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Desmopressin
Terms modified by Desmopressin Selected AbstractsThe 80th anniversary of von Willebrand's disease: history, management and researchHAEMOPHILIA, Issue 6 2006A. B. FEDERICI Summary., The history of von Willebrand's disease (VWD) is fascinating because it demonstrates how good clinical observations, genetic studies and biochemical skills can improve basic understanding of a disease and its management. The continuous efforts of scientists and clinicians during the last 80 years have significantly improved the knowledge of von Willebrand factor (VWF) structure and function and the management of VWD. Diagnosis of phenotype and genotype is now available in many countries and treatment is becoming more specific according to the VWD type. Any therapeutic agents must correct the dual defect of haemostasis, i.e. the abnormal platelet adhesion due to reduced and/or dysfunctional and low levels of factor VIII (FVIII) associated with VWF defects. Desmopressin (DDAVP) is the treatment of choice for type 1 VWD because it induces release of VWF from cellular compartments. Plasma virally inactivated VWF concentrates containing FVIII are effective and safe in patients unresponsive to DDAVP. There are advanced plans to develop a recombinant VWF but this product will require the concomitant administration of FVIII for the control of acute bleeds. Basic research studies on cellular biology, biochemistry and immunology have confirmed the role of VWF as a crucial participant in both haemostasis and thrombosis as its main biological activity is to support platelet adhesion,aggregation in the circulation. Retrospective and prospective clinical research studies, including bleeding history and laboratory markers for diagnosis as well as the use of DDAVP and VWF concentrates to manage or prevent bleeds in patients with VWD have been essential to provide general guidelines for VWD management. The large number of publications quoting VWD and VWF emphasizes the important role of VWF in medicine. [source] Effect kinetics of desmopressin-induced platelet retention in healthy volunteers treated with aspirin or placeboHAEMOPHILIA, Issue 1 2000Lethagen Desmopressin is often used for haemostatic treatment in platelet dysfunction, but the effect kinetics of platelet responses and the mechanism of action are poorly known. This study aimed to determine the kinetics of platelet function responses induced by desmopressin in healthy volunteers treated with aspirin or placebo. Another aim was to correlate platelet responses to changes of von Willebrand factor (vWF) in plasma. We measured platelet function with a glass bead retention test, Ivy bleeding time, vWF:Ag and multimeric structure in plasma. Median baseline platelet retention was 12% (normal reference range 16,27%) during aspirin treatment and 18% during placebo. Median peak platelet retention after desmopressin was 33% during aspirin treatment and 34% during placebo. After about 3 h platelet function had returned to baseline. A second desmopressin dose after 3 h stimulated platelet retention to a similar extent as the first dose. There was no correlation between platelet responses and quantitative or qualitative changes of vWF in plasma. Platelet count did not change significantly. Thus, desmopressin's effect on platelet function lasts for about 3 h, but may be prolonged by a second dose immediately thereafter. These findings may have important clinical implications for patients with aspirin-induced platelet dysfunction undergoing surgery. [source] Long-term desmopressin response in primary nocturnal enuresis: open-label, multinational studyINTERNATIONAL JOURNAL OF CLINICAL PRACTICE, Issue 1 2009H. Lottmann Summary Background:, Primary nocturnal enuresis (PNE) is a distressing condition, particularly in severe cases (, 3 wet nights/week). A prevalent pathophysiological mechanism, especially in monosymptomatic PNE (PMNE), is commonly believed to be an insufficient increase in night-time release of antidiuretic hormone. Desmopressin, a synthetic analogue of antidiuretic hormone, has been shown to reduce the number of wet nights experienced by PMNE patients in several controlled trials. Aim: This study was performed to evaluate desmopressin treatment in the real-life clinical setting and was a large-scale, 6-month investigation of efficacy and safety in patients with severe PNE. Predictive factors for desmopressin response were also evaluated. A total of 744 children aged 5 years and above from four countries were involved in the study. Results: At baseline, patients had a median of 6 wet nights/week; at 6 months, 41% of patients had experienced , 50% reduction in the mean number of wet nights. Long-term desmopressin treatment was consistently well-tolerated across all ages, with 5% of patients experiencing any treatment-related adverse events. The strength of treatment response was associated with nocturnal diuresis (p < 0.0001) and age (p = 0.0167) in logistic regression analyses. Compliance and dosage were also associated with response and more patients experienced , 50% reduction in wet nights after 6 months' treatment than earlier in the study, suggesting the value of persistent treatment. Conclusion: This study shows that long-term desmopressin treatment in the clinical setting is effective and well-tolerated in PNE patients of 5 years and upwards. Early improvements in bedwetting of any appreciable magnitude may be rewarding, may facilitate compliance and enable good long-term response. [source] A randomised comparison of oral desmopressin lyophilisate (MELT) and tablet formulations in children and adolescents with primary nocturnal enuresisINTERNATIONAL JOURNAL OF CLINICAL PRACTICE, Issue 9 2007H. Lottmann Summary Aims:, Desmopressin is a useful treatment for primary nocturnal enuresis (PNE), a common childhood condition that can persist into adolescence. This open-label, randomised, cross-over study evaluated the preference of children and adolescents with PNE for sublingual desmopressin oral lyophilisate (MELT) vs. tablet treatment, and the efficacy, safety, compliance and ease of use associated with each formulation. In total, 221 patients aged 5,15 years who were already receiving desmopressin tablets were randomised 1 : 1 to receive desmopressin treatment in the order MELT/tablet (n = 110) or tablet/MELT (n = 111) for 3 weeks each. Each formulation was administered in bioequivalent doses (0.2/0.4 mg tablets , 120/240 ,g MELT). Following treatment, patients were questioned regarding treatment preference. Diary card data and 100 mm Visual Analogue Scale scores were also recorded. Results:, Overall, patients preferred the MELT formulation to the tablet (56% vs. 44%; p = 0.112). This preference was age dependent (p = 0.006); patients aged < 12 years had a statistically significant preference for desmopressin MELT (p = 0.0089). Efficacy was similar for both formulations (MELT: 1.88 ± 1.94 bedwetting episodes/week; tablet: 1.90 ± 1.85 episodes/week). Ease of use of both formulations was high. Compliance (, 80%) was 94.5% for MELT patients vs. 88.9% for the tablet (p = 0.059). No serious/severe adverse events were reported. Conclusions:, There was an overall preference for the MELT, and a statistically significant preference for desmopressin MELT in children aged 5,11 years. Desmopressin MELT had similar levels of efficacy and safety at lower dosing levels than the tablet, and therefore facilitates early initiation of PNE treatment in children aged 5,6 years. [source] The Relationship Between the Action of Arginine Vasopressin and Responsiveness to Oral Desmopressin in Older Men: A Pilot StudyJOURNAL OF AMERICAN GERIATRICS SOCIETY, Issue 4 2007Theodore M. Johnson II OBJECTIVES: To identify whether oral desmopressin (ddAVP) reduced nocturnal urine volume (NUV) in older men with nocturia without obvious bladder outlet obstruction and to determine whether deficiencies in arginine vasopressin (AVP) release and action demonstrated using water deprivation testing predicted responsiveness to ddAVP. DESIGN: Participants had a 2-day Clinical Research Center (CRC) evaluation followed by a double-blinded, placebo-controlled, crossover trial of individually titrated oral ddAVP. SETTING: Participants were from a single Department of Veterans Affairs Medical Center. MEASUREMENTS: Maximum urine osmolality and percentage increase in osmolality were measured after subjects received aqueous vasopressin as part of the overnight water deprivation study; these data were used to categorize participants as normal, having partial central AVP deficiency, or having impaired renal responsiveness to AVP. Response to ddAVP was assessed using data from frequency-volume records. RESULTS: Fourteen participants completed the CRC stay and ddAVP trial. Subjects given ddAVP reduced NUV significantly from baseline (P=.02) and had significantly lower NUV than when on placebo (P=.01). The mean net reduction in NUV from ddAVP compared to placebo was 14±18%. Using water deprivation testing to categorize participants, 10 were normal, two had partial central AVP deficiency, and two had impaired renal responsiveness. The mean net reduction in NUV for those with abnormal water deprivation tests was 11±25%, versus 15±16% for those with normal water deprivation testing (P=.70). CONCLUSION: In this small randomized, controlled trial in older men with nocturia, ddAVP reduced NUV. Counter to expectations, participants deemed normal according to water deprivation tests had approximately equivalent responsiveness to ddAVP. Although this study cannot offer definitive conclusions on the lack of prediction of water deprivation testing for ddAVP benefit, these data offer additional information that may help clarify the pathophysiology and optimal treatment of nocturia in older men. [source] Desmopressin, an unexpected link between nocturnal enuresis and inherited thrombotic thrombocytopenic purpura (Upshaw-Schulman syndrome)JOURNAL OF THROMBOSIS AND HAEMOSTASIS, Issue 3 2006A. VEYRADIER [source] The use of desmopressin as a hemostatic agent: A concise reviewAMERICAN JOURNAL OF HEMATOLOGY, Issue 8 2007Massimo Franchini Desmopressin, a synthetic derivative of the antidiuretic hormone vasopressin, is the treatment of choice for most patients with von Willebrand disease and mild hemophilia A. Moreover, the compound has been shown to be useful in a variety of inherited and acquired hemorrhagic conditions, including some congenital platelet function defects, chronic liver disease, uremia, and hemostatic defects induced by the therapeutic use of antithrombotic drugs such as aspirin and ticlopidine. Finally, desmopressin has been used as a blood saving agent in patients undergoing operations characterized by large blood loss and transfusion requirements, but studies suggest that this is not as effective as other methods. This review briefly summarizes the current clinical indications on the use of desmopressin as a hemostatic agent. Am. J. Hematol., 2007. © 2007 Wiley-Liss, Inc. [source] Effects of desmopressin on platelet function under conditions of hypothermia and acidosis: an in vitro study using multiple electrode aggregometry,ANAESTHESIA, Issue 7 2010A. A. Hanke Summary Hypothermia and acidosis lead to an impairment of coagulation. It has been demonstrated that desmopressin improves platelet function under hypothermia. We tested platelet function ex vivo during hypothermia and acidosis. Blood samples were taken from 12 healthy subjects and assigned as follows: normal pH, pH 7.2, and pH 7.0, each with and without incubation with desmopressin. Platelet aggregation was assessed by multiple electrode aggregometry. Baseline was normal pH and 36 °C. The other samples were incubated for 30 min and measured at 32 °C. Acidosis significantly impaired aggregation. Desmopressin significantly increased aggregability during hypothermia and acidosis regardless of pH, but did not return it to normal values at low pH. During acidosis and hypothermia, acidosis should be corrected first; desmopressin can then be administered to improve platelet function as a bridge until normothermia can be achieved. [source] Vasopressin-induced facilitation of adrenergic responses in the rat mesenteric artery is V1 -receptor dependentAUTONOMIC & AUTACOID PHARMACOLOGY, Issue 1 2003J. O. Streefkerk Summary 1 The present study was designed to analyse the possible involvement of V1 - and V2 -receptors in vasopressin (AVP)-induced facilitation of the sympathetic nervous system. Furthermore, we aimed to determine whether the site of facilitation by AVP is located pre- or postsynaptically. 2 Electrical field stimulation (EFS) was applied on the rat mesteric artery to activate the sympathetic nervous system. In addition, we evaluated the direct vascular effects of AVP. The postsynaptic effect of AVP on the sympathetic nervous system was investigated by exposing the vessels to exogenous noradrenaline. These experiments were performed in the absence or presence of selective V1 and V2 receptor antagonists SR 49059 and SR 121463, respectively. Desmopressin was applied as a selective V2 agonist. 3 The direct vasoconstrictor effect of AVP was antagonized by SR 49059 and not by SR 121463. Desmopressin neither showed any direct vasoconstrictor effect nor produced vasodilatation after a precontraction induced by noradrenaline (10 ,m). The EFS-induced rise in vascular tone could be increased by a sub-pressor concentration of AVP. This fascilitation could be antagonized by SR 49059, but not by SR 121463. Desmopressin did not influence the increase in vascular tone during EFS. Vasoconstriction induced by exogenous noradrenaline could be facilitated by a sub-pressor concentration of AVP and this selective postsynaptic effect could be antagonized by V1 -receptor blockade. 4 In conclusion, the AVP-induced facilitation of the sympathetic nervous system is completely V1 -receptor dependent and at least partly postsynaptically mediated. [source] Antidiuretic hormone in elderly male patients with severe nocturia: a circadian studyBJU INTERNATIONAL, Issue 4 2004Du Geon Moon OBJECTIVE To investigate the circadian variation of plasma antidiuretic hormone (ADH) and urine output in patients with severe nocturia (> three times per night) and to assess the effect of oral desmopressin on nocturnal urine output in these patients. PATIENTS AND METHODS Twelve patients with severe nocturia and five age-matched controls without were assessed over 24 h (circadian sampling) during a 72-h hospital admission. Blood levels of ADH and changes of urine output were measured in the patients before and after the oral administration of desmopressin (0.2 mg, at 22.00 hours in the second day), and in the controls not treated with desmopressin. RESULTS Compared with the normal control, the patients had no diurnal variation in urine output and greater nocturnal urine production, associated with a lack of nocturnal increase in ADH level. Compared with the baseline urine output, desmopressin significantly decreased night-time (23.00,08.00 hour) urine output in the patients (P < 0.05). Desmopressin significantly increased the osmolality of night-time urine (P < 0.05), and there was no systemic adverse reaction. CONCLUSIONS Severe nocturia in a large proportion of elderly men with lower urinary tract symptoms is caused by nocturnal polyuria and natriuresis, because they have no nocturnal increase in ADH. These results suggest that desmopressin may be effective in decreasing nocturnal urine production in patients with severe nocturia who do not respond to conventional treatment. [source] Desmopressin in elderly patients with nocturia: short-term safety and effects on urine output, sleep and voiding patternsBJU INTERNATIONAL, Issue 7 2003A. Rembratt OBJECTIVE To investigate the short-term safety of desmopressin in elderly patients with nocturia, with special focus on the risk of hyponatraemia, and to assess the short-term effects on urine output, sleep and voiding patterns. PATIENTS AND METHODS Patients (72) were recruited from a study using frequency-volume charts, which in turn was preceded by a questionnaire study. Each patient took one 0.2 mg desmopressin tablet at bedtime for three consecutive nights and kept a frequency-volume chart. Serum sodium was assessed in the morning after the first and the third dose. Patients with a mean serum sodium level during treatment deviating more than five units from baseline were considered sensitive to change in serum sodium. Potential predictors for sodium sensitivity and response were investigated with logistic and multiple regression. RESULTS All 72 enrolled patients completed the trial; no serious adverse events occurred and no adverse events of severe intensity were recorded. Six patients were sensitive to change in serum sodium. The risk (odds ratio, 95% confidence interval) increased with increasing age (1.3, 1.1,1.6), concomitant cardiac disease (10.0, 0.9,105.8) and increasing baseline 24-h urine output (1.2, 1.0,1.5). Patients sensitive to change in serum sodium were pharmacological responders and desmopressin had a greater effect on their 24-h diuresis, indicating that the drug effect was not limited to the night only. CONCLUSION Desmopressin was well tolerated in elderly patients with nocturia, but the results suggest that serum sodium should be measured before and after a few days of treatment. [source] The role of desmopressin in bilateral and simultaneous inferior petrosal sinus sampling for differential diagnosis of ACTH-dependent Cushing's syndromeCLINICAL ENDOCRINOLOGY, Issue 1 2007Marcio Carlos Machado Summary Objective, ,Bilateral inferior petrosal sinus sampling (BIPSS) with corticotrophin-releasing hormone (CRH) stimulation is currently the gold standard test for the differential diagnosis of ACTH-dependent Cushing's syndrome. Reports on the use of desmopressin in this approach are limited. The aim of this study was to evaluate the use of desmopressin during BIPSS in a cohort of patients with ACTH-dependent Cushing's syndrome. Design, ,A retrospective case-record study. Patients,, Fifty-six patients with confirmed ACTH-dependent Cushing's syndrome underwent BIPSS with desmopressin stimulation when presenting negative pituitary tumour imaging. Measurements,, Central to peripheral (CEN:PER) ACTH gradient, lateralization of the ACTH source and surgical tumour confirmation were evaluated. Results,, A CEN:PER ACTH gradient was found in 40 patients under basal conditions (CEN:PER , 2) and in 47 patients after desmopressin stimulation (CEN:PER , 3). Ectopic ACTH-producing tumours (three lung carcinoid tumour, one thymus carcinoid tumour and one thymus hyperplasia) were confirmed in five out of nine patients without the CEN:PER ACTH gradient, and four cases were false negative for Cushing's disease. Lateralization (IPS:IPS , 1·4) was observed in 80·8% of patients under basal conditions (38/47) and in 97·8% after desmopressin (46/47), and it was surgically confirmed in 78·7%. There were no false-positive cases. Sensitivity and specificity were 92·1% and 100%, respectively. Conclusions, ,Desmopressin improves the differential diagnosis of ACTH-dependent Cushing's syndrome by amplifying the CEN:PER and IPS:IPS ACTH gradients, and is therefore a useful ACTH secretagogue in BIPSS. [source] Mild haemophilia: a disease with many faces and many unexpected pitfallsHAEMOPHILIA, Issue 2010K. PEERLINCK Summary., Despite major advances in diagnosis and treatment, the management of patients with mild haemophilia (MH) remains a major challenge. Mild haemophilia is defined by factor levels between 0.05 and 0.40 IU mL,1. The bleeding associated with mild haemophilia is most frequently episodic, occurring during surgery or following trauma. Spontaneous bleeding is rare. Diagnosis is sometimes delayed because of insensitivity of screening clotting assays or discrepancies in factor VIII activity as measured by different assays. The treatment of choice in mild haemophilia A is desmopressin, which typically induces a 2,6-fold increase of factor VIII over baseline. However, desmopressin has its limitations in this setting such as the occurrence of tachyphylaxis and failure to respond in an undetermined proportion of patients. Factors underlying poor biological response or magnitude of response to desmopressin are incompletely understood. Inhibitor development in mild haemophilia is particularly distressing. This complication arises at an older age in this patient group because of infrequent need for factor VIII replacement. Inhibitors in mild haemophilia patients often cross-react with endogenous factor VIII resulting in severe spontaneous bleeding frequently in a postoperative setting. Intensive perioperative use of factor VIII and some specific mutations induce a particularly high risk for inhibitor development, but risk factors are incompletely understood. For reasons of the older age of the patients, treatment of bleeding with bypassing agents may cause major thrombotic complications. Data on therapeutic options for inhibitor eradication in patients with mild haemophilia are particularly scarce. With increased life-expectancy for all haemophilia patients, the group of elderly patients with mild haemophilia requiring major surgery will further increase. Prevention of inhibitors, particularly in this patient group, should be a major topic of interest in both clinic and research. [source] Efficacy of desmopressin as surgical prophylaxis in patients with acquired von Willebrand disease undergoing thyroid surgeryHAEMOPHILIA, Issue 2 2002M. FRANCHINI Coagulation abnormalities may occur in patients with thyroid diseases. We report on 14 patients undergoing thyroid surgery for a thyroid disease with an alteration of coagulation parameters resembling von Willebrand disease. Subcutaneous desmopressin was first tested and then used successfully in these patients as surgical prophylaxis, with no side-effects or bleeding complications during or after surgery. This study highlights the need for coagulation studies in patients with thyroid diseases undergoing thyroid surgery. Subcutaneous desmopressin may be used in these patients in order to prevent a surgically related bleeding risk. [source] Use of ristocetin cofactor activity in the management of von Willebrand diseaseHAEMOPHILIA, Issue 2001B.M. Ewenstein von Willebrand disease (vWD), the most common of the hereditary bleeding disorders, arises from quantitative or qualitative defects in von Willebrand factor (vWF). vWF is a multimeric plasma protein that plays a key role in primary and secondary haemostasis. In the current classification scheme, vWD is divided into six subtypes that are based on the nature of the vWF defect. Therapeutic strategies depend on the accurate identification of these subtypes. In most clinical situations, desmopressin is effective treatment for the great majority of patients with mild (type 1) disease, while replacement therapy with factor VIII/vWF concentrates that contain high levels of vWF activity is required for most type 2 and nearly all type 3 vWD patients. Several factor VIII/vWF replacement products are available, one of which (Humate P) has been approved for the treatment of vWD by the US Food and Drug Administration. Preliminary results of recent studies support the hypothesis that treatment with factor VIII/vWF concentrates based upon the content of vWF activity as reflected in the ristocetin cofactor assay is practicable, safe and efficacious. The establishment of optimal treatment regimens with respect to dose intensity and duration will require further study. [source] Factor XI deficiency and its managementHAEMOPHILIA, Issue 2000Bolton-Maggs Factor XI deficiency has a more variable bleeding tendency than haemophilia A or B. Individuals with severe deficiency have only a mild bleeding tendency, which is typically provoked by surgery, but the risk of bleeding is not restricted to individuals with severe deficiency. The bleeding tendency varies between individuals with similar factor XI levels, and sometimes the bleeding tendency of an individual may vary. The reasons for this are not fully understood, although in cases of severe deficiency there is some correlation between phenotype and genotype. Factor XI is activated by thrombin. The role of factor XI in physiological processes has become clearer since this fact was discovered, and the discovery has contributed to a revised model of blood coagulation. Factor XI deficiency occurs in all racial groups, but is particularly common in Ashkenazi Jews. The factor XI gene is 23 kilobases long. Two mutations are responsible for most factor XI deficiency in the Ashkenazi population, but a number of other mutations have now been reported in other racial groups. Individuals with factor XI deficiency may need specific therapy for surgery, accidents, and dental extractions. Several therapies are available which include fresh frozen plasma, factor XI concentrates, fibrin glue, antifibrinolytic drugs, and desmopressin. Each has advantages and risks to be considered. Factor XI concentrate may be indicated for procedures with a significant risk of bleeding especially in younger patients with severe deficiency, but its use in older patients has been associated with thrombotic phenomena. If fresh frozen plasma is to be used it is preferable to obtain one of the virally inactivated products. Fibrin glue is a useful treatment which deserves further study. [source] Effect kinetics of desmopressin-induced platelet retention in healthy volunteers treated with aspirin or placeboHAEMOPHILIA, Issue 1 2000Lethagen Desmopressin is often used for haemostatic treatment in platelet dysfunction, but the effect kinetics of platelet responses and the mechanism of action are poorly known. This study aimed to determine the kinetics of platelet function responses induced by desmopressin in healthy volunteers treated with aspirin or placebo. Another aim was to correlate platelet responses to changes of von Willebrand factor (vWF) in plasma. We measured platelet function with a glass bead retention test, Ivy bleeding time, vWF:Ag and multimeric structure in plasma. Median baseline platelet retention was 12% (normal reference range 16,27%) during aspirin treatment and 18% during placebo. Median peak platelet retention after desmopressin was 33% during aspirin treatment and 34% during placebo. After about 3 h platelet function had returned to baseline. A second desmopressin dose after 3 h stimulated platelet retention to a similar extent as the first dose. There was no correlation between platelet responses and quantitative or qualitative changes of vWF in plasma. Platelet count did not change significantly. Thus, desmopressin's effect on platelet function lasts for about 3 h, but may be prolonged by a second dose immediately thereafter. These findings may have important clinical implications for patients with aspirin-induced platelet dysfunction undergoing surgery. [source] Nocturia in older people: A review of causes, consequences, assessment and managementINTERNATIONAL JOURNAL OF CLINICAL PRACTICE, Issue 4 2004A. Ali Summary Nocturia is common in older people and it may be bothersome for both patients and carers. It is most commonly related to bladder storage difficulties and nocturnal polyuria. The former results most frequently from an uninhibited overactive bladder. The latter occurs as a consequence of age-associated changes in the circadian rhythm of urine excretion. The management of an overactive bladder includes both behavioural and drug treatment. The management options for nocturnal polyuria include an afternoon diuretic and desmopressin, but caution is required, particularly with the latter, as it can cause significant hyponatraemia. [source] The effect of desmopressin on blood loss in patients with rheumatoid arthritis undergoing hip arthroplastyACTA ANAESTHESIOLOGICA SCANDINAVICA, Issue 7 2010K. A. LEINO Background: Blood loss is an important issue for patients with rheumatoid arthritis undergoing hip surgery. We hypothesised that intraoperative desmopressin treatment would result in a reduction in blood loss in rheumatoid patients undergoing total hip arthroplasty. Methods: Seventy-five patients scheduled for elective total hip arthroplasty were randomised to three groups to receive 0.4 ,g/kg desmopressin (D 0.4), 0.2 ,g/kg desmopressin (D 0.2) or placebo intraoperatively in a double-blind fashion. Blood transfusions were based on calculated safe allowable blood loss and haemoglobin measurements (trigger 90 g/l, 5.59 mmol/l). The primary endpoint was the total blood loss measured till the end of the fourth post-operative day. Secondary endpoints included red cell transfusion requirements and haemoglobin. Results: Total blood loss during the study period was not significantly different between the groups (D 0.4 1829 ± 1068; D 0.2 2240 ± 843 and placebo 2254 ± 1040 ml; P= 0.50). The total amount of red cell transfusions was fewer in group D 0.4 (3.6 ± 1.6 U) when compared with D 0.2 (4.4 ± 1.7 U; P=0.009) and placebo (4.5 ± 2.0 U; P= 0.011) groups. Haemoglobin concentration was lower in the placebo group in the first (5.42 ± 1.16 vs. 5.98 ± 0.47 mmol/l; P=0.033) and the second (6.28 ± 0.66 vs. 6.69 ± 0.47 mmol/l; P=0.033) post-operative mornings compared with group D 0.4. Conclusion: Despite a lack of difference in the primary outcome, total blood loss, intraoperative administration of 0.4 ,g/kg desmopressin resulted in fewer total red cell transfusion requirements in rheumatoid patients undergoing total hip arthroplasty when compared with 0.2 ,g/kg treatment and placebo. [source] Clinical guidelines for nocturiaINTERNATIONAL JOURNAL OF UROLOGY, Issue 5 2010The Committee for Establishment of the Clinical Guidelines for Nocturia of the Neurogenic Bladder Society Abstract Nocturia is a bothersome condition, defined as a complaint whereby the individual has to wake one or more times per night in order to void. Nocturia that occurs twice or more per night can have a substantial adverse effect on the patient's quality of life (QOL), and in many cases treatment may be required. These guidelines provide a treatment algorithm for use by primary care physicians. The initial assessment is conducted through a history taking interview. With a clear understanding of symptoms, patients can be classified into three broad categories: (1) nocturia only, (2) nocturia and diurnal pollakisuria without other lower urinary tract symptoms, and (3) nocturia and diurnal pollakisuria accompanying other lower urinary tract symptoms. For treatment, the literature supporting each form of drug therapy was ranked and a recommendation grade was determined for each form of therapy. A grade of ,F (pending)' was applied to any drug not currently approved for use in Japan or for which the efficacy and safety in Japanese patients was unconfirmed at the time of evaluation. We recommend instruction and guidance on water intake that will generally result in 24-h urine volume of 20 to 25 mL/kg. This corresponds to a daily water intake of 2.0% to 2.5% of body weight. In Japan, desmopressin is indicated for central diabetes insipidus and nocturnal enuresis, but not indicated for nocturia. The therapeutic mechanism of the anticholinergic drugs for nocturia may depend on the action of the sensory nerve mediated by the muscarinic receptors. [source] The Relationship Between the Action of Arginine Vasopressin and Responsiveness to Oral Desmopressin in Older Men: A Pilot StudyJOURNAL OF AMERICAN GERIATRICS SOCIETY, Issue 4 2007Theodore M. Johnson II OBJECTIVES: To identify whether oral desmopressin (ddAVP) reduced nocturnal urine volume (NUV) in older men with nocturia without obvious bladder outlet obstruction and to determine whether deficiencies in arginine vasopressin (AVP) release and action demonstrated using water deprivation testing predicted responsiveness to ddAVP. DESIGN: Participants had a 2-day Clinical Research Center (CRC) evaluation followed by a double-blinded, placebo-controlled, crossover trial of individually titrated oral ddAVP. SETTING: Participants were from a single Department of Veterans Affairs Medical Center. MEASUREMENTS: Maximum urine osmolality and percentage increase in osmolality were measured after subjects received aqueous vasopressin as part of the overnight water deprivation study; these data were used to categorize participants as normal, having partial central AVP deficiency, or having impaired renal responsiveness to AVP. Response to ddAVP was assessed using data from frequency-volume records. RESULTS: Fourteen participants completed the CRC stay and ddAVP trial. Subjects given ddAVP reduced NUV significantly from baseline (P=.02) and had significantly lower NUV than when on placebo (P=.01). The mean net reduction in NUV from ddAVP compared to placebo was 14±18%. Using water deprivation testing to categorize participants, 10 were normal, two had partial central AVP deficiency, and two had impaired renal responsiveness. The mean net reduction in NUV for those with abnormal water deprivation tests was 11±25%, versus 15±16% for those with normal water deprivation testing (P=.70). CONCLUSION: In this small randomized, controlled trial in older men with nocturia, ddAVP reduced NUV. Counter to expectations, participants deemed normal according to water deprivation tests had approximately equivalent responsiveness to ddAVP. Although this study cannot offer definitive conclusions on the lack of prediction of water deprivation testing for ddAVP benefit, these data offer additional information that may help clarify the pathophysiology and optimal treatment of nocturia in older men. [source] Living without aprotinin: the results of a 5-year blood saving program in cardiac surgeryACTA ANAESTHESIOLOGICA SCANDINAVICA, Issue 5 2009M. RANUCCI Background: After 20 years of regular use in cardiac surgery patients, aprotinin has recently been withdrawn from the market due to many concerns about its safety. For a number of reasons aprotinin has not been available in Italy since 1998. The present study presents an aprotinin-free treatment protocol applied at our institution during the last 5 years, and aims to verify the results of this protocol in terms of allogeneic blood product transfusions, postoperative blood loss and surgical re-exploration rate. Methods: Retrospective study on 7988 consecutive patients who underwent cardiac surgery during the years 2003,2007. All the patients received specific hemostasis/coagulation management based on (a) routine use of tranexamic acid, (b) heparin dose,response monitoring, thromboelastography, platelet (PLT) function analysis in a select population of patients, and (c) use of fresh frozen plasma (FFP), PLTs, and desmopressin according to the hemostasis/coagulation profile. Data retrieved from the institutional database were quantity of packed red cells (PRCs), FFP, PLT transfusion rate, blood loss in the first 12 postoperative hours, and surgical re-exploration rate. Results: PRCs were transfused in 40.4% of patients (with higher rates for selected high-risk subpopulations), FFP in 12.9% and PLTs in 2.6%. Surgical re-exploration rate was 3.7%. With respect to historical controls, a significant reduction of PRCs and FFP transfusions was obtained using closed circuits, point of care coagulation tests, and combination of the two. Conclusion: This aprotinin-free blood saving program is an effective strategy for allogeneic blood products transfusion containment. [source] Vasopressin Preferentially Depresses Excitatory Over Inhibitory Synaptic Transmission in the Rat Supraoptic Nucleus In VitroJOURNAL OF NEUROENDOCRINOLOGY, Issue 4 2000Kombian1 Endogenous arginine-vasopressin (AVP) in the supraoptic nucleus is known to decrease the firing rate of some supraoptic nucleus neurones. To determine a possible mechanism by which this locally released AVP produces this change in neuronal excitability, we investigated the effects of AVP on evoked excitatory (e.p.s.c.) and inhibitory post-synaptic (i.p.s.c.) responses recorded in magnocellular neurones in a hypothalamic slice preparation, using the perforated-patch recording technique. Our data show that AVP produces a dose-dependent decrease in the evoked e.p.s.c. in about 80% of magnocellular neurones tested with an estimated EC50 of about 0.9 ,M. The maximum decrease in e.p.s.c. amplitude was about 31% of control and was obtained with an AVP concentration of 2 ,M. The AVP-induced synaptic depression was blocked by Manning Compound (MC), a non-selective antagonist of oxytocin (OXT) and vasopressin (AVP) receptors, but not by a selective OXT receptor antagonist. It was not mimicked by desmopressin (ddAVP), a V2-receptor subtype agonist. By contrast, AVP used at the same concentration (2 ,M), had no global effect on pharmacologically isolated i.p.s.c.s in the majority of magnocellular neurones tested. These results show that AVP acts in the supraoptic nucleus to reduce excitatory synaptic transmission to magnocellular neurones by activating a non-OXT receptor, presumably the V1 receptor subtype. [source] The influence of lithium on the antidiuretic effect of desmopressinJOURNAL OF PHARMACY AND PHARMACOLOGY: AN INTERNATI ONAL JOURNAL OF PHARMACEUTICAL SCIENCE, Issue 9 2002Torbjörn Callréus ABSTRACT The objective of this study was to investigate the graded influence from lithium on the antidiuretic effects of desmopressin. Eight healthy male subjects participated in this open, randomised cross-over study with two periods comprising 6 days each. For each subject, one of the study days (6th day) was preceded by a period of lithium treatment. On the study days the subjects were orally water loaded to achieve a state of overhydration with a high urine flow rate. When a steady-state diuresis was achieved after approximately 2 h, 0.396 ,g of desmopressin was administered intravenously as a bolus injection. An indirect-response model, where desmopressin was assumed to inhibit the elimination of response, was fitted to the urine osmolarity data. The effects of the independent variables, Uflow (baseline) (baseline urine flow rate), R0 (baseline osmolarity) and serum lithium concentration, on IC50 (concentration producing 50% of the maximum inhibition) could be expressed by multiple linear regression. In conclusion, we found that an indirect-response model can be a useful tool in investigating and describing the pharmacodynamic interaction between drugs, in this particular case, between lithium and desmopressin. [source] Cerebral and conjunctival haemorrhages associated with von Willebrand factor deficiency and canine angiostrongylosisJOURNAL OF SMALL ANIMAL PRACTICE, Issue 2 2005N. T. Whitley A case of angiostrongylosis is described in a 14-month-old golden retriever bitch. Conjunctival haemorrhage and neurological signs, referable to a space-occupying cerebral lesion, were associated with defective primary haemostasis caused by low levels of von Willebrand factor. Full clinical recovery followed treatment with desmopressin, fresh whole blood transfusion, fenbendazole and supportive care. The magnetic resonance image of the suspected organising haematoma is described. Similarities to the human condition, acquired von Willebrand syndrome, and a possible role for aberrant larval migration in haematoma formation are suggested. [source] Expression studies on a novel type 2B variant of the von Willebrand factor gene (R1308L) characterized by defective collagen bindingJOURNAL OF THROMBOSIS AND HAEMOSTASIS, Issue 12 2005L. BARONCIANI Summary., A novel mutation, R1308L (3923G > T) was present in the heterozygous state in five members of a family with type 2B von Willebrand disease (VWD) characterized by a full set of von Willebrand factor (VWF) multimers in plasma and by the absence of thrombocytopenia before and after desmopressin (DDAVP). The defect (R1308L) was located at the same amino acid position of one of the most common mutations associated with type 2B VWD (R1308C), which is characterized by the loss of high molecular weight VWF multimers (HMWM) in plasma and the occurrence of thrombocytopenia. To understand the mechanisms of this defect, the novel (R1308L) and ,common' (R1308C) mutations were expressed in COS-7 cells, either alone or, to mimic the patients' heterozygous state, together with wild-type VWF. R1308L recombinant VWF (rVWF) had a higher affinity for the platelet glycoprotein Ib, (GPIb,) receptor than wild-type rVWF, R1308C rVWF showing an even higher affinity. A novel finding was that both mutant rVWFs showed a similarly reduced binding to collagen type I and type III in comparison with wild-type rVWF. The latter finding suggests a more important role than recognized so far for the VWF A1 domain in VWF binding to collagen, which may contribute to the in vivo hemostatic defect associated with type 2B VWD. [source] Desmopressin treatment in nocturia; an analysis of risk factors for hyponatremiaNEUROUROLOGY AND URODYNAMICS, Issue 2 2006A. Rembratt Abstract Aims To explore the incidence, severity, time course, and risk factors of clinically significant hyponatremia in desmopressin treatment for nocturia. Methods Data from three multi-center phase III trials were pooled. Hyponatremia was categorised as borderline (134,130 mmol/L) or significant (<130 mmol/L). Risk factors were explored with logistic regression and subgroup analysis performed to explore threshold values for contra-indication. Results In total 632 patients (344 men, 288 women) were analyzed. During dose-titration, serum sodium concentration below normal range was recorded in 95 patients (15%) and 31 patients (4.9%) experienced significant hyponatremia. The risk increased with age, lower serum sodium concentration at baseline, higher basal 24-hr urine volume per bodyweight and weight gain at time of minimum serum sodium concentration. Age was the best single predictor. Elderly patients (,65 years of age) with a baseline serum sodium concentration below normal range were at high risk (75%). Limiting treatment in elderly with normal basal serum sodium concentration to those below 79 years and with a 24-hr urine output below 28 ml/kg would reduce the risk from 8.1% to 3.0% at the cost of 34% fulfilling the contra-indication. Conclusions The majority of nocturia patients tolerate desmopressin treatment without clinically significant hyponatremia. However, the risk increases with increasing age and decreasing baseline serum sodium concentration. Treatment of nocturia in elderly patients with desmopressin should only be undertaken together with careful monitoring of the serum sodium concentration. Patients with a baseline serum sodium concentration below normal range should not be treated. © 2005 Wiley-Liss, Inc. [source] The use of desmopressin as a hemostatic agent: A concise reviewAMERICAN JOURNAL OF HEMATOLOGY, Issue 8 2007Massimo Franchini Desmopressin, a synthetic derivative of the antidiuretic hormone vasopressin, is the treatment of choice for most patients with von Willebrand disease and mild hemophilia A. Moreover, the compound has been shown to be useful in a variety of inherited and acquired hemorrhagic conditions, including some congenital platelet function defects, chronic liver disease, uremia, and hemostatic defects induced by the therapeutic use of antithrombotic drugs such as aspirin and ticlopidine. Finally, desmopressin has been used as a blood saving agent in patients undergoing operations characterized by large blood loss and transfusion requirements, but studies suggest that this is not as effective as other methods. This review briefly summarizes the current clinical indications on the use of desmopressin as a hemostatic agent. Am. J. Hematol., 2007. © 2007 Wiley-Liss, Inc. [source] Latest news and product developmentsPRESCRIBER, Issue 2 2008Article first published online: 11 FEB 200 NICE should evaluate all new medicines NICE should determine the cost effectiveness of all new medicines, the Health Select Committee has concluded in its second review of the Institute. The review, prompted by criticisms from patients, health professionals and the pharmaceutical industry, found that NICE is doing ,a vital job in difficult circumstances'. The Committee called for the costs to carers and society to be included in cost effectiveness estimates (this is currently prohibited) and for cost per QALY thresholds to be aligned with NHS affordability. NICE should publish brief appraisals at the time of a product launch , these could be used to negotiate prices. GPs responsible for unlicensed co-proxamol GPs who prescribe co-proxamol are now responsible for the consequences, the MHRA warns. The Agency agrees that the drug may be needed by ,a small group of patients who are likely to find it very difficult to change from co-proxamol or where alternatives appear not to be effective or suitable'. Following the withdrawal of product licences, stock that is currently in the supply chain may be dispensed but no new stock should be released by suppliers. The Drug Tariff price of co-proxamol has now increased from £2.79 to £20.36 per 100 tablets. Vitamin D deficiency on the increase Pregnant and breastfeeding women may need vitamin D supplements, the Department of Health has warned, and GPs are seeing increasing numbers of patients with vitamin D deficiency. Endogenous synthesis may be low in some ethnic groups and dark-skinned people, and north of Birmingham there is no light of the appropriate wavelength for the synthesis of vitamin D during the winter. The Department says free vitamin supplements are available for eligible patients through its Healthy Start Scheme (www.healthystart.nhs.uk) and may also be supplied at low cost by some PCTs. Innovation and good practice recognised Innovative practice and better outcomes for patients have been recognised through awards from the NHS Alliance and Improvement Foundation presented by the Secretary of State for Health, Rt Hon Alan Johnson, at the annual NHS Alliance conference held in Manchester. The Mountwood Surgery in Northwood, Middlesex, won the CHD QOF GP Practice Award sponsored by Schering Plough for their outstanding multidisciplinary approach to tackling CHD. In addition to having a highly organised in-house cardiology team, they have produced an interactive, patient-empowering booklet for CHD. Mountwood Surgery achieved blood pressure targets of 96.79 per cent in their CHD patients. North Tees PCT wins the CHD QOF PCO Award, also sponsored by Schering Plough, for their support and encouragement to GP practices to ,own' CHD care. They provide timely feedback of performance data using funnel plots and regular communication by the CHD LIT and Cardiac Network. Even though North Tees PCT has a high CHD prevalence, 4.2 per cent vs 3.6 per cent nationally, across the 27 practices 85 per cent of patients achieved cholesterol targets and 91 per cent reached the QOF blood pressure target. The St Benedict's Hospice Day Centre Project (for the Sunderland Teaching Primary Care Trust) won the Guy Rotherham Award for its excellent multidisciplinary team improvement of the palliative care provided. This team demonstrated a thorough understanding of the use of quality improvement methods to improve patient care, and carefully measured the individual improvements they made. Through the use of a referral ,decision tree', nonattenders were reduced by 300 per cent and average waiting times halved. The Extended Primary Care (EPC) Gynaecology Service (for the Practice Based Commissioning Consortium South Manchester Hub) was highly commended for its development of an effective and innovative service offering gynaecological treatment managed within a primary care setting, allowing patients improved access closer to home. The Salford Perinatal Mental Health Project was also highly commended for effectively challenging the high levels of maternal suicides. The awards were also supported by Prescriber, the British Cardiac Patients Association and the British Cardiac Society. Anastrozole superior to tamoxifen in long term A new analysis of the ATAC trial (Lancet Oncology 2008;9:45-53) shows that the advantages of the aromatase inhibitor anastrozole (Arimidex) over tamoxifen as adjuvant therapy for breast cancer persist for at least four years after the end of treatment. After primary treatment with surgery, chemotherapy or radiotherapy, postmenopausal women with localised invasive breast cancer were randomised to five years' treatment with anastrozole or tamoxifen. Among 5216 women who were hormone-receptor positive, anastrozole increased disease-free survival by 15 per cent after 100 months. Time to recurrence and distant recurrence were also increased, though overall survival was similar; the absolute difference in time to recurrence was greater at nine years (4.8 per cent) than at five years (2.8 per cent). Joint symptoms and fractures were more frequent with anastrozole during treatment but not thereafter. Use a steroid with a LABA , MHRA reminder The MHRA has reminded clinicians that patients treated with an inhaled long-acting beta-agonist (LABA) should also use an inhaled steroid. In the latest edition of Drug Safety Update (2008;1:No.6), the Agency reviews the implications of the SMART study (Chest 2006;129:15-26), which reported an increased risk of respiratory- and asthma-related deaths among patients using salmeterol (Serevent). This is contradicted by epidemiological data suggesting that asthma-related admissions have declined since LABAs were introduced. Randomised trials also do not support such a risk, probably because inhaled steroids are used more consistently in trial settings. The latest Update notes that product licences for carisoprodol (Carisoma) have been suspended due to concerns about the risk of abuse and psychomotor effects. It also includes a comprehensive summary of drug interactions with statins, a warning that methylene blue should not be prescribed for a patient taking a drug with serotonergic activity, and a reminder that only oral formulations of desmopressin are now licensed for primary nocturnal enuresis. This issue of Update is available at www.mhra.gov.uk. Copyright © 2008 Wiley Interface Ltd [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] | |||||||||||||||||||||||||||||||