Pharmacotherapies for obesity: past, current, and future therapies.

Past therapies for the treatment of obesity have typically involved pharmacological agents usually in combination with a calorie-controlled diet. This paper reviews the efficacy and safety of pharmacotherapies for obesity focusing on drugs approved for long-term therapy (orlistat), drugs approved for short-term use (amfepramone [diethylpropion], phentermine), recently withdrawn therapies (rimonabant, sibutamine) and drugs evaluated in Phase III studies (taranabant, pramlintide, lorcaserin and tesofensine and combination therapies of topiramate plus phentermine, bupropion plus naltrexone, and bupropion plus zonisamide). No current pharmacotherapy possesses the efficacy needed to produce substantial weight loss in morbidly obese patients. Meta-analyses support a significant though modest loss in bodyweight with a mean weight difference of 4.7 kg (95% CI 4.1 to 5.3 kg) for rimonabant, 4.2 kg (95% CI 3.6 to 4.8 kg) for sibutramine and 2.9 kg (95% CI 2.5 to 3.2 kg) for orlistat compared to placebo at ≥12 months. Of the Phase III pharmacotherapies, lorcaserin, taranabant, topiramate and bupropion with naltrexone have demonstrated significant weight loss compared to placebo at ≥12 months. Some pharmacotherapies have also demonstrated clinical benefits. Further studies are required in some populations such as younger and older people whilst the long term safety continues to be a major consideration and has led to the withdrawal of several drugs.

Smoking cessation-recent advances.

BACKGROUND: Smoking continues to be a major contributor to the burden of disease across the world although there has been a decrease in some developed countries such as USA and Australia. In countries of South-East Asia with a high prevalence of smoking, the incidence of tobacco-related diseases will continue to increase. METHODS: We reviewed the literature in relation to the pharmacology of nicotine, the measures used to determine the efficacy of anti-smoking therapies, and the randomised controlled trials and systematic reviews of pharmacotherapies published between 2004 and 2010. We focused primarily on the three first line therapies that are currently available: nicotine replacement therapy (NRT), bupropion and varenicline. RESULTS: Randomised controlled trials and meta-analyses have demonstrated that single therapy with either NRT, bupropion or varenicline are all more effective than placebo for smoking cessation. Abstinence rates for monotherapies varies from 13.3% to 19% for NRT compared to 7.5% to 14% for placebo, 19% to 19.7% for bupropion versus 10.9% to 11% for placebo and 25.5% to 25.6% for varenicline versus 11.2% to 14.8% for placebo. Of current therapies varenicline appears to be more effective at achieving abstinence. Some combination therapies with one or two formulations of NRT or NRT plus bupropion have demonstrated superior results to monotherapy. To date there are no randomised controlled trials of varenicline in combination with NRT or bupropion. CONCLUSION: Further studies are required to address the uncertainty that exists on the most appropriate duration of therapy as well as the effectiveness and safety of combination pharmacotherapy. Post-marketing surveillance continues to play an important role in monitoring the adverse effects events associated with these therapies.

Cost of myocardial infarction to the Australian community: a prospective, multicentre survey.

BACKGROUND: in order to evaluate the cost effectiveness of preventive strategies for myocardial infarction (MI), direct cost estimates are required. However, Australian-specific cost estimates for MI are not available. OBJECTIVE: the CosMIC (Cost of Myocardial Infarction to the Community) in Australia study was designed to determine the resource use and estimate the direct costs associated with MI in the Australian Health Care System. This information could subsequently be used in cost-effectiveness evaluations. METHODS: a prospective, multicentre survey was undertaken to investigate the costs associated with the initial hospitalization and the 12-month sequelae for patients with a first-ever MI. During the recruitment period 312 patients with MI from ten hospitals met the eligibility criteria. Of the 141 who consented to participate and were enrolled, three were withdrawn and 138 were included in the final analysis. Detailed data were collected for 12 months after the index hospitalization from several overlapping sources. All costs were considered from the point of view of total direct cost of care, i.e. regardless of who generated or paid for the service. RESULTS: the mean length of hospital stay for the initial acute episode was 7.4 days and the mean cost was $A10 934 (95% confidence interval [CI] 9588, 12 280) based on 2005 Australian dollars. There were 127 cardiac-related readmissions for 55 (40%) patients and the mean length of stay was 2.6 days. The mean total direct cost of an MI per patient was $A20 502 (95% CI 18 428, 22 576). The majority of the costs were for hospitalizations (initial and readmissions), which accounted for 77% of the total 12-month costs, whilst hospitalization costs for the initial acute event accounted for 53% of all costs. During the 12-month follow-up period, out-of-hospital medical service costs (Medicare Benefits Schedule services) contributed to 7% of the total costs incurred, medications 6%, ambulance costs 3% and all other outpatient services and carer costs 7%. CONCLUSION: the CosMIC study addresses the significant uncertainty associated with MI cost-of-illness data in Australia by providing an estimation of direct costs associated with MI in an Australian population. These direct costs can be used to determine the cost effectiveness of prevention strategies.

Safety of drug therapies used for weight loss and treatment of obesity.

Some of the medications used for weight loss in the management of obesity have been associated with unacceptable morbidity and mortality. Safety concerns have led to the withdrawal of aminorex, followed by the fenfluramines in 1997, and phenylpropanolamine (norephedrine) in 2000. Aminorex was associated with an increased prevalence of primary pulmonary hypertension (PPH), fenfluramines with an increased prevalence of PPH and valvulopathy, and phenylpropanolamine with an increased risk of haemorrhagic stroke. Several studies have investigated the safety of the fenfluramines, yet the benefit-risk profile has not been conclusively quantified. This is due to several deficiencies in the published studies, including a lack of data on the baseline prevalences of comorbid conditions in obese subjects, and potential confounders and biases in the study designs. Although several studies and systematic reviews support an increased risk of PPH and valvulopathy in patients who have taken fenfluramines, without knowledge of the background prevalence it is not possible to determine if the exposure preceded the outcome. The population at higher risk of these adverse effects includes those taking higher doses or with a longer duration of exposure to fenfluramines and those with pre-existing cardiac disease or a genetic predisposition. Patients exposed to fenfluramines continue to be monitored, with some follow-up studies indicating no overall worsening in valvulopathy over time. There are limited efficacy and safety data for amfepramone (diethylpropion) and phentermine and their approval for the management of obesity is limited to short-term use. Orlistat and sibutramine are the only currently approved medications for long-term management of obesity. Although the benefit-risk profiles of sibutramine and orlistat appear positive, sibutramine continues to be monitored because of long-term safety concerns. The safety and efficacy of currently approved drug therapies have not been evaluated in children and elderly patient populations and there is limited information in adolescents, whilst the long-term safety of current and potential new drug therapies in adults will require several years of postmarketing surveillance to fully elucidate their adverse effect profiles.

Pharmacotherapy for obesity.

Pharmacotherapy for the management of obesity is primarily aimed at weight loss, weight loss maintenance and risk reduction, and has included thyroid hormone, amphetamines, phentermine, amfepramone (diethylpropion), phenylpropanolamine, mazindol, fenfluramines and, more recently, sibutramine and orlistat. These agents decrease appetite, reduce absorption of fat or increase energy expenditure. Primary endpoints used to evaluate anti-obesity drugs most frequently include mean weight loss, percentage weight loss and proportion of patients losing >or=5% and >or=10% of initial bodyweight. Secondary endpoints may include reduction in body fat, risk factors for cardiovascular disease and the incidences of diseases such as diabetes mellitus. Most pharmacotherapies have demonstrated significantly greater weight loss in patients on active treatment than those receiving placebo in short-term (or=10% loss of initial bodyweight in 46% of patients. For patients taking orlistat, weight loss was 2.2 kg greater than those on placebo at 4 years (p<0.001), with significantly more patients achieving >or=10% loss of initial bodyweight (26.2% and 15.6%, respectively; p<0.001). Other drugs that have been evaluated for weight loss include ephedrine, the antidepressants fluoxetine and bupropion, and the antiepileptics topiramate and zonisamide. Two clinical trials with fluoxetine both reported no significant difference in weight loss compared with placebo at 52 weeks. Clinical trials evaluating ephedrine, bupropion, topiramate and zonisamide have demonstrated significantly greater weight loss than placebo but have been limited to 16-26 weeks' treatment. A major obstacle to the evaluation of the clinical trials is the potential bias resulting from low study completion rates. Completion rates varied from 52.8% of phentermine recipients in a 9-month study, to 40% of fenfluramine recipients in a 24-week comparative study with phentermine and 18% of amfepramone recipients in a 24-week study. One-year completion rates range from 51% to 73% for sibutramine and from 66% to 85% for orlistat. Other potential sources of bias include run-in periods and subsequent patient selection based on compliance or initial weight loss. Several potential new therapies targeting weight loss and obesity through the CNS pathways or peripheral adiposity signals are in early phase clinical trials. Over the next decade the drug treatment of obesity is likely to change significantly because of the availability of new pharmacotherapies to regulate eating behaviours, nutrient partitioning and/or energy expenditure.

Use of complementary and alternative medicines by patients with chronic obstructive pulmonary disease.

OBJECTIVES: To investigate complementary and alternative medicine (CAM) use by patients with chronic obstructive pulmonary disease (COPD) and to explore their beliefs about CAM. DESIGN AND PARTICIPANTS: Cross-sectional study of 173 patients with moderate to severe COPD, and in depth interviews with a purposive sample of 28 patients. SETTING: Ambulatory care. MAIN OUTCOME MEASURES: Use of CAM; beliefs about the value of CAM. RESULTS: 71 patients (41%) claimed to be using some form of CAM. Most commonly used were multivitamins and minerals, and garlic was the most commonly used herbal preparation. Patients reported that advertisements and people with prior experience of using CAM were their major sources of information. Extent of knowledge about CAM, degree of faith in CAM and personal attitudes influenced decisions to try CAM. Patients used CAM to promote general wellbeing, to counteract drug side effects, to compensate for dietary deficiencies and to ameliorate their disease. Efficacy appeared less important to users than safety. CAM practitioners were regarded as more convincing, informative, considerate and available compared with mainstream health professionals. CONCLUSIONS: Communication between patients and mainstream health professionals about CAM use could be improved by health professionals being more accepting of CAM use and having some basic knowledge about commonly used CAM preparations.

Fenitrothion: toxicokinetics and toxicologic evaluation in human volunteers.

An unblinded crossover study of fenitrothion 0.18 mg/kg/day [36 times the acceptable daily intake (ADI)] and 0.36 mg/kg/day (72 X ADI) administered as two daily divided doses for 4 days in 12 human volunteers was designed and undertaken after results from a pilot study. On days 1 and 4, blood and urine samples were collected for analysis of fenitrothion and its major metabolites, as well as plasma and red blood cell cholinesterase activities, and biochemistry and hematology examination. Pharmacokinetic parameters could only be determined at the higher dosage, as there were insufficient measurable fenitrothion blood levels at the lower dosage and the fenitrooxone metabolite could not be measured. There was a wide range of interindividual variability in blood levels, with peak levels achieved between 1 and 4 hr and a half-life for fenitrothion of 0.8-4.5 hr. Although based on the half-life, steady-state levels should have been achieved; the area under the curve (AUC)(0-12 hr) to AUC(0-(infinity) )ratio of 1:3 suggested accumulation of fenitrothion. There was no significant change in plasma or red blood cell cholinesterase activity with repeated dosing at either dosage level of fenitrothion, and there were no significant abnormalities detected on biochemical or hematologic monitoring.

Reference-based pricing schemes: effect on pharmaceutical expenditure, resource utilisation and health outcomes.

Pharmaceutical expenditure is rising more rapidly than the general inflation rate in most advanced countries. One strategy that has been introduced to control pharmaceutical costs is reference-based pricing (RBP). Its potential is restricted to those specific segments of the drug market where several drugs (and/or their generic forms) exist without substantial evidence that any particular agent is superior. Three broad approaches have been adopted. These involve the aggregation of drugs into generic groups, related drug groups (e.g. ACE inhibitors) or drugs grouped by therapeutic indication (e.g. antihypertensives). For each drug group, a single reimbursement level or reference price is set. Drugs above the reference price require part or total payment by the patient. The experience with RBP ranges from over 10 years in Germany (involving all levels of RBP) to the more recent implementation of RBP for related drug groups in Australia. This review summarises the current state of knowledge on RBP from the published experiences in the countries where RBP has been adopted. The published systematic reviews of RBP from the countries that have implemented it suggest that RBP has been successful at temporarily capping drug prices for the RBP drug groups and achieving short term cost savings. However, other factors influencing total pharmaceutical expenditure have often occurred simultaneously and make it difficult to isolate specific effects of RBP. Further investigation is required before any valid conclusions can be drawn about the net effect of RBP on healthcare costs. RBP has withstood the initial legal challenges of pharmaceutical companies and the criticisms of some clinicians. Where the reference price is based on the lowest priced drug(s) in the group, RBP appears to be one of the few strategies likely to be effective at encouraging doctors to use the least expensive agents as first-line therapy and utilise more expensive agents in those who experience side effects or poor efficacy.

Ceftriaxone and cefotaxime use in Victorian hospitals.

OBJECTIVE: To determine patterns of use of ceftriaxone and cefotaxime (CEFX) in Victorian hospitals and to identify areas for improvement. DESIGN, PATIENTS AND SETTING: A concurrent, observational evaluation of CEFX use in patients commencing a course of these drugs between 8 and 14 September, 1999, in 51 Victorian hospitals. MAIN OUTCOME MEASURES: Proportion of patients treated with CEFX; indications; duration of use; concordance with recommendations of national antibiotic guidelines (Therapeutic guidelines: antibiotic, 10th edition [AG10]). RESULTS: 671 patients were treated with CEFX. The overall rate of use was 43 patients per 1000 inpatient separations. Treatment of respiratory tract infection accounted for 352 patients (52%) and surgical prophylaxis for 99 patients (15%). Treatment of skin/soft tissue, urinary tract and gastrointestinal tract infections accounted for about 7% of patients each. The median duration of CEFX courses was 3.0 days. The overall rate of concordance with indications recommended in AG10 was 27%. The rate of concordance for empirical treatment of respiratory tract infection was 24%. Of the 195 patients treated empirically with CEFX for community-acquired respiratory tract infection and assessed as non-concordant, 64% did not have radiological evidence of pneumonia, and a further 30% did not fulfill the criteria for severe pneumonia. All courses given for surgical prophylaxis were non-concordant. CONCLUSIONS: CEFX is widely used in Victorian hospitals, mostly to treat lower respiratory tract infection and in surgical prophylaxis of infection. The rate of concordance with AG10 is low. Potential areas for intervention include empirical treatment of respiratory tract infection and use in surgical prophylaxis.