its contributions to organizational goals. The CLIS approach involves seven steps: (1) selecting appropriate organizational goals that are meaningful in a specific setting; (2) linking LIS contributions to organizational goals; (3) obtaining data from users on the correspondence between LIS contributions and LIS services; (4) selecting measures for LIS services; (5) collecting and analyzing data for the selected measures; (6) planning and sustaining communication with administrators about LIS contributions; and (7) evaluating findings and revising selected goals, contributions, and services as necessary. CONCLUSIONS: The taxonomy of LIS contributions and the CLIS approach emerged from research conducted in hospitals and academic health sciences centers and reflect the mission and goals common in these organizations. However, both the taxonomy and the CLIS approach may be adapted for communicating the value of LIS in other settings.

Academic Medical Centers↗

PubMed2006

Treatment of excessive anticoagulation with phytonadione (vitamin K): a meta-analysis.

BACKGROUND: Patients taking oral anticoagulants with an international normalized ratio (INR) greater than 4.0 are at increased risk for bleeding. We performed a meta-analysis to determine the effectiveness of phytonadione (vitamin K) in treating excessive anticoagulation. METHODS: The MEDLINE, EMBASE, and Cochrane Library databases were searched (without language restrictions) for articles published between January 1985 and September 2004. Randomized controlled trials or prospective, nonrandomized trials that used vitamin K to treat patients without major hemorrhage with an INR greater than 4.0 due to oral anticoagulant use were included. The primary outcome was achievement of the target INR (1.8-4.0) at 24 hours after vitamin K administration. Summary estimates were calculated using a random effects model. RESULTS: Twenty-one studies (10 randomized and 11 prospective trials) were included. Among oral vitamin K treatment arms (4, n = 75), the proportion with a target INR at 24 hours was 82% (95% confidence interval [CI], 70%-93%), which was similar to intravenous vitamin K treatment arms (6, n = 69; target INR, 77%; 95% CI, 60%-95%). Treatment arms of subcutaneous vitamin K (3, n = 58; 31%; 95% CI, 7%-55%) and placebo/observation (2, n = 27; 20%; 95% CI, 0%-47%) were less likely to achieve target INR at 24 hours. Only 1 of 21 trials appropriately assessed for adverse events, so a summary estimate for bleeding risk could not be generated. CONCLUSIONS: Limited evidence suggests that oral and intravenous vitamin K are equivalent and more effective for excessive anticoagulation than simply withholding warfarin sodium. Subcutaneous vitamin K, however, is inferior to oral and intravenous vitamin K for this indication and is similar to placebo. Whether treatment with vitamin K decreases hemorrhagic events cannot be determined from the published literature.

Anticoagulants↗

PubMed2004

Zuclopenthixol acetate for acute schizophrenia and similar serious mental illnesses.

BACKGROUND: Medication used for acute aggression in psychiatry must have rapid onset of effect, low frequency of administration and low levels of adverse effects. Zuclopenthixol acetate is said to have these properties. OBJECTIVES: To estimate the clinical effects of zuclopenthixol acetate for the management of acute aggression or violence thought to be due to serious mental illnesses, in comparison to other drugs used to treat similar conditions. SEARCH STRATEGY: We supplemented past searches of Current Controlled Trials (10/2000), the Cochrane Library (1997) and MEDLINE (1966-1997) and appeals for unpublished data with an update search of the Cochrane Schizophrenia Group's Register of trials (September 2003). SELECTION CRITERIA: All randomised clinical trials involving people thought to have serious mental illnesses comparing zuclopenthixol acetate with other drugs. DATA COLLECTION AND ANALYSIS: Data were extracted independently by two reviewers and cross-checked. We calculated fixed effects relative risks (RR) and 95% confidence intervals (CI) for dichotomous data. Where possible, the number needed to treat/harm statistic (NNT/H) was calculated. We analyzed by intention-to-treat. Mean differences were used for continuous variables. MAIN RESULTS: We found no data for the primary outcome, tranquilisation. Compared with haloperidol, zuclopenthixol acetate was no more sedating at two hours (n=40, 1 RCT, RR 0.60 CI 0.27 to 1.34). People given zuclopenthixol acetate were not at reduced risk of being given supplementary antipsychotics (n=134, 3 RCTs, RR 1.49 CI 0.97 to 2.30) although additional use of benzodiazepines was less (n=50, 1 RCT, RR 0.03 CI 0.00 to 0.47, NNT 2 CI 2 to 4). People given zuclopenthixol acetate had fewer injections over seven days compared with those allocated to haloperidol IM (n=70, 1 RCT, RR 0.39 CI 0.18 to 0.84, NNT 4 CI 3 to 14). We found no data on more episodes of aggression or harm to self or others. One trial (n=148) reported no significant difference in adverse effects for people receiving zuclopenthixol acetate compared with those allocated haloperidol at one, three and six days (RR 0.74 CI 0.43 to 1.27). Compared with haloperidol or clotiapine, people allocated zuclopenthixol did not seem to be at more risk of a range of movement disorders (<20%). Three studies found no difference in the proportion of people getting blurred vision/ dry mouth (n=192, 2 RCTs, RR at 24 hours 0.90 CI 0.48 to 1.70). Similarly dizziness was equally infrequent for those allocated zuclopenthixol acetate compared with haloperidol (n=192, 2 RCTs, RR at 24 hours 1.15 CI 0.46 to 2.88). There was no difference between treatments for leaving the study before completion (n=522, RR 0.85 CI 0.31 to 2.31). REVIEWERS' CONCLUSIONS: Recommendations on the use of zuclopenthixol acetate for the management of psychiatric emergencies in preference to 'standard' treatment have to be viewed with caution. Most trials present important methodological flaws and findings are poorly reported. This review did not find any suggestion that zuclopenthixol acetate is more or less effective in controlling aggressive acute psychosis, or in preventing adverse effects than intramuscular haloperidol, and neither seemed to have a rapid onset of action. Well-conducted pragmatic randomised controlled trials are needed.

Acute Disease↗

PubMed2006

Oxygen therapy in the pre-hospital setting for acute exacerbations of chronic obstructive pulmonary disease.

BACKGROUND: Chronic obstructive pulmonary disease (COPD), a leading cause of morbidity and mortality in the developed world, is characterised by acute deterioration in symptoms. During these exacerbations, people are prone to developing alveolar hypoventilation, which may be contributed to by the administration of high inspired oxygen concentrations. OBJECTIVES: The objective of the review was to determine the effect of different inspired oxygen concentrations ("high flow" compared to "controlled") in the pre-hospital setting on outcome for people with acute exacerbations of COPD. SEARCH STRATEGY: We searched the Cochrane Airways Group Specialised Register (August 2005), the Cochrane Central Register of Controlled Trials (The Cochrane Library Issue 3, 2005), MEDLINE (1966 to August 2005), EMBASE (1980 to wk 32, 2005), CINAHL (1982 to August wk 1, 2005) and reference lists of articles. We also contacted authors of identified RCTs for details of other relevant, published and unpublished studies. SELECTION CRITERIA: Randomised controlled trials comparing oxygen therapy at different concentrations or oxygen therapy versus placebo in the pre-hospital setting for treatment of acute exacerbations of COPD were eligible. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed trial quality and extracted data. MAIN RESULTS: The search identified a total of 741 abstracts, of which 18 were selected as potentially relevant, only two of the 18 studies were randomised controlled trials and eligible for inclusion in the review, but were ongoing and had no data available for analysis. AUTHORS' CONCLUSIONS: No relevant trials have been published to date, so there is no evidence to indicate whether different oxygen therapies in the pre-hospital setting have an effect on outcome for people with acute exacerbations of COPD. There is an urgent need for robust, well-designed randomised controlled trials to investigate the effect of oxygen therapies in the pre-hospital setting for people with acute exacerbations of COPD.

Emergency Medical Services↗

PubMed2000

Anorexigenic cocaine- and amphetamine-regulated transcript peptide intensifies fear reactions in rats.

An increasing number of appetite-regulating peptides are being discovered. The list of regulators inhibiting food intake is considerably longer than that of appetite stimulators. In many cases, the peptides inhibiting food intake facilitate fear reactions, whereas the majority of the agents reducing anxiety responses stimulate appetite. Cocaine- and amphetamine-regulated transcript (CART) cDNA was isolated from hypothalamic libraries and CART was reported to inhibit food intake and to mediate the anorectic effects of leptin. Here, we show that the active core fragment of CART (CART(89-103), 0.04-5.0 nmol) injected into lateral cerebral ventricle not only inhibits food intake, but also causes a dose-dependent increase in anxiety-like reactions in elevated plus-maze test. Intracerebroventricular administration of CART(82-103) (0.04-5.0 nmol) did not inhibit water intake and did not affect spontaneous locomotor activity in the open field test ruling out unspecific effects of the peptide. Our results suggest that CART could be an endogenous factor in the brain mediating the effects of stress on appetite.

Animals↗

PubMed2002

Low molecular weight peptides restore the procoagulant activity of factor VIII in the presence of the potent inhibitor antibody ESH8.

Following repeated administration of factor VIII (FVIII), a significant number of hemophilia A patients develop antibodies (Abs), inhibiting the procoagulant activity of infused FVIII. We have designed an approach based on the blocking of the deleterious activity of these Abs by peptide decoys mimicking the anti-FVIII Ab epitopes. Here, the well characterized inhibitory monoclonal Ab ESH8 served as a model. Several phage peptide libraries were screened for specific binding to ESH8. Seven constrained dodecapeptide sequences were obtained. Six sequences carried the consensus motif, hydrophobic-(Y/F)GKTXL. This motif showed a certain similarity with the (2231)QVDFQKTMKV(2240) sequence of the C(2) domain. In the seventh sequence, YCNPSIGDKNCR, the residues GDKN are similar to the sequence (2267)DGHQ(2270). Upon inspection of the C(2) domain crystallographic structure, the two stretches QVDFQKTMKV and DGHQ appeared close together in space and might constitute a discontinuous epitope. Corresponding synthetic peptides were able to inhibit the binding of ESH8 to FVIII in a specific and dose-dependent manner. Moreover, the ability of the selected peptides to neutralize the inhibitory activity of ESH8 was demonstrated in functional tests as well as in vivo in a murine model of hemophilia A. This study demonstrates the potential of this approach to neutralize the activity of potent inhibitory Abs.

Amino Acid Motifs↗

PubMed2000

What's the basis for treating infections your way? Quality assessment of review articles on the treatment of urinary and respiratory tract infections in older people.

OBJECTIVE: To assess the quality of readily available review articles on urinary and respiratory tract infections in older people. METHODS: Data sources were articles identified by MEDLINE search (1988-1998), review of the bibliographies of identified publications, textbooks from the library of a geriatric university hospital, and booklets with general guidelines on antibiotic therapy. Selection was made of review articles or book chapters about urinary and/or respiratory tract infections in older people that were readily available, ie, in Swiss medical libraries. Quality was assessed according to clinical applicability of the recommendations, methodology of the review, type of literature cited in the bibliography, and age of the population included in these reference articles. RESULTS: Only 13 of 29 (45%) review articles about urinary tract infections and seven of 29 (24%) articles about respiratory tract infections satisfied our criteria of applicability. Specifically, dosage, route of administration, and treatment duration were often not described. The overall methodological quality was low (mean score 1.9 +/- 1.0 on a scale of 9). No review specified the methods used to identify, select, and validate included information. Authors of the review articles quoted an important number of other review articles and only a small number of clinical trials. Less than one-quarter of these clinical trials actually comprised primarily an older population. CONCLUSIONS: Review articles on treatment of common infectious diseases in older people are often neither clinically applicable nor of good methodological quality. Therefore, more systematic review articles regarding treatment of older patients, as well as evidence-based practice guidelines, are needed.

Geriatrics↗

PubMed1976

Dental learning resources center.

The University of Kentucky College of Dentistry has been operating the Dental Sciences Study Center since 1971 to support a curriculum with a large percentage of individualized instruction. Three crucial aspects of the Study Center were discussed: the facilities, the instructional materials, and the atmosphere. Administrative attention to and support of each aspect are essential to the successful functioning of a learning resources center in a largely individualized dental curriculum.

Audiovisual Aids↗

PubMed2000

Sucrose for analgesia in newborn infants undergoing painful procedures.

BACKGROUND: Management of pain for neonates is less than optimal. The administration of sucrose with and without non-nutritive sucking (pacifiers) has been the most frequently studied non-pharmacological intervention for relief of procedural pain in neonates. OBJECTIVES: To determine the efficacy, effect of dose, and safety of sucrose for relieving procedural pain as assessed by physiologic and/or behavioural indicators. SEARCH STRATEGY: Standard methods as per the Neonatal Collaborative Review Group. A MEDLINE search was carried out for relevant randomized controlled trials (RCTs) published from January 1966 - November 1, 1997; EMBASE from 1993-1997; Reference Update search on November 11, 1997 and search of the Cochrane Library Issue 4 on November 11, 1997. Key words and (MeSH) terms included, infant/newborn, pain, analgesia and sucrose. Personal files, bibliographies, the most recent relevant neonatal and pain journals and conference proceedings were searched manually. Unpublished studies were not included. Language restrictions were not imposed. SELECTION CRITERIA: RCTs in which term and/or preterm neonates undergoing heel lance, venepuncture or intramuscular injection (immunization) received sucrose or water/placebo or no intervention. DATA COLLECTION AND ANALYSIS: Trial quality was assessed according to the methods of the Neonatal Collaborative Review Group. Quality measures included; blinding of randomization, blinding of intervention, completeness of follow up and blinding of outcome measurement. Data were abstracted and independently checked for accuracy by the two investigators. The inconsistency in outcome measures and differences in the statistical reporting of results made meta-analysis impossible. We were not able to identify two studies in which the same physiologic and/or behavioral outcomes following a noxious stimulus (heel-lance, venepuncture, intramuscular injection) were measured and reported in an identical fashion using means and standard deviations (or standard errors). The results are therefore reported for each accepted study separately. MAIN RESULTS: Fifteen studies were identified for possible inclusion in this systematic review. Five studies were excluded; three RCTs were excluded as in these trials the number of infants randomized to treatment vs. placebo groups were not reported; one study was not an RCT, and in one RCT the neonates did not undergo a painful procedure. Ten RCTs were included in this review. Sucrose in a wide range of dosages was generally found to decrease univariate physiologic (heart rate) and behavioural (the mean percent time crying, total cry duration, duration of first cry, and facial action) pain indicators and multivariate [Premature Infant Pain Profile (PIPP)] pain outcomes in neonates undergoing heelstick or venepuncture. An optimal dose of sucrose to reduce pain associated with procedures in preterm and term neonates could not be identified through this systematic review. REVIEWER'S CONCLUSIONS: Sucrose reduces physiologic and/or behavioral indicators of stress/pain in neonates following procedural pain stimuli (heel lance, venepuncture, immunization). There was inconsistency in the dose of sucrose that was effective and an optimal dose to be used in preterm and/or term infants could not be identified. Considerations for future research are to describe the painful procedure and intervention in detail, to use appropriate sample size to show a statistically significant reduction in pain, to use a multidimensional conceptualization of pain, to select outcome measures that are reliable and valid pain indicators and to account for the variation in the infant's response and context in which the pain is experienced. The use of repeated administrations of sucrose in neonates needs to be investigated. Use of sucrose in neonates that are very low birth weight, unstable and/or ventilated also needs to be addressed. (ABSTRACT TRUNCATED)

Analgesics↗

PubMed2004

Single dose oral naproxen and naproxen sodium for acute postoperative pain.

BACKGROUND: Postoperative pain is often poorly managed. Treatment options include a range of drug therapies such as non-steroidal anti-inflammatory drugs (NSAIDs) of which naproxen is one. Naproxen is used to treat a variety of painful conditions including acute postoperative pain, and is often combined with sodium to improve its solubility for oral administration. Naproxen sodium 550 mg (equivalent to 500 mg of naproxen) is considered to be an effective dose for treating postoperative pain but to date no systematic review of the effectiveness of naproxen/naproxen sodium at different doses has been published. OBJECTIVES: To assess the efficacy, safety and duration of action of a single oral dose of naproxen or naproxen sodium for acute postoperative pain in adults. SEARCH STRATEGY: We searched The Cochrane Library, MEDLINE, EMBASE and the Oxford Pain Relief Database for relevant studies. Additional studies were identified from the reference list of retrieved reports. The most recent search was undertaken in July 2004. SELECTION CRITERIA: Included studies were randomised, double blind, placebo-controlled trials of a single dose of orally administered naproxen or naproxen sodium in adults with moderate to severe acute postoperative pain. DATA COLLECTION AND ANALYSIS: Pain relief or pain intensity data were extracted and converted into dichotomous information to give the number of patients with at least 50% pain relief over four to six hours. Relative risk estimates (RR) and the number-needed-to-treat (NNT) for at least 50% pain relief were then calculated. Information was sought on the percentage of patients experiencing any adverse event, and the number-needed-to-harm was derived. Time to remedication was also estimated. MAIN RESULTS: Ten trials (996 patients) met the inclusion criteria: nine assessed naproxen sodium; one combined the results from two small trials of naproxen alone. Included studies scored well for methodological quality. Meta-analysis of six trials (500 patients) that compared naproxen sodium 550 mg with placebo gave a RR for at least 50% pain relief over 4 to 6 hours of 4.2 (95% confidence interval (CI) 2.9 to 6.0) and an NNT of 2.6 (95% CI 2.2 to 3.2). Three trials (334 patients) assessed naproxen 400 mg and naproxen sodium 440 mg, giving a RR of 4.8 (95% CI 2.75 to 8.38). Two small studies indicated that naproxen 200 mg and naproxen sodium 220 mg may provide effective postoperative pain relief. There was no significant difference between the number of patients experiencing any adverse event on treatment compared with placebo. Weighted mean time to remedication for naproxen sodium 550 mg was 7.6 hours compared with 2.6 hours for placebo. REVIEWERS' CONCLUSIONS: Naproxen sodium 550 mg, naproxen 400 mg and naproxen sodium 440 mg administered orally are effective analgesics for the treatment of acute postoperative pain in adults. A low incidence of adverse events was found but reporting was not consistent.

Acute Disease↗

PubMed2000

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

BACKGROUND: Currently the most frequently used secondary treatment for patients with venous thromboembolism are vitamin K antagonists targeted at an INR of 2.5 (range 2.0 - 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 reviewers sought publications through computerized searches of MEDLINE and EMBASE, and by hand-searching relevant journals, using the search strategy described by the Cochrane Review Group on Peripheral Vascular Diseases. They also contacted colleagues. 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 extracted the data and assessed the quality of the trials independently. MAIN RESULTS: Four studies with a total of exactly 1500 patients were included. A consistent reduction for the risk of recurrent events was observed during prolonged treatment with vitamin K antagonists (OR 0.15; 95% CI [0.10 - 0.23]) 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 1.11; 95% CI [0.71 - 1.75]). In addition, a substantial increase in bleeding complications was found during the entire period after randomization (OR 7.75; 95% CI [1.08 - 55.57]). REVIEWER'S CONCLUSIONS: In conclusion this meta-analysis shows that treatment with vitamin K antagonists reduces the risk of recurrent venous thromboembolism 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 efficiency of vitamin K antagonist administration decreases over time since the index event.

Anticoagulants↗

PubMed2006

Drugs for preventing postoperative nausea and vomiting.

BACKGROUND: Drugs can prevent postoperative nausea and vomiting, but their relative efficacies and side effects have not been compared within one systematic review. OBJECTIVES: The objective of this review was to assess the prevention of postoperative nausea and vomiting by drugs and the development of any side effects. SEARCH STRATEGY: We searched The Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library, Issue 2, 2004), MEDLINE (January 1966 to May 2004), EMBASE (January 1985 to May 2004), CINAHL (1982 to May 2004), AMED (1985 to May 2004), SIGLE (to May 2004), ISI WOS (to May 2004), LILAC (to May 2004) and INGENTA bibliographies. SELECTION CRITERIA: We included randomized controlled trials that compared a drug with placebo or another drug, or compared doses or timing of administration, that reported postoperative nausea or vomiting as an outcome. DATA COLLECTION AND ANALYSIS: Two authors independently assessed trial quality and extracted outcome data. MAIN RESULTS: We included 737 studies involving 103,237 people. Compared to placebo, eight drugs prevented postoperative nausea and vomiting: droperidol, metoclopramide, ondansetron, tropisetron, dolasetron, dexamethasone, cyclizine and granisetron. Publication bias makes evidence for differences among these drugs unreliable. The relative risks (RR) versus placebo varied between 0.60 and 0.80, depending upon the drug and outcome. Evidence for side effects was sparse: droperidol was sedative (RR 1.32) and headache was more common after ondansetron (RR 1.16). AUTHORS' CONCLUSIONS: Either nausea or vomiting is reported to affect, at most, 80 out of 100 people after surgery. If all 100 of these people are given one of the listed drugs, about 28 would benefit and 72 would not. Nausea and vomiting are usually less common and, therefore, drugs are less useful. For 100 people, of whom 30 would vomit or feel sick after surgery if given placebo, 10 people would benefit from a drug and 90 would not. Between one to five patients out of every 100 people may experience a mild side effect, such as sedation or headache, when given an antiemetic drug. Collaborative research should focus on determining whether antiemetic drugs cause more severe, probably rare, side effects. Further comparison of the antiemetic effect of one drug versus another is not a research priority.

Antiemetics↗

PubMed1995

Cloning and expression of SEZ-6, a brain-specific and seizure-related cDNA.

To clarify the molecular mechanism of neuronal bursting activity of seizures, we have constructed a cDNA library from mouse cerebrum cortex-derived cells treated with pentylentetrazole (PTZ), one of the convulsant drugs. Using a differential screening technique, several cDNA clones whose expressions change with PTZ-treatment were obtained. Among these clones, SEZ-6 was characterized by increased expression with PTZ. Detailed northern analysis showed that expression of SEZ-6 was limited to the brain and increased by the administration of PTZ not only in in vitro cultured cells but also in vivo. Analysis of SEZ-6 cDNA revealed multiple motifs, including typical signal sequence, threonine-rich domain, five copies of short consensus repeats (SCRs) or sushi domain (complement C3b/C4b binding site), two repeated sequences which were partially similar to the CUB domain or complement C1r/s-like repeat, one transmembrane domain and a short cytoplasmic segment in the C-terminal region. Although many proteins with multiple SCRs or CUB domains other than complement-related proteins have been found, this is the first report about a brain-specific cDNA which encodes membrane protein with both SCRs and CUB domain-like segments. Based on these findings, it is evident that SEZ-6 encodes a novel type of protein which may be related to seizure.

Animals↗