Choice of NSAID and management strategy in rheumatoid arthritis and osteoarthritis. The impact on costs and outcomes in the UK

OBJECTIVE: Although nonsteroidal anti-inflammatory drugs (NSAIDs) are an effective therapy for rheumatoid arthritis, they are associated with significant adverse effects, the management of which imposes additional costs on the healthcare system. Prescribing NSAIDs which have a lower risk of major adverse effects as the first-line NSAID for patients with rheumatoid arthritis and osteoarthritis may be expected to lead to an improvement in clinical outcomes and reduce overall treatment costs. This analysis examines data from a published randomised controlled trial of 5 NSAIDs to explore these hypotheses. DESIGN AND SETTING: Data from a clinical trial comparing 5 NSAIDs were combined with published cost data to construct 2 clinical decision models, reflecting alternative approaches to the management of major and minor adverse effects in the UK. INTERVENTIONS: The 5 NSAIDs evaluated in the analysis were nabumetone, diclofenac, ibuprofen, piroxicam and naproxen, although only the results for ibuprofen and nabumetone are reported. MAIN OUTCOME MEASURES AND RESULTS: The total cost of care per patient receiving nabumetone was estimated to be between 25 pounds sterling (Pound) and 41 Pounds more expensive than ibuprofen. In a hypothetical cohort of 100,000 patients, there were between 690 and 821 more major adverse effects using ibuprofen than nabumetone. The cost per life-year gained (LYG) from using nabumetone rather than ibuprofen ranged between 1880 Pounds and 2517 Pounds (1995 values), depending upon the management of adverse effects. CONCLUSIONS: These results indicate that: (i) prescribing the newer, currently more expensive, NSAIDs will not necessarily lead to cost savings; (ii) the management of adverse effects can have a significant impact on costs; and (iii) the additional cost may be justifiable in terms of the mortality and morbidity gains associated with the new lower-risk NSAIDs.     

Anti-inflammatory and antipyretic effects of boldine

Boldine, and antioxidant alkaloid isolated fromPeumus boldus, exhibits a dose-dependent anti-inflammatory activity in the carrageenan-induced guinea pig paw edema test with an oral ED₅₀ of 34 mg/kg. Boldine also reduces bacterial pyrogen-induced hyperthermia in rabbits to an extent which varied between 51% and 98% at a dose of 60 mg/kg p.o.In vitro studies carried out in rat aortal rings revealed that boldine is an effective inhibitor of prostaglandin biosynthesis, promoting 53% inhibition at 75 M. The latterin vitro effect may be mechanistically linked to the anti-inflammatory and antipyretic effects of boldine exertedin vivo.     

Economic outcomes of colfosceril palmitate rescue therapy in infants weighing 1250g or more with respiratory distress syndrome: results from a randomised trial

An analysis of the economic data from a multicentre, randomised, placebo-controlled clinical trial of colfosceril palmitate in infants with neonatal respiratory distress syndrome (NRDS) and birthweights of 1250g or more is presented. Two 5 ml/kg (67.5 mg/kg) doses of a synthetic surfactant (colfosceril palmitate) or air placebo were administered to 1237 infants who were receiving mechanical ventilation and had an arterial/alveolar oxygen tension ratio of less than 0.22. In addition to the clinical end-points for safety and efficacy, data were collected on length of hospital stay, days in the neonatal intensive care unit, days on mechanical ventilation, days on oxygen, and hospital charges until the child reached 1-year adjusted age. One-year adjusted age is attained when the time elapsed since birth is equal to 365 days plus the number of days of prematurity. Rescue treatment with synthetic surfactant therapy has been shown to reduce the incidence of complications of NRDS. Growth and development of infants who received colfosceril palmitate therapy in the study and survived to 1-year adjusted age were equivalent to those of the survivors in the air placebo group. For the cohort of treated infants, colfosceril palmitate reduced the average length of stay at 2 levels of care needed during both the initial hospitalisation (a reduction of 8 days overall and 5 days in intensive care) and all first year hospitalisations (a reduction of 9 days overall and 5 days in intensive care). Total hospital charges for the initial hospitalisation and through 1-year adjusted age for a hypothetical cohort of 100 infants treated with colfosceril palmitate were less than those for a comparable cohort in the air placebo group. The results would, therefore, suggest that rescue therapy with colfosceril palmitate in infants with NRDS and birthweights over 1250g can result in substantial reductions in hospital resource utilisation and charges in addition to the clinical benefits associated with its use.     

Immunity to diphtheria and tetanus in Australia: a national serosurvey

OBJECTIVE: To determine immunity to tetanus and diphtheria in the Australian population. DESIGN AND SETTING: Analysis, using double antigen enzyme immunoassays, of a representative sample of sera (1950 samples tested for diphtheria and 2884 for tetanus) collected opportunistically from Australian laboratories between July 1996 and May 1999. MAIN OUTCOME MEASURE: Immunity to diphtheria and tetanus, defined as negative (susceptible) when the antitoxin level was < 0.01 IU/mL, positive (immune) when it was > or = 0.1 IU/mL, and low positive (partially immune) when it was in the range 0.01-< 0.1 IU/mL. RESULTS: About 99% of children aged 5-9 years had diphtheria and tetanus antitoxin levels > or = 0.01 IU/mL (immune or partially immune). Antitoxin levels declined with age and generally more markedly for diphtheria than tetanus. For subjects aged 50 years and over, less than 60% were immune or partially immune to diphtheria and less than 75% to tetanus. Men and women had similar diphtheria antitoxin levels, while women had lower levels of tetanus antitoxin compared with men of the same age, with the difference being most marked in the age group > or = 70 years (37% v 60%; P < 0.001). CONCLUSIONS: Immunity in children appears to be good, but adults, especially older people, may not be adequately protected. Recent changes to the Australian Standard Vaccination Schedule should improve immunity in cohorts now aged < 50 years. However, additional efforts are required to protect those over 50 years (especially travellers), who are most susceptible.     

In vivo pharmacokinetic-pharmacodynamic relationship and in vitro equivalence of two oral furosemide tablet formulations

A randomized, cross-over, open study of bioequivalence between two different furosemide (CAS 54-31-9) formulations was performed; simultaneously, diuretic effects (urine output, sodium, potassium and chloride excretion) were also compared. Both products meet the British Pharmacopoeia specification and the results of a previous in vitro comparative study ensure equivalence of the two dissolution curves. Twenty-four healthy volunteers (male/female) participated in the bioequivalence study. Each treatment was given as a single 40-mg tablet following an overnight fast. Furosemide concentrations in plasma (measured by HPLC) and electrolyte amounts in urine were determined up to 12 h after treatment. The pharmacokinetic parameters AUC0-infinity, Cmax and Cmax/AUC0-infinity were tested for bioequivalence after ln-transformation of data and ratios of tmax were evaluated nonparametrically. The parametric analysis revealed the following test/reference ratios and their 90% confidence intervals (90% CI): 1.06 (0.94-1.19) for AUC0-infinity, 1.12 (0.96-1.31) for Cmax, and 1.06 (0.97-1.16) for Cmax/AUC0-infinity. The 90% CI for tmax was 0.55-1.00. Bioequivalence between both formulations was concluded for all parameters except for tmax. No significant diuretic differences between both formulations (test and reference) were observed after drug administration in relation to the baseline period. Systolic and diastolic blood pressure and heart rate showed a similar time-course after the drug administration and there were no differences between both formulations. Both products were well tolerated. It can be concluded that both formulations are equivalent in vitro and in vivo.     

The use of isotonic fluid as maintenance therapy prevents iatrogenic hyponatremia in pediatrics: a randomized, controlled open study

OBJECTIVES: Hypotonic fluids are widely used in pediatrics. Several articles have reported the risk of iatrogenic hyponatremia secondary to this practice. We primarily intend to determine whether the use of isotonic fluids prevents hyponatremia and, secondly, whether these fluids increase the incidence of adverse events. STUDY DESIGN: One hundred twenty-two pediatric patients hospitalized in intensive care unit requiring maintenance fluid therapy were randomized to receive isotonic fluids (isotonic group, NaCl = 140 mEq/L) or hypotonic fluids (hypotonic group, NaCl <100 mEq/L). Electrolyte blood concentration, glycaemia, and blood pressure were measured at 0, 6, and 24 hrs after the beginning of fluid therapy. Plasma creatinine, urine specific gravity, and urine electrolyte concentration were measured at 6 hrs. Standard intention-to-treat analysis and Bayesian analysis were conducted to assess the probability of hyponatremia and hypernatremia in each group. RESULTS: At the time of admission to hospital, no differences in natremia or the percentage of hyponatremia were found between groups. At 24 hrs, the percentage of hyponatremia in the hypotonic group was 20.6% as opposed to 5.1% in the isotonic group (p = 0.02). No differences in the number of adverse events other than hyponatremia were observed between groups. CONCLUSIONS: The use of hypotonic fluids increases the risk of hyponatremia when compared with isotonic fluids at 24 hrs following infusion (number needed to harm [confidence interval 95%] = 7[4;25]). In our sample, the use of isotonic fluids did not increase the incidence of adverse events compared with hypotonic fluids.