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Selected AbstractsOvarian Cancer Protection from Oral Contraceptives Is Greatest with the Lowest Doses of HormonesPERSPECTIVES ON SEXUAL AND REPRODUCTIVE HEALTH, Issue 3 2007D. Hollander No abstract is available for this article. [source] The Effects of Ascorbic Acid on Penicillin-induced Epileptiform Activity in RatsEPILEPSIA, Issue 7 2007Mustafa Ayyildiz Summary:,Purpose: Epileptic seizure results from excessive discharge in a population of hyperexcitable neurons. A number of studies help to document the effects of active oxygen free radical scavengers such as ,-tocopherol or ascorbic acid (vitamin C). In the present study, we examined the effects of ascorbic acid, at the six different doses, on penicillin-induced epileptiform activity. Methods: A single microinjection of penicillin (2.5 ,l, 500 units, intracortically) into the left sensorimotor cortex induced epileptiform activity within 2,5 min, progressing to full seizure activity lasting ,3,5 h. In the first set of experiments, 30 min after penicillin injection, six different doses of ascorbic acid (25, 50, 100, 200, 400, or 800 mg/kg) were administered intraperitoneally (IP). The other group of animals received the effective dose of ascorbic acid (100 mg/kg, IP) for 7 days. Ascorbic acid administration was stopped 24 h before penicillin treatment. Another group of rats received the effective dose of ascorbic acid (100 mg/kg, IP) 30 min before penicillin treatment. In the second set of experiments, the lipid peroxidation (MDA) and reduced glutathione (GSH) levels of brain were measured in the control, control + ascorbic acid, penicillin, and penicillin + ascorbic acid groups. Results: Ascorbic acid, at the low dose (50, 100 mg/kg, 30 min after penicillin injection), decreased both the frequency and amplitude of penicillin-induced epileptiform activity in rats. Ascorbic acid, at intermediate doses (200, 400 mg/kg, 30 min after penicillin injection), decreased the frequency of epileptiform activity without changing the amplitude. Ascorbic acid, at the lowest dose (25 mg/kg) and highest dose (800 mg/kg) (30 min after penicillin injection), did not change either the frequency or amplitude of epileptiform activity. Ascorbic acid, at the low dose (100 mg/kg) was the most effective dose in changing the frequency and amplitude of penicillin-induced epileptiform activity. Pretreatment with ascorbic acid (100 mg/kg) 30 min before penicillin treatment caused a significant delay in the onset of penicillin-induced epileptiform activity. Pretreatment with ascorbic acid (100 mg/kg) for 7 days did not change the latency of epileptiform activity. The most effective dose of ascorbic acid (100 mg/kg) prevented both the decrease in GSH level and the increase in lipid peroxidation level (MDA) occurring after penicillin-induced epileptiform activity. Conclusions: These data indicate that ascorbic acid has neuroprotective activity against penicillin-induced epileptiform electrocorticogram activity. [source] Energy metabolism and lipid peroxidation of human erythrocytes as a function of increased oxidative stressFEBS JOURNAL, Issue 3 2000Barbara Tavazzi To study the influence of oxidative stress on energy metabolism and lipid peroxidation in erythrocytes, cells were incubated with increasing concentrations (0.5,10 mm) of hydrogen peroxide for 1 h at 37 °C and the main substances of energy metabolism (ATP, AMP, GTP and IMP) and one index of lipid peroxidation (malondialdehyde) were determined by HPLC on cell extracts. Using the same incubation conditions, the activity of AMP-deaminase was also determined. Under nonhaemolysing conditions (at up to 4 mm H2O2), oxidative stress produced, starting from 1 mm H2O2, progressive ATP depletion and a net decrease in the intracellular sum of adenine nucleotides (ATP + ADP + AMP), which were not paralleled by AMP formation. Concomitantly, the IMP level increased by up to 20-fold with respect to the value determined in control erythrocytes, when cells were challenged with the highest nonhaemolysing H2O2 concentration (4 mm). Efflux of inosine, hypoxanthine, xanthine and uric acid towards the extracellular medium was observed. The metabolic imbalance of erythrocytes following oxidative stress was due to a dramatic and unexpected activation of AMP-deaminase (a twofold increase of activity with respect to controls) that was already evident at the lowest dose of H2O2 used; this enzymatic activity increased with increasing H2O2 in the medium, and reached its maximum at 4 mm H2O2 -treated erythrocytes (10-fold higher activity than controls). Generation of malondialdehyde was strictly related to the dose of H2O2, being detectable at the lowest H2O2 concentration and increasing without appreciable haemolysis up to 4 mm H2O2. Besides demonstrating a close relationship between lipid peroxidation and haemolysis, these data suggest that glycolytic enzymes are moderately affected by oxygen radical action and strongly indicate, in the change of AMP-deaminase activity, a highly sensitive enzymatic site responsible for a profound modification of erythrocyte energy metabolism during oxidative stress. [source] Adverse effects of conventional non-steroidal anti-inflammatory drugs on the upper gastrointestinal tractFUNDAMENTAL & CLINICAL PHARMACOLOGY, Issue 4 2003Michael J. S. Langman Abstract This article reviews the clinical and epidemiological features of conventional non-steroidal anti-inflammatory drug (NSAID) related peptic ulcer complications, and the associated risk factors. The degree of gastrointestinal toxicity varies widely between the available drugs and with dose of each. The risk of ulcer complications can however be reduced, and perhaps completely removed, by using the lowest dose of the least toxic member of the class. Enteric coating and other delayed release formulations have not been shown to reduce risk. Estimates of the imposed disease burden have varied widely, in part through assuming that risks in selected patient groups will necessarily translate to the general population. Nevertheless, the imposed disease burden is one of the largest associated with current drug treatment. Associated risk factors such as prior ulcer, corticosteroid use and concurrent aspirin as well as general cardiovascular disease will raise the likelihood of an ulcer complication in NSAID takers and non-takers. Therefore, strategies dependent on substituting COX-selective drugs will then be only partially successful. [source] Systemic Lupus Erythematosus Presenting as Subacute Delirium in an 82-Year-Old WomanJOURNAL OF AMERICAN GERIATRICS SOCIETY, Issue 4 2001George A. Heckman MD OBJECTIVES: To describe an older patient with delirium attributed to systemic lupus erythematosus (SLE) and to review the literature on neuropsychiatric manifestations of SLE in older people. DESIGN: Case report and literature review. MEDLINE search using terms systemic lupus erythematosus, neurologic, psychiatric, neuropsychiatric, autoantibodies (antinuclear antibody (ANA), antiphospholipid, anticardiolipin, anti-double stranded deoxyribonucleic acid (anti-dsDNA), anti-Smith), and elderly. Additional articles obtained from hand-searched references and through experts. SETTING: Hospital (case report). PARTICIPANTS: Case report and literature cases. MEASUREMENTS: None. RESULTS: SLE is increasingly diagnosed in older adults. Onset is insidious and diagnosis is delayed because of a different clinical spectrum and immunological profile than in younger adults. Autoantibodies have an important role in the pathogenesis of neuropsychiatric manifestations, while vasculitis is less common. Aggressive immunosuppressive therapy is typically indicated, although recent case reports suggest that lower doses may suffice. The American College of Rheumatology 1982 revised criteria may be inadequate to diagnose neuropsychiatric lupus in older persons. CONCLUSION: Neuropsychiatric symptoms can be prominent in older people, presenting features of SLE. This case illustrates the lowest dose of corticosteroids shown to be effective in an older patient with delirium due to SLE. [source] Tunisian radish extract (Raphanus sativus) enhances the antioxidant status and protects against oxidative stress induced by zearalenone in Balb/c miceJOURNAL OF APPLIED TOXICOLOGY, Issue 1 2008Jalila Ben Salah-Abbès Abstract Radish (Raphanus sativus) is a food plant known worldwide. From antiquity it has been used in folk medicine as a natural drug against many toxicants. Zearalenone (zen) is a non-steroidal estrogenic mycotoxin present in corn and food mixture for farm animals and it is hepatotoxic, hematotoxic, immunotoxic, nephrotoxic and genotoxic. The objectives of the present study were to assess the biological activity of radish extract and to evaluate the protective role of radish extract against the toxicity of zen in female Balb/c mice. Animals were divided into seven groups and treated orally for 10 days as follows: a control, an olive oil group, groups treated with radish extract alone (5, 10 and 15 mg kg,1 b.w.), a group treated with zen (40 mg kg,1 b.w.) and a group treated with zen plus the lowest dose of radish extract. The results indicate that radish extract improved the antioxidant status and had no significant effects on hematological and biochemical parameters tested or histology of the liver and kidney. Treatment with zen results in a significant increase in ALT, AST, ALP, BILT, BILD, CRE accompanied with significant changes in most of hematological parameters and the antioxidant enzyme activities, co-treatment of zen and the radish extract results in a significant reestablishment of hematological, serum biochemical parameters, and the histology of the liver and kidney. These findings suggest that radish extract is safe and can be overcome or, at least, significantly diminish zen effects. Copyright © 2007 John Wiley & Sons, Ltd. [source] Long-Term Protective Effects of Zoledronic Acid on Cancellous and Cortical Bone in the Ovariectomized Rat,JOURNAL OF BONE AND MINERAL RESEARCH, Issue 4 2008Jürg A Gasser PhD Abstract Current bisphosphonate therapies effectively prevent bone loss in postmenopausal women. We studied the effect of a single intravenous dose of ZOL in ovariectomized rats. Protection from bone loss was dose dependent, lasting for up to 32 weeks, supporting the rationale for an annual intravenous dosing regimen of ZOL for treatment of postmenopausal osteoporosis. Introduction: Once-yearly dosing with zoledronic acid (ZOL) 5 mg can increase BMD and reduce fracture rate in postmenopausal women with low BMD. The primary objective of this study was to determine the duration of bone protective effects of a single dose of ZOL in ovariectomized rats, an animal model of postmenopausal osteopenia. Secondary objectives were to determine the effects on bone turnover and mechanical properties. Materials and Methods: Female Wistar rats (10 per group) received single intravenous doses of ZOL 0.8, 4, 20, 100, or 500 ,g/kg, alendronate 200 ,g/kg, or isotonic saline 4 days before bilateral ovariectomy. Sham-operated controls were pretreated with saline. Mass and density of cancellous and cortical bone (pQCT) were measured at 4-wk intervals for 32 wk. Bone architecture (,CT), bone formation dynamics (fluorochrome label-based histomorphometry), and biomechanical strength in compression testing were also assessed at 32 wk. Results: Ovariectomy-associated BMD loss was significantly attenuated for 32 wk by ZOL ,4 ,g/kg for total BMD, ZOL ,20 ,g/kg for cortical BMD, and ZOL ,4 ,g/kg for cancellous BMD (p < 0.01 versus ovariectomized controls). Alendronate 200 ,g/kg was of equivalent potency to ZOL 20 ,g/kg. Ovariectomy-associated decreases in trabecular architectural parameters were dose-dependently attenuated by ZOL. Alendronate 200 ,g/kg was equivalent to ZOL 20 ,g/kg. The bone resorption marker TRACP5b indicated transient suppression of elevated osteoclast activity by ZOL relative to OVX-rats even at the lowest dose of 0.8 ,g/kg, whereas at 100,500 ,g/kg, the effect was significant relative to the OVX control for the entire duration of the study of 32 wk. Bone formation parameters were not significantly affected by ZOL 20 ,g/kg but were significantly reduced by ZOL 100,500 ,g/kg. Alendronate 200 ,g/kg was equivalent to ZOL 100 ,g/kg. ZOL produced dose-related improvements in bone strength parameters after ovariectomy. Alendronate 200 ,g/kg was of similar potency to ZOL 20 ,g/kg. Conclusions: The duration and magnitude of the bone-protecting effect of a single intravenous dose of ZOL in ovariectomized rats is dose dependent and lasts for up to 32 wk. Compared with alendronate, ZOL shows 10-fold higher potency in preventing bone loss. These data support the use of an annual intravenous ZOL dosing regimen for the treatment of osteoporosis. [source] Differential Appetite-Related Responses to Central Neuropeptide S in Lines of Chickens Divergently Selected for Low or High Body WeightJOURNAL OF NEUROENDOCRINOLOGY, Issue 7 2008M. A. Cline The anorexigenic 20 amino acid neuropeptide S (NPS) has not been studied in an animal model of hypo- or hyperphagia. The present study aimed to elucidate whether central NPS appetite-related effects are different in lines of chickens that had undergone long-term divergent selection for low (LWS) or high (HWS) body weight and that were hypo- and hyperphagic, respectively. It took a longer time for food intake to be reduced in LWS than HWS chicks administered the lowest dose of NPS tested (0.14 nmol) and, at the highest dose tested (0.56 nmol), they had a greater reduction in food intake than did HWS chicks. HWS chicks responded with a similar magnitude of food intake reduction that was independent of NPS dose. Although water intake was reduced concurrently with food intake after central NPS in both lines, blood glucose concentrations were not affected. Hypothalamic signalling was different between the lines. Although both lines respond to central NPS with decreased c-Fos immunoreactivity in the lateral hypothalamus, the periventricular nucleus had increased c-Fos immunoreactivity in LWS but not HWS chicks. After central NPS treatment, there was increased c-Fos immunoreactivity in the paraventricular nucleus in HWS but not LWS chicks. These data support the notion of differences in the central NPS system between the LWS and HWS lines and infer that central NPS may differentially affect appetite-related processes in other species that contain hypo- and hyperphagic individuals. [source] Carboxy terminus of secreted phosphoprotein-24 kDa (spp24) is essential for full inhibition of BMP-2 activityJOURNAL OF ORTHOPAEDIC RESEARCH, Issue 9 2010Elsa J. Brochmann Abstract Secreted phosphoprotein-24,kDa (spp24) is a bone morphogenetic protein (BMP)-binding protein isolated from bone. It exists in a number of size forms and is hypothesized to function as a BMP latency protein and/or a "slow release" mechanism for BMPs involved in bone turnover and repair. We have examined the hypothesis that proteolytic modification of the C-terminus of spp24 affects its BMP-2,binding properties and bioactivity in the BMP-2,stimulated ectopic bone forming bioassay. Three different size forms of recombinant spp24 that correspond to predicted 18.1,kDa, 16.0,kDa, and 14.5,kDa proteolytic products were compared to full-length (fl) spp24. One of these forms (spp18.1) we hypothesize to be the protein which Urist initially, but apparently inaccurately, called "BMP." Only full-length spp24 completely inhibited BMP-2,induced bone formation. The 18.1,kDa truncated isoform of spp24 which we hypothesize to be Urist's protein did not. The inhibitory capacity of the proteins was correlated with their kinetic constants, assessed by surface plasmon resonance. At the highest, inhibitory, dose of spp24 and its derivatives, kd ("stability") best predicted the extent of ectopic bone formation whereas at the lowest dose, which was not inhibitory, ka ("recognition") best predicted the extent of ectopic bone formation. We conclude that proteolytic processing of spp24 affects the interaction of this protein with BMP-2 and this affects the function of the protein. © 2010 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 28:1200,1207, 2010 [source] The Relationship Between Vaccine Dose and Efficacy in Channel Catfish Ictalurus punctatus Vaccinated as Fry with a Live Attenuated Strain of Edwardsiella ictaluri (RE-33),JOURNAL OF THE WORLD AQUACULTURE SOCIETY, Issue 2 2001David J. Wise Channel catfish Ictalurus punctatus were vaccinated at 12 d of age (post-hatch) by a 2-min bath immersion with attenuated Edwardsiella ictaluri RE-33 at doses of 2.5 × 105, 2.5 × 106, and 2.4 × 107 colony-forming units CFU/mL of water. Following vaccination, RE-33 was recovered from a greater percentage of fry that were vaccinated at the high and intermediate doses compared to fry vaccinated at the lowest dose. Independent of dose, the greatest percentage of RE-33 positive fry occurred between 1 and 6 d post-vaccination with a significant decrease in positive fry observed on day 12. A significant increase in mortality occurred 6 to 12 d post-vaccination in fry vaccinated at the highest dose. No differences in post-vaccination mortalities occurred between the other treatments. Following virulent E. ictaluri challenge, mortalities of fish vaccinated at doses of 2.5 × 106 and 2.4 × 107 CFU/mL were significantly less than those of fish vaccinated at 2.5 × 105 CFU/mL and sham-vaccinated control fish. These data show that vaccination with RE-33 can offer protection against subsequent virulent E. ictaluri infection. [source] Genetics of spinosad resistance in a multi-resistant field-selected population of Plutella xylostellaPEST MANAGEMENT SCIENCE (FORMERLY: PESTICIDE SCIENCE), Issue 8 2004Ali H Sayyed Abstract Resistance to the bacteria-derived insecticides spinosad (Conserve), abamectin (Vertimec), Bacillus thuringiensis var kurstaki (Btk) (Dipel), B thuringiensis var aizawai (Bta) (Xentari), B thuringiensis crystal endotoxins Cry1Ac and Cry1Ca, and to the synthetic insecticide fipronil was estimated in a freshly-collected field population (CH1 strain) of Plutella xylostella (L) from the Cameron Highlands, Malaysia. Laboratory bioassays at G1 indicated significant levels of resistance to spinosad, abamectin, Cry1Ac, Btk, Cry1Ca, fipronil and Bta when compared with a laboratory insecticide-susceptible population. Logit regression analysis of F1 reciprocal crosses indicated that resistance to spinosad in the CH1 population was inherited as a co-dominant trait. At the highest dose of spinosad tested, resistance was close to completely recessive, while at the lowest dose it was incompletely dominant. A direct test of monogenic inheritance based on a back-cross of F1 progeny with CH1 suggested that resistance to spinosad was controlled by a single locus. Copyright © 2004 Society of Chemical Industry [source] Cross-resistance and inheritance of resistance to Bacillus thuringiensis toxin Cry1Ac in diamondback moth (Plutella xylostella L) from lowland MalaysiaPEST MANAGEMENT SCIENCE (FORMERLY: PESTICIDE SCIENCE), Issue 5 2001Ali H Sayyed Abstract A field population of Plutella xylostella from Malaysia (SERD4) was divided into five sub-populations and four were selected (G2,G5) with the Bacillus thuringiensis insecticidal crystal (Cry) toxins Cry1Ac, Cry1Ab, Cry1Ca and Cry1Da. Bioassay at G6 gave resistance ratios of 88, 5, 2 and 3 for Cry1Ac, Cry1Ab, Cry1Ca and Cry1Da respectively compared with the unselected sub-population (UNSEL-SERD4). The Cry1Ac-selected population showed little cross-resistance to Cry1Ab, Cry1Ca and Cry1Da, (3-, 2- and 3-fold compared with UNSEL-SERD4), whereas the Cry1Ab-SEL sub-population showed marked cross-resistance to Cry1Ac (40-fold), much greater than Cry1Ab itself. In contrast, the Cry1Ca- and Cry1Da-SEL sub-populations showed little if any cross-resistance to Cry1Ac and Cry1Ab. The mode of inheritance of resistance to Cry1Ac was examined in Cry1Ac-selected SERD4 by standard reciprocal crosses and back-crosses using a laboratory insecticide-susceptible population (ROTH). Logit regression analysis of F1 reciprocal crosses indicated that resistance to Cry1Ac was inherited as an incompletely dominant trait. At the highest dose of Cry1Ac tested, resistance was recessive, while at the lowest dose it was almost completely dominant. The F2 progeny from a back-cross of F1 progeny with ROTH were tested with a concentration of Cry1Ac that would kill 100% of ROTH. The mortality ranged between 50 and 95% in seven families of back-cross progeny, which indicated that more than one allele on separate loci were responsible for resistance to Cry1Ac. © 2001 Society of Chemical Industry [source] Electrophysiological and behavioural identification of host kairomones as olfactory cues for Culicoides impunctatus and C. nubeculosusPHYSIOLOGICAL ENTOMOLOGY, Issue 1 2000A. Bhasin Summary Electroantennograms (EAGs) were recorded from wild-caught parous, female Culicoides impunctatus (Goetghebuer) in response to components of host odour. Nine synthetic compounds were found to be electrophysiologically active, eliciting EAGs which were significantly different from solvent control. An EAG hierarchy was established, in which 1-octen-3-ol elicited the highest amplitude EAGs, followed by acetone, lactic acid and butanone. The overall responses to phenolic compounds were reduced compared to the non-phenolics. Subsequent behavioural analyses of the effects of these compounds when tested singly revealed 1-octen-3-ol, acetone and butanone to be attractive over specific stimulus doses. Exposure to supra-optimal doses modified the insects' behaviour; insects either ceased to respond or were repelled. Lactic acid was attractive at the lowest dose tested but was repellent at high doses. Behavioural responses to the phenolic components of host odour and lactic acid were similar, generally causing arrestment at low doses and repelling at the higher doses tested. A comparison of EAG profiles and behavioural assays between laboratory-reared Culicoides nubeculosus (Meigen) and C. impunctatus suggested that the same kairomones are utilized by both species, with C. nubeculosus being less sensitive than C. impunctatus. The EAG hierarchy of C. nubeculosus to the four non-phenolics was identical to that of C. impunctatus. [source] Latest news and product developmentsPRESCRIBER, Issue 19 2007Article first published online: 22 NOV 200 UK data suggest OCs may reduce cancer risk The latest analysis of the RCGP oral contraception (OC) study suggests that oral contraceptives may be associated with an overall reduction in the risk of cancer (Br Med J online: 11 September 2007; doi:10.1136/bmj.39289. 649410.55). The cohort of 46 000 women provided 744 000 woman-years for ever use of an oral contraceptive and 339 000 woman-years of never use. Longer use was associated with increasing risks of cervical (RR 2.73), and pituitary or CNS (RR 5.51) cancers, but decreasing risks of uterine (RR 0.57) and ovarian (RR 0.38) cancers. OC use was also associated with a lower overall risk of colorectal cancers. The overall risk of any cancer was reduced by 12 per cent (RR 0.88). CombAT two-year data Two-year data revealed at the 29th Congress of the Société Internationale d'Urologie in Paris in September show that dutasteride (Avodart) and tamsulosin combination therapy provides significantly improved symptom control in BPH compared with either therapy alone. The Combination therapy with Avodart (dutasteride) and tamsulosin (CombAT) study took over 4800 eligible men (age ,50 years with a prostate volume ,30cc, serum PSA level ,1.5-10ng per ml and IPSS ,12) who received placebo for four weeks before being randomised in a 1:1:1 ratio to either dutasteride monotherapy (0.5mg per day), tamsulosin monotherapy (0.4mg per day) or a combination of both drugs. At two years the primary efficacy end-point was achieved: combination therapy was significantly more effective than either monotherapy, and continuous improvement could be observed throughout the two years. The combination therapy was also well tolerated, although drug-related adverse events were more common with combination therapy (24 per cent) than either monotherapy (dutasteride 18 per cent, tamsulosin 14 per cent). Dutasteride, a 5-, reductase inhibitor, has been shown to be more effective for long-term use in men than tamsulosin, while tamsulosin, an alpha blocker, has been shown to be effective in the short term. CombAT is the first study to demonstrate that the combination therapy of both drugs could lead to greater symptom improvement over time than an alpha blocker alone. Aliskiren - new class of antihypertensive Novartis has introduced aliskiren (Rasilez), the first direct renin inhibitor for the treatment of hypertension. It is likely to be used in combination with other agents but is also licensed as monotherapy. The commonest adverse effect is diarrhoea. At the recommended dose of 150-300mg per day, a month's treatment costs £19.80-£23.80. MHRA updates drug safety advice The balance of benefit and risks from HRT may be more favourable for younger women, the MHRA says in its monthly bulletin, Drug Update (September 2007). GPs considering prescribing HRT should evaluate the potential risks and benefits for each individual, the MHRA says. The bulletin summarises the risks of cardiovascular events and cancers associated with HRT. Cardiovascular risk is a particular concern for women over 60, whose baseline risk is high; although evidence for the safety of HRT in younger women is limited, their baseline risk is lower. Overall, the lowest dose of HRT should be used for the shortest possible time, and HRT should be prescribed to prevent osteoporosis only when alternatives are not suitable. The MHRA also advises in the bulletin that: Individual risk of stroke, breast cancer and endometrial cancer should be considered before prescribing tibolone (Livial). Nasal formulations of desmopressin are no longer indicated for primary nocturnal enuresis; prescribers are reminded to adhere to product guidance on fluid intake. Patients and carers should be warned of the risk of psychiatric effects associated with corticosteroids; symptoms may develop within a few days or weeks in children and adults, and may be more common at higher doses. Patients taking steroids for more than three weeks are reminded not to stop treatment abruptly. A list of questions and answers for patients is available at www.mhra.gov.uk. The use of parenteral B vitamins plus ascorbic acid (Pabrinex) may rarely be associated with severe allergic reactions, but this should not preclude its use for patients who need it. Study claims statin switch may increase CV morbidity Switching patients from atorvastatin (Lipitor) to simvastatin may increase the risk of cardiovascular events, according to a UK study presented at the European Society of Cardiology Congress in Vienna. The analysis, from The Health Improvement Network database, included 11 520 patients taking atorvastatin for at least six months, of whom 2511 were switched to simvastatin. Switching was associated with a 30 per cent increase in the relative risk of cardiovascular events, though absolute figures have not been reported. Patients who were switched were also more likely to discontinue treatment (21 vs 8 per cent of those continuing atorvastatin). Details of the conduct of the study, which will be published in the British Journal of Cardiology, are not available. Glitazones controversy rumbles on New systematic reviews have fuelled the controversy over the cardiac safety of rosiglitazone and pioglitazone. A meta-analysis of four trials involving 14 291 patients and lasting one to four years found that rosiglitazone was associated with a significantly increased risk of myocardial infarction (relative risk, RR, 1.42) and heart failure (RR 2.09) but not cardiovascular mortality (RR 0.90) (J Am Med Assoc 2007;298:1189-95). The second review included 19 trials of pioglitazone involving 16 390 patients, with follow-up from four months to 3.5 years. Pioglitazone was associated with a lower risk of composite events (death, myocardial infarction, stroke; hazard ratio, HR, 0.82) but an increased risk of serious heart failure (HR 1.41) (J Am Med Assoc 2007;298: 1180-8). Neither review reported significant heterogeneity between the included studies. Another systematic review of eight controlled and cohort studies concluded that metformin is the only antidiabetic drug not associated with an increased risk of harm in patients with diabetes and heart failure (Br Med J Online First 30 August; doi:10.1136/bmj.39314. 620174.80). The Canadian authors found methodological problems with all studies, and concluded that results for sulphonylureas were conflicting due to differences between the studies. Asthma prescribing education Health professionals need more education about rational prescribing for children with asthma, say researchers from Australia (Arch Dis Child online: 4 September 2007; doi: 10. 1136/adc.2007.119834). Analysing trends in asthma medication prescriptions for children in the UK between 2000 and 2006, they found the proportion of steroid inhalers prescribed as combinations increased from 2.7 per cent in 2000 to 25 per cent in 2006. The authors say this excessive increase is inconsistent with guidance that steroid-only inhalers should be the mainstay for most people with asthma. Copyright © 2007 Wiley Interface Ltd [source] An Adaptive Hierarchical Test Procedure for Selecting Safe and Efficient TreatmentsBIOMETRICAL JOURNAL, Issue 4 2006Franz König Abstract We consider the situation where during a multiple treatment (dose) control comparison high doses are truncated because of lack of safety and low doses are truncated because of lack of efficacy, e.g., by decisions of a data safety monitoring committee in multiple interim looks. We investigate the properties of a hierarchical test procedure for the efficacy outcome in the set of doses carried on until the end of the trial, starting with the highest selected dose group to be compared with the placebo at the full level ,. Left truncation, i.e., dropping doses in a sequence starting with the lowest dose, does not inflate the type I error rate. It is shown that right truncation does not inflate the type I error if efficacy and toxicity are positively related and dose selection is based on monotone functions of the safety data. A positive relation is given e.g. in the case where the efficacy and toxicity data are normally distributed with a positive pairwise correlation. A positive relation also applies if the probability for an adverse event is increasing with a normally distributed efficacy outcome. The properties of such truncation procedures are investigated by simulations. There is a conflict between achieving a small number of unsafely treated patients and a high power to detect safe and efficient doses. We also investigated a procedure to increase power where a reallocation of the sample size to the truncated treatments and the control remaining at the following stages is performed. (© 2006 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim) [source] Sensitivity to ultraviolet B is a risk factor for cutaneous melanoma in a Mediterranean population: results from an Italian case,control studyCLINICAL & EXPERIMENTAL DERMATOLOGY, Issue 1 2009A. Chiarugi Summary Background., Sun sensitivity is one of the predictors of melanoma risk, together with other individual characteristics such as skin and eye colour and number of naevi. However, it is unclear how best to measure sun sensitivity in order to quantify the individual risk of melanoma. Objectives., In this case,control study, the relationship between minimal erythema dose (MED) and skin colour (both instrumentally assessed) was investigated, and their possible role as independent risk factors for melanoma in a Mediterranean population evaluated. Methods., In total, 143 patients with cutaneous melanoma and 102 controls were enrolled in the study. Skin colour was assessed using a Minolta CR-200 chromameter. For MED calculation, a fluorescent lamp (Philips TL 4W/12) was used as a source of ultraviolet B light. MED was defined as the lowest dose that produced an increase of 2.5 in the redness value, expressed by the parameter a* of the Commission Internationale d'Eclairage (CIE) L*a*b* colour space (,a* = 2.5). Results., A significant excess of risk was associated with increasing L* values of skin colour (P < 0.05; OR = 1.12; 95% CI 1.01,1.24) for each unit of change. Low MED values were also associated with an increasing risk of melanoma, with an excess of risk of 18% (OR = 1.18, 95% CI 1.04,1.35) for every 10 mJ/cm2 of MED reduction. Compared with the highest MED values (> 97.7 mJ/cm2), subjects with MED values , ,50 mJ/cm2 or lower had a > 2-fold increased risk of melanoma (OR = 2.37, 95% CI 1.05,5.38). The effect of decreasing MED value as a melanoma risk factor persisted after adjustment for skin colour and atypical naevi in a multivariate model. Conclusions., In conclusion, both instrumentally assessed skin colour and MED are significant risk factors for malignant melanoma in a Mediterranean population. MED seems be an independent variable in establishing the subject's risk profile. [source] PERIPHERAL AND CENTRALLY MEDIATED EFFECTS OF INSULIN ON SMALL INTESTINAL TRANSIT IN HEALTHY MICECLINICAL AND EXPERIMENTAL PHARMACOLOGY AND PHYSIOLOGY, Issue 7 2006MK Peddyreddy SUMMARY 1Insulin is the drug of choice in the management of type 1 diabetes mellitus. Approximately 76% of diabetic patients suffer from gastrointestinal disorders. An important area of investigating the inherent effect of insulin on small intestinal transit (SIT) remains unexplored. Hence, the present study was planned to investigate the effects of insulin (2 × 10,6, 2 × 10,3 and 2 U/kg) on small intestinal transit following two different routes of administration in healthy animals. 2Insulin or vehicle was administered subcutaneously or intracerebroventricularly in eight groups of healthy, overnight-fasted mice. Blood glucose (BG) levels were measured 2 min before insulin administration and at the time coinciding with SIT determination. Small intestinal transit was determined 50 min after insulin administration using the charcoal meal method. 3Following subcutaneous administration, the lowest dose of insulin (2 × 10,6 U/kg) produced a significant acceleration in SIT without altering BG levels. However, the highest dose of insulin (2 U/kg) produced an acceleration of SIT that was associated with a significant fall in BG levels. 4Following intracerebroventricular administration, the lowest dose of insulin (2 × 10,6 U/kg) attenuated SIT, without producing any alteration in BG levels, but the highest dose (2 U/kg) mimicked the effects seen following subcutaneous administration. Peripherally administered insulin produced significant acceleration of SIT at lower doses (2 × 10,6 or 2 × 10,3 mU/kg) compared with centrally administered insulin at similar doses. However, at the highest dose of insulin (2 U/kg), both routes (s.c. and i.c.v.) produced acceleration of SIT. 5In the present study, peripherally and centrally administered insulin at 2 × 10,6 U/kg produced contrasting effects on SIT, without any hypoglycaemia. However, 2 U/kg insulin accelerated SIT similarly following both s.c. and i.c.v. administration that was associated with hypoglycaemia in healthy animals. [source] Postnatal dexamethasone: what is the real cost-benefit ratio?ACTA PAEDIATRICA, Issue 8 2003HL Halliday Postnatal corticosteroids given early after birth reduce the risk of chronic lung disease in preterm infants but are associated with an approximate doubling of the risk of adverse neurosensory outcomes. Corticosteroids given after 7,10 d of age appear not to have these increased risks of neurosensory sequelae and reduce time on the ventilator. Conclusion: Further research is needed to determine the lowest dose of corticosteroid that will improve lung function and minimize risks to the developing brain. [source] Developmental toxicity of UV filters and environmental exposure: a reviewINTERNATIONAL JOURNAL OF ANDROLOGY, Issue 2 2008Margret Schlumpf Summary Several ultraviolet (UV) filters exhibit estrogenic, some also anti-androgenic activity. They are present in waste water treatment plants, surface waters and biosphere including human milk, suggesting potential exposure during development. Developmental toxicity was studied in rats for the UV filters 4-methylbenzylidene camphor (4-MBC, 0.7, 7, 24, 47 mg/kg/day) and 3-benzylidene camphor (3-BC, 0.07, 0.24, 0.7, 2.4, 7 mg/kg/day) administered in chow to the parent generation before mating, during pregnancy and lactation, and to the offspring until adulthood. Neonates exhibited enhanced prostate growth after 4-MBC and altered uterine gene expression after both chemicals. 4-MBC and 3-BC delayed male puberty and affected reproductive organ weights of adult offspring. Effects on the thyroid axis were also noted. Expression and oestrogen sensitivity of oestrogen-regulated genes and nuclear receptor coregulator levels were altered at mRNA and protein levels in adult uterus, prostate and brain regions involved in gonadal control and sexual behaviour. Female sexual behaviour was impaired by both filters; 3-benzylidene camphor caused irregular cycles. Classical endpoints exhibited lowest observed adverse effect levels (LOAELs) and no observed adverse effect levels (NOAELs) of 7/0.7 mg/kg for 4-MBC and 0.24/0.07 mg/kg for 3-BC. Molecular endpoints were affected by the lowest doses studied. Our data indicate that the potential risk posed by endocrine active UV filters warrants further investigations. [source] Evaluation of the Photosensitizer Tookad® for Photodynamic Therapy on the Syrian Golden Hamster Cheek Pouch Model: Light Dose, Drug Dose and Drug,light Interval Effects,PHOTOCHEMISTRY & PHOTOBIOLOGY, Issue 4 2003François Borle ABSTRACT We have evaluated the efficacy of the new photosensitizer (PS) Tookad® in photodynamic therapy (PDT) in vivo. This PS is a palladium-bacteriopheophorbide presenting absorption peaks at 762 and 538 nm. The light dose, drug dose and drug injection,light irradiation interval (DLI), ranging between 100 and 300 J/cm2, 1 and 5 mg/kg and from 10 to 240 min, respectively, were varied, and the response to PDT was analyzed by staging the macroscopic response and by the histological examination of the sections of the irradiated cheek pouch. The level of PDT response, macroscopically and histologically, shows a strong dependence on the DLI, light dose and drug dose at the applied conditions in the normal hamster cheek pouch. A decay of the tissular response with increasing DLI is observed corresponding to a time of half-maximum response ranging from 10 to 120 min, depending on drug dose and light dose. The tissues affected at the lowest doses are predominantly the vascularized diffuse connective tissue situated between the inner and outer striated muscle (SM) layers as well as these muscle layers themselves. The highest response at the shortest DLI and the absence of a measurable response at DLI longer than 240 min at 300 J/cm2 and drug dose of 5 mg/kg are characteristics of a predominantly vascular effect of this PS. This observation suggests that Tookad® could be effective in PDT of vascularized lesions or pathologies associated with the proliferation of neovessels. [source] | |||||||||||||||||||