Impact of effective health care bulletin on treatment of persistent glue ear in children: time series analysis.
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Child↗
Biomedical subjects
J Mason
Publications and source records attributed to J Mason.
Psychiatric illness and mortality after hip fracture.
People with dementia or delirium have increased mortality in the 6 months after hip fracture, but depression might take longer to have an effect. We assessed the psychiatric status of 731 participants with hip fracture and analysed the effect of psychiatric illness on mortality during the next 2 years. We found that dementia, delirium, and depression all increased the risk of mortality (p<0.0001, p<0.0001, and p=0.0359, respectively), and that mortality differed significantly between hospitals (p=0.0003). We suggest that psychiatric interventions should be asssessed in hip-fracture patients with adequate follow up of outcome measures.
Aged↗
Noninvasive control of stochastic resonance.
External feedback can enhance (or depress) the response of a noisy bistable system to monochromatic signals, significantly magnifying its natural stochastic resonance. We compare and contrast a variety of such feedback strategies, using both numerical simulations and analog electronic experiments. These noninvasive control techniques are especially valuable for noisy bistable systems that are difficult or impossible to modify internally.
Journal Article↗
Lefty proteins exhibit unique processing and activate the MAPK pathway.
Lefty polypeptides, novel members of the transforming growth factor-beta (TGF-beta) superfamily, are involved in the formation of embryonic lateral patterning. Members of the TGF-beta superfamily require processing for their activation, suggesting cleavage to be an essential step for lefty activation. Transfection of different cell lines with lefty resulted in expression of a 42-kDa protein, which was proteolytically processed to release two polypeptides of 34 and 28 kDa. Since members of the proprotein convertase (PC) family cleave different TGF-beta factors and are involved in the establishment of embryonic laterality, we studied their role in lefty processing. Cotransfection analysis showed that PC5A processed the lefty precursor to the 34-kDa form in vivo, whereas furin, PACE4, PC5B, and PC7 had a limited activity. None of these PCs showed activity in the processing of the lefty polypeptide to the 28-kDa lefty form. The mutation of the consensus sequences for PC cleavage in the lefty protein allowed the lefty cleavage sites to be identified. Mutations of the sequence RGKR to GGKG (amino acids 74-77) and of RHGR to GHGR (amino acids 132-135) prevented the proteolytic processing of the lefty precursor to the 34- and 28-kDa forms, respectively. To identify the biologically active form of lefty, we studied the effect of lefty treatment on pluripotent P19 cells. Lefty did not induce Smad2 or Smad5 phosphorylation, Smad2/Smad4 heterodimerization, or nuclear translocation of Smad2 or Smad4, but activated the MAPK pathway in a time- and dose-dependent fashion. Further analysis showed the 28-kDa (but not the 34-kDa) polypeptide to induce MAPK activity. Surprisingly, the 42-kDa lefty protein was also capable of inducing MAPK activity, indicating that the lefty precursor is biologically active. The data support a molecular model of processing as a mechanism for regulation of lefty signaling.
3T3 Cells↗
Vascular endothelial growth factor receptor-1 modulates vascular endothelial growth factor-mediated angiogenesis via nitric oxide.
The known responses of vascular endothelial growth factor (VEGF) are mediated through VEGF receptor-2 (VEGFR-2/KDR) in endothelial cells. However, it is unknown whether VEGFR-1 (Flt-1) is an inert decoy or a signaling receptor for VEGF during physiological or pathological angiogenesis. Here we report that VEGF-stimulated nitric oxide (NO) release is inhibited by blockade of VEGFR-1 and that VEGFR-1 via NO negatively regulates of VEGFR-2-mediated proliferation and promotes formation of capillary networks in human umbilical vein endothelial cells (HUVECs). Inhibition of VEGFR-1 in a murine Matrigel angiogenesis assay induced large aneurysm-like structures. VEGF-induced capillary growth over 14 days was inhibited by anti-VEGFR-2-blocking antibody as determined by reduced tube length between capillary connections (P < 0.0001) in an in vitro angiogenesis assay. In contrast, loss of VEGFR-1 activity with a neutralizing anti-VEGFR-1 antibody resulted in an increase in the accumulation of endothelial cells (P < 0.0001) and a dramatic decrease in the number of capillary connections that were restored by the addition of NO donor. Porcine aortic endothelial (PAE) cells expressing human VEGFR-1 but not VEGFR-2 plated on growth factor-reduced Matrigel rearranged into tube-like structures that were prevented by anti-VEGFR-1 antibody or a cGMP inhibitor. VEGF stimulated NO release from VEGFR-1- but not VEGFR-2-transfected endothelial cells and placenta growth factor-1 stimulated NO release in HUVECs. Blockade of VEGFR-1 increased VEGF-mediated HUVEC proliferation that was inhibited by NO donors, and potentiated by NO synthase inhibitors. These data indicate that VEGFR-1 is a signaling receptor that promotes endothelial cell differentiation into vascular tubes, in part by limiting VEGFR-2-mediated endothelial cell proliferation via NO, which seems to be a molecular switch for endothelial cell differentiation.
Cell Division↗
Gene expression in the embryonic Xenopus liver.
In recent years, significant progress has been made in uncovering the molecular basis of endoderm specification in Xenopus. Much less is understood, however, about endodermal patterning and how endoderm-derived organs such as the liver are formed. Progress has been hampered by the lack of good molecular markers of presumptive liver tissue. Here, we have examined the embryonic expression of a number of marker genes during liver organogenesis, including the transcription factors hex, sox17alpha, and hnf3beta, as well as a number of proteins specific to the adult liver. Interestingly, sox17alpha appears to specifically mark the gall bladder precursors. At 7 days of development expression of the liver differentiation markers albumin, alpha1-microglobulin/bikunin precursor, fibrinogen, transferrin and transthyretin is restricted to the differentiating liver bud. Surprisingly, however, at 3 days of development most of these genes have a more widespread endodermal expression pattern. In addition to expression in the undifferentiated liver bud they were expressed extensively throughout the presumptive intestinal tissue, which may reflect some general feature of how the hepatic gene program is developmentally regulated.
Albumins↗
TNF alpha promotes proliferation of oligodendrocyte progenitors and remyelination.
Here we used mice lacking tumor necrosis factor-alpha (TNF alpha) and its associated receptors to study a model of demyelination and remyelination in which these events could be carefully controlled using a toxin, cuprizone. Unexpectedly, the lack of TNF alpha led to a significant delay in remyelination as assessed by histology, immunohistochemistry for myelin proteins and electron microscopy coupled with morphometric analysis. Failure of repair correlated with a reduction in the pool of proliferating oligodendrocyte progenitors (bromodeoxyuridine-labeled NG2(+) cells) followed by a reduction in the number of mature oligodendrocytes. Analysis of mice lacking TNF receptor 1 (TNFR1) or TNFR2 indicated that TNFR2, not TNFR1, is critical to oligodendrocyte regeneration. This unexpected reparative role for TNF alpha in the CNS is important for understanding oligodendrocyte regeneration/proliferation, nerve remyelination and the design of new therapeutics for demyelinating diseases.
Animals↗
Autotransplants for Hodgkin's disease in first relapse or second remission: a report from the autologous blood and marrow transplant registry (ABMTR).
Although patients with relapsed Hodgkin's disease have a poor prognosis with conventional therapies, high-dose chemotherapy and autologous hematopoietic stem cell transplantation (autotransplantation) may provide long-term progression-free survival. We reviewed data from the Autologous Blood and Marrow Transplant Registry (ABMTR) to determine relapse, disease-free survival, overall survival, and prognostic factors in this group of patients. Detailed records from the ABMTR on 414 patients with Hodgkin's disease in first relapse (n = 295) or second complete remission (CR) (n = 119) receiving an autotransplant from 1989 to 1995 were reviewed. Median age was 29 (range, 7-64) years. Median time from diagnosis to relapse was 18 (range, 6-219) months; median time from relapse to transplant was 5 (range, <1-215) months. Most patients received high-dose chemotherapy without total body irradiation for conditioning (n = 370). The most frequently used high-dose regimen was cyclophosphamide, BCNU, VP-16 (CBV) (n = 240). The graft consisted of bone marrow (n = 246), blood stem cells (n = 112), or both (n = 56). Median follow-up was 46 (range, 5-96) months. One hundred-day mortality (95% confidence interval) was 7 (5-9)%. One hundred and sixty-five of 295 patients (56%) transplanted in relapse achieved CR after autotransplantation. Of these, 61 (37%) recurred. Twenty-four of 119 patients (20%) transplanted in CR recurred. The probability of disease-free survival at 3 years was 46 (40-52)% for transplants in first relapse and 64 (53-72)% for those in second remission (P < 0.001). Overall survival at 3 years was 58 (52-64)% after transplantation in first relapse and 75 (66-83)% after transplantation in second CR (P < 0.001). In multivariate analysis, Karnofsky performance score <90% at transplant, abnormal serum LDH at transplant, and chemotherapy resistance were adverse prognostic factors for outcome. Progression of Hodgkin's disease accounted for 69% of all deaths. Autotransplantation should be considered for patients with Hodgkin's disease in first relapse or second remission. Future investigations should focus on strategies designed to decrease relapse after autotransplantation, particularly in patients at high risk for relapse.
Adolescent↗
Effect of aprotinin on endothelial cell activation.
BACKGROUND: Cardiopulmonary bypass surgery is often accompanied by a systemic inflammatory response, which can lead to postoperative complications in high-risk patients. This is mediated in part through a systemic rise in inflammatory cytokine levels and the sequestration of leukocytes within organs. Aprotinin has previously been shown to exert an anti-inflammatory effect by preventing the capacity of leukocytes to transmigrate through vascular endothelium. Here we have focused on whether aprotinin has an effect on endothelial cell activation and adhesion molecule expression in response to tumor necrosis factor-alpha, particularly with reference to whether aprotinin inhibits tumor necrosis factor-stimulated neutrophil transendothelial migration. METHODS AND RESULTS: Intercellular adhesion molecule-1, vascular cell adhesion molecule-1, and E-selectin expression was studied in tumor necrosis factor-alpha-activated human umbilical vein endothelial cells in the presence of aprotinin at 200, 800, and 1600 kIU/mL. Aprotinin inhibited tumor necrosis factor-alpha-stimulated expression of intercellular adhesion molecule-1 (P =.019 at 1600 kIU/mL) and vascular cell adhesion molecule-1 (P =.003 at 1600 kIU/mL) but not E-selectin. Similar results were obtained in the dermal microvascular endothelial cell line, HMEC-1, which exhibited diminished intercellular adhesion molecule-1 expression in the presence of aprotinin (P =.040 at 800 kIU/mL and P <.001 at 1600 kIU/mL). Aprotinin also significantly inhibited neutrophil transmigration across tumor necrosis factor-alpha-activated human umbilical vein endothelial cells (P =.046 at 1600 kIU/mL). CONCLUSIONS: We have demonstrated that aprotinin inhibits intercellular adhesion molecule-1 and vascular cell adhesion molecule-1, but not E-selectin, expression on tumor necrosis factor-alpha-activated endothelial cells and that transendothelial migration by neutrophils is also specifically suppressed under these conditions. Our results indicate that endothelial cells can be specifically targeted by aprotinin, therefore adding to our understanding of the anti-inflammatory mechanism of action of aprotinin during cardiopulmonary bypass.
Aprotinin↗
How to develop cost-conscious guidelines.
BACKGROUND: Clinical guidelines, defined as 'systematically developed statements to assist both practitioner and patient decisions in specific circumstances', have become an increasingly familiar part of clinical care. Guidelines are viewed as useful tools for making care more consistent and efficient and for closing the gap between what clinicians do and what scientific evidence supports. Interest in clinical guidelines is international and has its origin in issues faced by most healthcare systems: rising healthcare costs; variations in service delivery with the presumption that at least some of this variation stems from inappropriate care; the intrinsic desire of healthcare professionals to offer, and patients to receive, the best care possible. Within the UK, there is ongoing interest in the development of guidelines and a fast-developing clinical-effectiveness agenda within which guidelines figure prominently. Over the last decade, the methods of developing guidelines have steadily improved, moving from solely consensus methods to methods that take explicit account of relevant evidence. However, UK guidelines have tended to focus on issues of effectiveness and have not explicitly considered broader issues, particularly cost. This report describes the methods developed to handle benefit, harm and cost concepts in clinical guidelines. It reports a series of case studies, each describing the development of a clinical guideline; each case study illustrates different issues in incorporating these different types of evidence. HEALTH ECONOMICS AND CLINICAL GUIDELINES: There has been no widely accepted successful way of incorporating economic considerations into guidelines. Unlike other areas of guideline development, there is little practical or theoretical experience to direct the incorporation of cost issues within clinical guidelines. However, the reasons for considering costs are clearly stated: "health interventions are not free, people are not infinitely rich, and the budgets of [health care] programmes are limited. For every dollar's worth of health care that is consumed, a dollar will be paid. While these payments can be laundered, disguised or hidden, they will not go away" (Eddy DM. A manual for assessing health practices and designing practice policies: the explicit approach. Philadelphia: American College of Physicians; 1992). Such opportunity costs are a universal phenomenon. In the USA it has been recommended that every set of clinical guidelines should include information on the cost implications of the alternative preventive, diagnostic, and management strategies for each clinical situation. The stated rationale was that this information would help potential users to evaluate better the potential consequences of different practices. However, it was acknowledged that "the reality is that this recommendation poses major methodological and practical challenges" (Institute of Medicine. Guidelines for clinical practice: from development to use. Washington: National Academy Press; 1992). METHODS OF DEVELOPING CLINICAL GUIDELINES: A guideline development process summarises the technical information about the value of treatments in a manner that makes them accessible and ready for use in clinical practice, alongside information on contextual issues. The requirement is that the presentation of costs and benefits of treatments is methodologically sound, robust and accessible. This report includes a summary of the current best practice in evidence-based guideline development, including recent methodological advances. The manner in which cost and cost-effectiveness concepts have been successfully incorporated into the guideline process is introduced. GUIDELINE DEVELOPMENT CASE STUDIES: The 'cost-effectiveness' sections of 11 guidelines are reported to illustrate both the range of methods used and the nature of the recommendations reached by the guideline development groups when considering the profile of consequences of treatments including costs. These guidelines are broadly grouped as: (1) those using qualitative evidence summary methods; (2) those using quantitative evidence summary methods and addressing relatively narrow clinical questions; (3) those using quantitative evidence summary methods and addressing a broad clinical area; (4) a guideline based upon a decision analysis model. CONCLUSIONS: The focus of this project was to explore the methods of incorporating cost issues within clinical guidelines. However, the process of reviewing evidence in guideline development groups is becoming increasingly sophisticated, not only in considerations of cost but also in review techniques and group process. At the outset of the project it was unclear how narrowly or broadly the concept of 'cost' could be considered. (ABSTRACT TRUNCATED)
Arthritis↗
Hypomethylation of p53 in peripheral blood DNA is associated with the development of lung cancer.
Alterations in DNA methylation have been associated with cancers at almost all tumor sites and represent one of the most consistent changes in neoplastic cells. The underlying etiological mechanisms for alteration of DNA methylation patterns are not understood, but experimental studies in animals suggest potential environmental and genetic influences. The purpose of this study was to investigate whether DNA hypomethylation in peripheral blood DNA (potentially representing status at the lung) was associated with increased risk for the development of lung cancer. We evaluated genome-wide and p53 gene-specific hypomethylation in 100 lung cancer cases and controls selected from a large clinical trial of male smokers, the Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study. Genome-wide methylation status was assessed using the in vitro methyl acceptance capacity assay and p53 gene-specific methylation status using the HpaII quantitative PCR assay. Hypomethylation was evaluated as a risk factor using multivariate conditional logistic regression analyses. Genome-wide methylation status was unrelated to lung cancer risk; the odds ratio was 1.25 and the 95% confidence interval was 0.48-3.21 for those in the highest versus lowest quartile of hypomethylation status. Hypomethylation of the p53 gene in exons 5-8, the hypermutable region, was associated with a 2-fold increased risk for lung cancer (odds ratio, 2.20; 95% confidence interval, 1.04-4.65), whereas there was no risk increase for hypomethylation at exons 2-4, a region of the gene not known for its mutability or functional significance in cancer. Our results indicate that hypomethylation status within exons 5-8 of p53 from peripheral lymphocyte DNA may be a relevant predictor of lung cancer among male smokers.
Aged↗
Safety and costs of initiating angiotensin converting enzyme inhibitors for heart failure in primary care: analysis of individual patient data from studies of left ventricular dysfunction.
OBJECTIVE: To estimate the costs and consequences of diagnosing symptomatic heart failure with left ventricular systolic dysfunction and initiating angiotensin converting enzyme inhibitors in primary care. DESIGN: Analysis of individual patient data from studies of left ventricular dysfunction (SOLVD) to identify complications during test dose and titration phases. SETTING: Two randomised controlled trials in secondary care. PARTICIPANTS: 7487 patients taking a test dose of enalapril at enrolment to the treatment and prevention trials; 2569 patients with clinical signs of heart failure and established left ventricular dysfunction entered the treatment trial. MAIN OUTCOME MEASURES: Discontinuation during the test dose period. Discontinuation or reduction of dose during the first year of treatment for heart failure. Costs of diagnosis and titration of treatment. RESULTS: During the test dose phase, 585 patients (7.8%) reported side effects; 136 (1.8%) of these discontinued because of severe side effects. During the titration phase, compared with placebo, enalapril was associated with an increased risk of dose reduction due to hypotension (odds ratio 2.09, 95% confidence interval 1.15 to 3.82). However, overall, there was no difference in the rates of side effects leading to dose reduction or withdrawal between the enalapril and placebo groups. The costs of diagnosing heart failure with left ventricular systolic dysfunction and initiating and titrating an angiotensin converting enzyme inhibitor in primary care are pound300 to pound400. CONCLUSIONS: Treatment with angiotensin converting enzyme inhibitors can be safely started for patients with heart failure and left ventricular systolic dysfunction in primary care.
Adult↗
Location of death (in-hospital or out-of-hospital) and type of death (arrhythmic, nonarrhythmic, noncardiac) after inducible sustained ventricular tachyarrhythmias after syncope, sustained ventricular tachycardia, or nonfatal cardiac arrest (the ESVEM trial).
The ESVEM Trial evaluated methods to guide antiarrhythmic drug use in patients with spontaneous, inducible sustained tachyarrhythmias at electrophysiologic testing and frequent ventricular premature complexes (VPCs) per hour (>/=10). We assessed the relation between location (in-hospital or out-of-hospital) and classification of death (arrhythmic, nonarrhythmic, cardiac and/or noncardiac) for 486 randomized patients. Deaths were classified as out-of-hospital arrhythmic deaths if arrhythmic death occurred out-of-hospital, or if an arrhythmia preceded hospital admission and directly caused death. Of the 486 randomized patients, 188 (39%) died during 6 years of follow-up. The location and type of death could be determined clearly in 171 patients (91%). Ninety-one deaths were in-hospital (53%); 80 were out-of-hospital (47%). Arrhythmic deaths occurred in 85% out-of-hospital patients and in 30% in-hospital patients (p <0.001). Baseline characteristics were comparable for patients with out-of-hospital and in-hospital arrhythmic deaths. Twenty-seven of 95 arrhythmic deaths occurred in-hospital (28%); 72% occurred out-of-hospital. Out-of-hospital arrhythmic death accounted for 40% of deaths for which location and type of information were available. The 1- and 4-year actuarial out-of-hospital arrhythmic death rates were 9% and 18%, respectively. Of nonarrhythmic cardiac deaths, 91% were in-hospital and 9% were out-of-hospital. Of noncardiac deaths, 74% were in-hospital and 26% were out-of-hospital. Similar results were seen in the 296 patients for whom a drug was considered to be effective. Thus, over half the deaths in the ESVEM trial occurred in-hospital. The long-term actuarial risk of out-of-hospital arrhythmic death in ESVEM was unexpectedly low.
Actuarial Analysis↗
Systematic review and economic evaluation of Helicobacter pylori eradication treatment for non-ulcer dyspepsia. Dyspepsia Review Group.
OBJECTIVES: To evaluate efficacy and cost effectiveness of Helicobacter pylori eradication treatment in patients with non-ulcer dyspepsia infected with H pylori. DESIGN: Systematic review of randomised controlled trials comparing H pylori eradication with placebo or another drug treatment. Results were incorporated into a Markov model comparing health service costs and benefits of H pylori eradication with antacid treatment over one year. DATA SOURCES: Six electronic databases were searched for randomised controlled trials from January 1966 to May 2000. Experts in the field, pharmaceutical companies, and journals were contacted for information on any unpublished trials. Trial reports were reviewed according to predefined eligibility and quality criteria. MAIN OUTCOME MEASURES: Relative risk reduction for remaining dyspeptic symptoms (the same or worse) at 3-12 months. Cost per dyspepsia-free month estimated from Markov model based on estimated relative risk reduction. RESULTS: Twelve trials were included in the systematic review, nine of which evaluated dyspepsia at 3-12 months in 2541 patients. H pylori eradication treatment was significantly superior to placebo in treating non-ulcer dyspepsia (relative risk reduction 9% (95% confidence interval 4% to 14%)), one case of dyspepsia being cured for every 15 people treated. H pylori eradication cost pound56 per dyspepsia-free month during first year after treatment. CONCLUSION: H pylori eradication may be cost effective treatment for non-ulcer dyspepsia in infected patients but further evidence is needed on decision makers' willingness to pay for relief of dyspepsia.
Antacids↗
Hormone profiles in humans experiencing military survival training.
BACKGROUND: Clinical models of the human response to intense, acute stress have been limited to laboratory settings or cross sectional characterizations. As a result, data about the sensitivity of the human neuroendocrine activation to realistic stressors of varying magnitudes are limited. The U.S. Army survival course offers a unique opportunity to examine, in a controlled manner, the human response to acute, realistic, military stress. METHODS: Salivary data were collected in 109 subjects at baseline during four stress exposure time points and at recovery. Serum data was collected at baseline and recovery in 72 subjects and at baseline and during stress exposure in a subgroup of subjects (n = 21). RESULTS: Cortisol significantly increased during the captivity experience and was greatest after subjects' exposure to interrogations. Cortisol remained significantly elevated at recovery. Testosterone was significantly reduced within 12 hours of captivity. Reductions of both total and free T4 and of total and free T3 were observed, as were increases in thyrotropin. CONCLUSIONS: The stress of military survival training produced dramatic alterations in cortisol, percent free cortisol, testosterone, and thyroid indices. Different types of stressors had varying effects on the neuroendocrine indices. The degree of neuroendocrine changes observed may have significant implications for subsequent responses to stress.
Adult↗
Effect of population screening and treatment for Helicobacter pylori on dyspepsia and quality of life in the community: a randomised controlled trial. Leeds HELP Study Group.
BACKGROUND: Infection with Helicobacter pylori is the main cause of peptic-ulcer disease. Treatment of this infection might lower the prevalence of dyspepsia in the community and improve quality of life. We investigated this possibility in a double-blind randomised controlled trial. METHODS: Individuals aged 40-49 years were randomly selected from the lists of 36 primary-care centres. A researcher interviewed participants with a validated dyspepsia questionnaire and the psychological general wellbeing index (PGWB). H. pylori status was assessed by the carbon-13-labelled urea breath test. Infected participants were randomly assigned active treatment (omeprazole 20 mg, clarithromycin 250 mg, and tinidazole 500 mg, each twice daily for 7 days) or identical placebo. Participants were followed up at 6 months and 2 years. FINDINGS: Of 32,929 individuals invited, 8455 attended and were eligible; 2324 were positive for H. pylori and were assigned active treatment (1161) or placebo (1163). 1773 (76%) returned at 2 years. Dyspepsia or symptoms of gastro-oesophageal reflux were reported in 247 (28%) of 880 in the treatment group and 291 (33%) of 871 in the placebo group (absolute-risk reduction 5% [95% CI 1-10]). H. pylori treatment had no significant effect on quality of life (mean difference in PGWB score between groups 0.86 [-0.33 to 2.05]). INTERPRETATION: Community screening and treatment for H. pylori produced only a 5% reduction in dyspepsia. This small benefit had no impact on quality of life.
Adult↗
Determination of baseline human nasal pH and the effect of intranasally administered buffers.
The nose is becoming a common route of drug administration, however, little is known about the pH of the human nasal cavity. Local pH may have a direct effect on the rate and extent of absorption of ionizable compounds and hence this study was performed to investigate normal pH values and whether pH could be manipulated by various buffers. Twelve healthy volunteers participated in a study to measure pH in the anterior and posterior sites of the nasal cavity. Miniature pH electrodes were placed 3 cm apart in the nasal cavity and a baseline was recorded for 30 min once the pH had stabilized. One hundred microlitres of isotonic solution was sprayed into the nostril and the pH was measured for 4 h post-dose. The following five formulations were tested: formulation A--sodium chloride (0.9%) at pH 7.2; formulation B--sodium chloride (0.9%) at pH 5.8; formulation C--Sorensens phosphate buffer (0.06 M) at pH 5. 8; formulation D--Sorensens phosphate buffer (0.13 M) at pH 5.8 and formulation E--formulation as (c) but adjusted to pH 5.0. Each formulation also contained saccharin sodium (0.5%) as a taste marker for nasal clearance. The time at which each subject detected the taste of saccharin was noted. The 30-minute baseline recording prior to administration of the nasal spray formulation demonstrates that there was both considerable intersubject and intrasubject variation in nasal pH. The average pH in the anterior of the nose was 6.40 (+0. 11, -0.15 S.D.) when calculated from H(+) values. The pH in the posterior of the nasal cavity was 6.27 (+0.13, -0.18 S.D.). The overall range in pH was 5.17-8.13 for anterior pH and 5.20-8.00 for posterior pH. Formulation A caused the pH in the anterior part of the nasal cavity to reach a maximum of 7.06 in 11.25 min from the baseline of pH 6.14 (P<0.05). The mean baseline pH was 6.5 for the posterior part of the nose which did not change over the recording period. Formulation B caused the anterior pH to increase from pH 6. 60 to 7.25 within the first minute. This fell back to a mean pH of 7.07 over the first hour which was still significantly above the baseline. It remained at this value for the remainder of the recording period. The initial average posterior pH was 6.32 and again this did not significantly change over the recording period. Formulation C produced a sustained increase in anterior nasal pH from a baseline pH of 6.57-7.12. A small transient decrease was observed in the pH in the posterior of the nose but baseline pH of 6. 6 was re-established within 15 min post dose. Formulation D significantly reduced anterior nasal pH from 6.30 to 5.87 by 30 min reaching a pH of 5.95 by 90 min where it remained for the remainder of the recording period. The posterior baseline pH was 6.3 and introduction of the pH 5.8 buffer caused a slow increase over 90 min to pH 6.6. Formulation E increased anterior pH from 6.1 to 6.7 for the remainder of the recording period. It had an insignificant effect on posterior nasal pH. The mean (+/-S.D.) time to taste saccharin for formulations A to E was 13.42+/-10.21, 14.67+/-8.37, 11.67+/-8.08, 10.08+/-7.6, 9.80+/-6.73 min, respectively. There was no significant difference between the clearance times for the different formulations. In conclusion, average baseline human nasal pH is approximately 6.3. Nasal anterior pH can be decreased when buffers of 0.13 M and above are used. Mildly acidic solutions produce an increase in pH presumably due to reflux bicarbonate secretion. Posterior nasal pH was not altered by administration of any buffer except the 0.13 M buffer at pH 5.8. This produced a rise in posterior pH.
Administration, Intranasal↗
SSRIs versus other antidepressants for depressive disorder.
OBJECTIVES: To examine the relative efficacy of selective serotonin reuptake inhibitors (SSRIs) compared to other antidepressants. SEARCH STRATEGY: The search strategy included a search of (a) Electronic bibliographic databases (MEDLINE, EMBASE); (b) reference lists of related reviews (c) reference lists of all located studies (d) contact with the manufacturer and (e) the Cochrane Group register of controlled trials SELECTION CRITERIA: Randomised controlled trials comparing selective serotonin reuptake inhibitors with other kinds of antidepressants in the treatment of patients with depressive disorders. The outcome measures assessed included measures of the severity of depression. DATA COLLECTION AND ANALYSIS: Data were collected from each study the main outcome measurefrom each study. These included: mean Hamilton depression rating scale, mean Montgomery & Asberg depression rating scale, Clinical Global Impression rating scale. An analysis of standardised mean difference of these scales was performed using Review Manager 3. 1 software. The presence of heterogeneity of treatment effect was assessed MAIN RESULTS: Ninety-eight trials contributed data to the analysis of the relative efficacy of SSRIs and related drugs with comparator antidepressants (Figure 3 & Appendix 3). Analysis of efficacy was based upon 5044 patients treated with an SSRI or related drug, and 4510 treated with an alternative antidepressant. The standardised effect size for SSRIs and related drugs together versus alternative antidepressants using a fixed effects model was 0. 035 (95% CI -0.006 to 0.076; Q = 149.25, df = 97, p < 0.001). REVIEWER'S CONCLUSIONS: There are no clinically significant differences in effectiveness between selective serotonin reuptake inhibitors and tricyclic antidepressants. Treatment decisions need to be based on considerations of relative patient acceptability, toxicity and cost.
Antidepressive Agents↗