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Budesonide/formoterol maintenance plus reliever therapy: a new strategy in pediatric asthma.

OBJECTIVES: A fixed combination of long-acting beta(2)-agonists (LABA) plus inhaled corticosteroids (ICS) has never been proven to reduce asthma exacerbations vs ICS alone in children. This 12-month, double-blind, randomized study in 341 children (age range, 4 to 11 years) with asthma uncontrolled on ICS investigated whether a novel regimen using budesonide/formoterol for maintenance and reliever therapy (Symbicort maintenance and relief therapy [SMART]) [Symbicort; AstraZeneca R&D, Lund, Sweden] could reduce exacerbations. METHODS: Patients received SMART (budesonide/formoterol 80/4.5 microg qd maintenance plus additional inhalations for symptom relief), budesonide/formoterol 80/4.5 microg qd for maintenance (fixed combination), or higher-dose budesonide 320 microg qd (fixed-dose budesonide). Blinded as-needed medication (terbutaline 0.4 microg) was provided in both fixed-dose groups. RESULTS: SMART prolonged the time to first exacerbation vs fixed-dose budesonide (p = 0.02) and fixed-dose combination (p < 0.001). Rates of exacerbation requiring medical intervention were reduced by 70 to 79% with SMART vs fixed-dose budesonide and fixed-dose combination (0.08/patient vs 0.28/patient and 0.40/patient, respectively; both p < 0.001). Mild exacerbation days and awakenings were significantly lower with SMART; yearly growth improved by 1.0 cm vs fixed-dose budesonide (p < 0.01). CONCLUSION: The SMART regimen using budesonide/formoterol for both maintenance and as-needed symptom relief reduces the exacerbation rate compared with both fixed-dose combination and higher fixed-dose ICS alone in children with asthma.

Adrenal Cortex Hormones↗

Content- and task-specific dissociations of frontal activity during maintenance and manipulation in visual working memory.

Working memory, the short-term maintenance and manipulation of information, relies strongly on neural activity in the frontal cortex. Understanding the functional role of this activity is a prerequisite for the understanding of cognitive control mechanisms. Functional imaging studies in human participants have attempted to reveal neural correlates of the subdivision of visual working memory into different processes (maintenance vs manipulation) and according to the type of memorized content. Here, we show, using functional magnetic resonance imaging, a content-specific dissociation of frontal activity, with dorsal premotor areas supporting both maintenance and manipulation of spatial features and more ventral areas supporting maintenance and manipulation of color. Manipulation-specific activity was observed in the anterior middle frontal gyrus, the inferior frontal junction, and the inferior parietal lobe bilaterally. These areas have been implicated in cognitive control, and their activation by the manipulation task conforms to the demand on central executive resources in this condition. We suggest that the enhanced demand on cognitive resources in manipulation compared with maintenance was met by interplay of content- and task-specific modules in a frontoparietal network.

Brain Mapping↗

Mycophenolate mofetil for maintenance therapy of Wegener's granulomatosis and microscopic polyangiitis: a pilot study in 11 patients with renal involvement.

Successful maintenance therapy with mycophenolate mofetil (MMF) 2 g/d and low-dose oral corticosteroids (OCS) over a period of 15 mo was given to patients with Wegener's granulomatosis (WG) (n = 9) and microscopic polyangiitis (MPA) (n = 2). All patients had severe generalized disease with pauci-immune necrotizing glomerulonephritis and received standard induction therapy with oral cyclophosphamide and OCS for a mean of 14 wk until remission was achieved. Of 11 patients, only one WG patient relapsed in the 14th month of maintenance therapy. Maintenance therapy with MMF was able to further reduce grumbling disease activity as measured by the Birmingham vasculitis activity score (BVAS2) and proteinuria that were still present by the end of induction therapy. OCS could be reduced to a median daily dose of 5 mg and discontinued in three patients. Possible drug-related adverse effects were transient and included abdominal pain, respiratory infection, diarrhea, leukopenia, and a cytomegalovirus-colitis in one patient that was successfully treated with ganciclovir. It is concluded that MMF in combination with low-dose OCS is well tolerated and effective for maintenance therapy of WG and MPA. Long-term treatment with MMF in these diseases is attractive because of its low toxicity. MMF will have to be studied further and compared with cyclophosphamide or azathioprine maintenance therapy in randomized trials.

Adrenal Cortex Hormones↗

Effects of L-carnitine supplementation in maintenance hemodialysis patients: a systematic review.

There are many causes for carnitine depletion during maintenance hemodialysis. Supplementation with L-carnitine in animals has been associated with improvement in some abnormalities also present in chronic renal failure. However, it is still controversial whether restoring plasma or tissue carnitine will correct clinical or biologic symptoms observed in maintenance hemodialysis. A systematic review is here performed to determine the effects of L-carnitine in maintenance hemodialysis patients. Eighty-three prospective trials were identified from 1978 to 1999 in which L-carnitine was randomly allocated in 21 trials. Change in serum triglycerides, cholesterol fractions, hemoglobin levels, erythropoietin dose, and other symptoms (muscle function, exercise capacity, and quality of life) were examined. A total of 482 patients in 18 trials were considered for analysis. There was no effect of L-carnitine on triglycerides, total cholesterol, or any of its fractions. Before the erythropoietin (EPO) era, L-carnitine treatment was associated with improved hemoglobin (P < 0.01) and with a decreased EPO dose (P < 0.01) and improved resistance to EPO when patients routinely received EPO. Muscle function, exercise capacity, and quality of life could not be reliably assessed because of the noncombinable nature of end points and the limited number of trials. In conclusion, L-carnitine cannot be recommended for treating the dyslipidemia of maintenance hemodialysis patients. By contrast, this review suggests a promising effect of L-carnitine on anemia management. The route of L-carnitine administration should be evaluated because there is no evidence as to the most efficient method of administration in maintenance hemodialysis.

Anemia↗

Evaluation of a 6-month chemotherapy protocol with no maintenance therapy for dogs with lymphoma.

The purpose of this study was to compare a maintenance-free chemotherapy protocol based on CHOP (H from hydroxydaunorubicin = doxorubicin, O from Oncovin = vincristine) to a similar protocol with a maintenance phase for the treatment of canine lymphoma. Fifty-three dogs with multicentric lymphoma were treated with a 6-month modified version of the University of Wisconsin (UW)-Madison chemotherapy protocol (UW-25). Disease-free interval (DFI) and survival were compared to a historical control group of 55 dogs treated with a similar protocol with a prolonged maintenance phase. Remission rate for the study dogs was 94.2% (complete remission = 92.3%, partial remission = 1.9%). DFI and survival between the 2 groups did not differ significantly, with median DFI and survival of the study dogs equal to 282 and 397 days compared to 220 and 303 days for the control dogs (P = .2835 and .3365, respectively). Univariate analysis identified substage b (P = .0087), German Shepherd breed (P = .0199), and body weight > 18 kg (P = .0016) as significant for worse survival. Longer survival was associated with thrombocytopenia (P = .0436). Multivariate analysis revealed that substage (P = .0388) and weight (P = .0125) retained significance for DFI, whereas substage (P = .0093), thrombocytopenia (P = .0150), and weight (P = 0 .0050) retained significance for survival. Overall, the protocol was well tolerated by the dogs, with 41.5% (22/53) requiring a treatment delay or dose modification, but only 9.4% (5/53) needing hospitalization. The 6-month chemotherapy protocol based on CHOP with no maintenance phase provides similar DFI and survival times when compared to a similar protocol with a prolonged maintenance phase.

Animals↗

Programming generalization and maintenance of treatment effects across time and across settings.

Effects of three experimental and one control strategy were investigated in facilitating generalization and maintenance of treatment effects after two months in a token-economy classroom. At the conclusion of treatment, subjects were randomly assigned to one of three maintenance strategies or a control group and returned to their regular classrooms. The maintenance strategies were peer reprogramming, equating stimulus conditions between the experimental and regular classrooms, and teacher training in behavior management techniques. The maintenance strategies were implemented in the regular classroom for a two-month period and then terminated. Results indicated a powerful treatment effect produced by the token economy. Behavior maintenance effects following treatment were also obtained. The mean per cent appropriate behavior for the peer reprogramming and equating stimulus conditions strategies was significantly greater than the mean for the control subjects. The teacher training and control group means were not significantly different.

Journal Article↗

Compliance with maintenance therapy in a private periodontal practice.

The purpose of this study was to determine patient compliance with suggested maintenance schedules. All patients eligible for maintenance therapy in a private periodontal practice were included. The study covered a period of 8 years. All patients had chronic inflammatory periodontal disease and had been eligible for at least 1 year of maintenance therapy before the close of data collection. A total of 961 patients were studied; only 16% complied with recommended maintenance schedules. Erratic compliance was found in 49% of the patients and 34% never reported for any maintenance therapy.

Adolescent↗

Tooth loss in maintenance patients in a private periodontal practice.

A group of 162 maintenance patients, previously studied for compliance to suggested maintenance schedules, were surveyed for tooth loss over a 5-year period. The group was divided into those who complied to suggested maintenance schedules and those whose compliance was erratic. It was found that none of the patients who had complied to suggested maintenance schedules lost any teeth. In the erratic group, where all tooth loss occurred, it was found that the more often a patient presented for maintenance, the less likely he was to lose teeth. These findings are discussed in relation to current studies on efficacy of various therapies for periodontal diseases.

Dental Scaling↗

A Markov process analysis comparing the cost effectiveness of maintenance therapy with citalopram versus standard therapy in major depression.

The objective of this study was to demonstrate the cost effectiveness of long term maintenance treatment with citalopram versus standard therapy (defined as short term antidepressant treatment) in patients with major depression in Germany. We chose doxepin, amitriptyline and trimipramine as standard therapy because these drugs are the leading antidepressants in that country. A Markov process analysis was used to model health status and economic outcomes as they accrued over a 1-year follow-up period. The main outcome measures were time without depression, direct costs and indirect costs (work days lost). All costs were in 1993 Deutsche marks. The clinical data were obtained from the published literature and US clinical practice guidelines; the associated unit costs of the medical resources used were derived from official German tariff lists. The results show that, compared with standard therapy, long-term maintenance treatment with citalopram is associated with a mean increase in time without depression of 7.9% (8.2 vs 7.6 months). The total costs of maintenance treatment with citalopram were substantially lower than with standard therapy (DM7985 vs DM11,948 per patient per year. In addition, both the direct and indirect costs of maintenance treatment with citalopram (DM3764 vs DM4221 per patient, respectively) were lower than with standard therapy (DM4577 vs DM7371 per patient, respectively). In conclusion, the study demonstrates that one year's maintenance treatment with citalopram is both more effective and less costly than standard therapy in the treatment of patients with major depression.

Amitriptyline↗

Incremental cost-effectiveness analysis of intravenous ganciclovir versus oral ganciclovir in the maintenance treatment of newly diagnosed cytomegalovirus retinitis in patients with AIDS.

OBJECTIVE: To evaluate the cost effectiveness of a new product, oral ganciclovir, in comparison to a current therapy, intravenous (i.v.) ganciclovir, in the maintenance treatment of newly diagnosed cytomegalovirus (CMV) retinitis in patients with AIDS. DESIGN: This was a retrospective economic study of a prospective non-blinded randomised clinical trial. The model included i.v. ganciclovir induction, i.v. or oral ganciclovir maintenance and i.v. ganciclovir reinduction for patients whose CMV retinitis progressed. Safety and efficacy data were derived from the trial. A panel of Canadian infectious disease physicians and family physicians estimated the following in relation to i.v. ganciclovir treatment for CMV retinitis and related adverse events: healthcare resource utilisation, clinical practice patterns, patient out-of-pocket expenses and time loss from work. The incremental cost-effectiveness analysis is reported from a societal and a Ministry of Health perspective. SETTING: The trial was conducted in Canada (2 centres) and the US (13 centres) between March 1991 and November 1992. The model assumed that patients received either inpatient or outpatient care, or both. The model provided an analysis in a Canadian setting. PATIENTS AND PARTICIPANTS: Participants were patients with AIDS and newly diagnosed CMV retinitis. INTERVENTIONS: All patients received induction therapy with i.v. ganciclovir 5 mg/kg, twice daily for 14 days then once daily for 7 days. Patients whose CMV retinitis stabilised were randomised to maintenance therapy with either i.v. ganciclovir (5 mg/kg/day; n = 57) or oral ganciclovir (3000 mg/day; n = 60) and were followed for up to 140 days after the start of maintenance therapy. MAIN OUTCOME MEASURES AND RESULTS: The trial demonstrated that the mean time to progression of CMV retinitis was 57 days for oral ganciclovir compared with 62 days for i.v. ganciclovir maintenance therapy, as measured by masked fundus photography, and 96 days with i.v. ganciclovir compared with 68 days with oral ganciclovir according to the funduscopy results. There were more adverse events in the i.v. ganciclovir group compared with the oral ganciclovir group. The cost-effectiveness results provide the dollar amount expended in order to continue to provide additional benefit using i.v. ganciclovir compared with oral ganciclovir. The incremental cost-effectiveness (C/E) ratio was 482 Canadian dollars ($Can: 1993 to 1995 values) per progression-free day gained with i.v. ganciclovir. Sensitivity analysis using funduscopy, rather than fundus photography, to document progression of CMV retinitis resulted in a C/E ratio of $Can42. CONCLUSIONS: This analysis found that i.v. ganciclovir provided additional days free of progression of CMV retinitis when compared with oral ganciclovir, but the costs were higher.

Administration, Oral↗

Decision analysis of histamine H2-receptor antagonist maintenance therapy versus Helicobacter pylori eradication therapy: a randomised controlled trial in patients with continuing pain after duodenal ulcer.

BACKGROUND: Much has been published on the efficacy and cost effectiveness of Helicobacter pylori eradication treatment as an alternative to histamine H2-receptor antagonist maintenance treatment in peptic ulcer disease. However, most studies have analysed and emphasised H. pylori eradication rates rather than management/control of symptoms and the associated cost savings. Although H. pylori eradication therapy is very successful in clearing the infection, dyspeptic symptoms may persist and management of these can be expensive. OBJECTIVE: The aim of this study was to assess the cost implications in controlling symptoms using either H2-receptor antagonist maintenance therapy or H. pylori eradication therapy in patients with duodenal ulcer disease. DESIGN: This was a non-blind, prospective, randomised, parallel-group study comparing maintenance H2-receptor antagonist treatment using ranitidine with H. pylori eradication therapy, with a 1-year follow-up. SETTING: This was a study of outpatients from general practices in Dundee, Scotland, or the Ninewells Hospital, Dundee, gastroenterology clinic. PATIENTS AND PARTICIPANTS: 119 patients with confirmed duodenal ulcer, free from active ulceration at study entry but positive for H. pylori infection, who were receiving maintenance H2-receptor antagonist therapy. INTERVENTIONS: Patients were randomised to receive either continuing maintenance therapy with ranitidine (initially 150 mg daily; 58 patients) or H. pylori eradication therapy using an omeprazole/amoxicillin/metronidazole regimen (or omeprazole/clarithromycin if allergic to penicillin). MAIN OUTCOME MEASURES AND RESULTS: Overall, H. pylori eradication rates were 100% per protocol and 95.1% intention-to-treat. At completion of 1 year of follow-up, 12 of the 61 (19.7%) patients successfully eradicated of H. pylori were still dependent on acid suppression for symptom relief. H. pylori eradication treatment was the least-cost strategy in managing/controlling symptoms at 1 year (168 Pounds vs 210 Pounds per patient; 1996 values). However, over time, post-eradication treatment costs were greater than H2-receptor antagonist therapy costs. Any potential savings were directly related to the proportion of patients needing further treatment post-eradication, the cost of endoscopy and the urea breath test. CONCLUSIONS: If dyspepsia persists long term, H. pylori eradication treatment may not be the least-cost option for patients with duodenal ulcer.

Decision Support Systems, Clinical↗

Economic assessment of adjustable maintenance treatment with budesonide/formoterol in a single inhaler versus fixed treatment in asthma.

OBJECTIVES: To compare the costs and effectiveness of adjustable maintenance dosing with budesonide/formoterol in a single inhaler versus fixed dosing in adults with asthma. METHODS: In this prospective, randomised, open-label, parallel-group, multicentre trial conducted in Germany, patients with asthma received budesonide/formoterol 160 microg/4.5 microg in a single inhaler (Symbicort Turbuhaler with two inhalations twice daily for a 4-week run-in period. Patients were then randomised to either adjustable maintenance dosing (one inhalation twice daily, stepping up to four inhalations twice daily for 1 week if asthma worsened; n=1679) or fixed dosing (two inhalations twice daily; n=1618) for 12 weeks. The primary efficacy variable was the change in health-related quality of life (HR-QOL), measured using the Asthma Quality of Life Questionnaire (standardised) during the randomised treatment period. Resource utilisation data were collected in parallel and combined with German unit costs to estimate direct and indirect costs (year 2001 values). RESULTS: Both treatment regimens were equally effective in maintaining HR-QOL and asthma control during the randomised treatment period. However, overall, patients in the adjustable maintenance dosing group took fewer daily inhalations of budesonide/formoterol than those in the fixed-dosing group (mean: 2.63 vs 3.82 inhalations; p<0.001). Adjustable maintenance dosing was associated with significantly lower asthma-related direct costs compared with fixed dosing (mean: 221 euro vs 292 euro; p<0.001). This pattern was maintained when patients were stratified into those with peak expiratory flow (PEF) of 60% to <80% predicted normal and those with PEF of>/=80% predicted normal and when total costs were considered. CONCLUSION: Adjustable maintenance dosing with budesonide/formoterol in a single inhaler maintained HR-QOL in adult patients with asthma at a significantly lower cost than fixed dosing.

Adolescent↗

Statistical selection of maintenance genes for normalization of gene expressions.

Maintenance genes can be used for normalization in the comparison of gene expressions. Even though the absolute expression levels of maintenance genes may vary considerably among different tissues or cells, a set of maintenance genes may provide suitable normalization if their expression levels are relatively constant in the specific tissues or cells of interest. A statistical procedure is proposed to select maintenance genes for normalization of gene expression data from tissues or cells of interest. This procedure is based on simultaneous confidence intervals for practical equivalence of relative gene expressions in these tissues or cells. As an illustration, the procedure is applied to the maintenance gene expression data from Vandesompele et al. (2002).

Data Interpretation, Statistical↗

Energy requirements for maintenance of crossbred beef cattle with different genetic potential for milk.

Maintenance energy requirements were estimated in two gestation and one lactation feeding trials for three groups of cows. All cows in the second gestation trial completed the first gestation and lactation trials. The three groups were chosen to represent cattle similar in growth rate and mature size but different in amount of milk provided to their calves. The low (L) group included Hereford x Angus, the medium (M) group included Red Poll x Angus and the high (H) group included Milking Shorthorn x Angus cows. Cows were individually fed to maintain net body weight (minus gravid uterus for gestation) constant. Allowances were made in energy intake for gestation and lactation. Cow weights were adjusted to an average condition score in each trial. Daily maintenance requirements during gestation were 18% lower than those during lactation. The H and M cows required 12% more energy per unit metabolic weight than L cows to maintain body weight during both gestation and lactation. Differences in milk production explained 23% of the variation in maintenance requirements, suggesting that important differences exist beyond those associated with milk production potential. Repeatabilities of maintenance requirement measurements ranged from .44 to .64. Maintenance requirements for calves under feedlot conditions in the postweaning phase were estimated from data collected from 494 calves, half-sibs and offspring of the cows described previously. Energy requirements were 11% higher for the H and M groups than for the L group.

Animals↗

The relationship of the maintenance energy requirement to heifer production efficiency.

Thirty-three Hereford x Angus first-calf heifers were used to determine the relationship between production efficiency (PE = calf weaning weight/[12-mo dam+calf ME intake]) and nonlactating dam maintenance ME requirement/BW.75 (MEm) and its components, the efficiency of ME use for maintenance (km), and fasting heat production/BW.75 (FHP). Each heifer was kept in drylot from 19 mo of age until weaning of its first calf, during which time individual feed intakes were measured. After the PE phase, heifers were moved to the metabolism facility and indirect respiration calorimetry was used to determine maintenance energy metabolism. Maintenance metabolism of the dam, determined in controlled conditions, contributed little to explaining PE variation (r2 < or = .04). This may have been due to the high plane of nutrition provided and (or) to the physiological state of the heifers during metabolism measurements. Selection for lower MEm, as determined by the procedures used in this study, is unlikely to improve heifer PE if nutrition is not limited relative to requirements. Additionally, MEm was closely related to FHP (r2 = .73), suggesting that it could be used as an indicator of fed maintenance requirements when determined within defined conditions.

Animal Feed↗

Quantitative and temporal relationships of alcohol use in narcotic addicts and methadone maintenance patients undergoing alcohol detoxification.

Evidence exists that alcohol abuse frequently coexists with narcotic addiction and methadone maintenance treatment, and it is the major factor in the development of cirrhosis and liver failure. This study of patients hospitalized for alcohol detoxification compares the quantity of alcohol consumed by alcohol abusers, addicted to narcotics or in a methadone maintenance treatment program, to that consumed by patients not involved with narcotic addiction. Mean daily alcohol consumption was not significantly different in either group using narcotics, including methadone, or in the subgroup of methadone maintenance patients, from the amount consumed by nonnarcotic abusers. Determination of temporal sequence in the use of these substances revealed that in 68% regular alcohol abuse preceded narcotic use. Alcohol abuse reportedly began after entering a methadone maintenance treatment program in 29% of our patients. Alcohol abusers who were in a methadone maintenance treatment program were significantly younger than those who did not use narcotics, including methadone. Time interval according to the patients' estimates, from onset of regular alcohol consumption to heavy drinking, was not significantly different in the two groups.

Age Factors↗

Prognostic significance of methotrexate and 6-mercaptopurine dosage during maintenance chemotherapy for childhood acute lymphoblastic leukemia.

Tolerance of full-dose methotrexate/6-mercaptopurine (MTX/6MP) maintenance therapy for childhood acute lymphoblastic leukemia (ALL) without side effects could reflect insufficient systemic drug exposure, and drug withdrawals due to toxicity might reduce the chance of cure. The present study included 122 children with non-B cell acute lymphoblastic leukemia with a median follow-up of 84 months. Leukopenia and hepatotoxicity were calculated as weighted means of all white cell counts and all serum aminotransferase measurements, respectively, registered for each patient. Forty-five patients relapsed (30 in bone marrow). Patients tolerating an average dose of MTX of more than 75% of the recommended protocol doses and having cumulated drug withdrawals of less than 1% of the period of maintenance therapy had an increased risk of hematological relapse (p = 0.008) as well as of any relapse (p = 0.03) when compared to the remaining patients. Patients with a cumulative withdrawal of MTX or of 6MP for greater than 10% of the maintenance therapy period had an increased risk of hematological relapse (MTX: p = 0.009, 6MP: p less than 0.0001) and of any relapse (MTX: p = 0.16, 6MP: p = 0.0002). Liver toxicity was the main reason for cumulative long-term drug withdrawals. However, patients with a mean aminotransferase level above the upper normal limit (40 IU/l) who were kept on therapy (cumulative withdrawals of neither drug for more than 5% of their maintenance therapy period) had a significantly lower risk of hematological relapse (p = 0.02) as well as of any relapse (p = 0.06) than the remaining children. The concept of treating to toxicity seems warranted for maintenance therapy of childhood lymphoblastic leukemia.

Antineoplastic Combined Chemotherapy Protocols↗

6-Mercaptopurine cumulative dose: a critical factor of maintenance therapy in average risk childhood acute lymphoblastic leukemia.

A multivariate survival analysis including gender, age, log white blood cell (WBC) count, liver and spleen size at diagnosis, mean log WBC count during maintenance therapy, and the prescribed cumulative doses of 6-mercaptopurine (6-MP), methotrexate (MTX), vincristine (VCR), and prednisone (PDN) during maintenance therapy was performed on 53 children with average-risk acute lymphoblastic leukemia (ALL). The 6-MP cumulative dose prescribed during maintenance therapy resulted in the most important statistically significant independent prognostic factor. Patients who received less than the median cumulative dose of 6-MP (86% of planned protocol dose) fared significantly worse than the other patients, regardless of WBC count at diagnosis, gender, age, and other factors studied. Therefore, 6-MP cumulative dose during maintenance therapy may be the critical factor for effective maintenance therapy in childhood ALL.

Adolescent↗