Assessing the value of atomoxetine in treating children and adolescents with ADHD in the UK.

BACKGROUND: Economic evaluation of healthcare technologies is becoming increasingly relevant, enabling decision makers to assess and compare treatments within the context of costs and outcomes. Moreover, it is increasingly important for clinicians and prescribers to have some understanding of economic evaluation. For attention-deficit/hyperactivity disorder (ADHD), economic evaluations have largely focused on pharmacotherapy, and results indicate that such treatments are cost-effective compared with other interventions. AIMS: This review provides an overview of ADHD, its consequences and pharmacotherapy; describes the principles of health economic analysis, health-related quality of life (HRQL) and a cost-effectiveness model of atomoxetine for ADHD treatment; and outlines guidance from the National Institute for Health and Clinical Excellence on ADHD pharmacotherapy. METHODS: The cost-effectiveness of atomoxetine for children with ADHD in the UK was compared with treatment alternatives using an economic model with Markov processes. The model evaluated atomoxetine in five patient subgroups according to treatment history and comorbidities precluding stimulants. Incremental cost per quality-adjusted life-year (QALY) was calculated and compared between treatment algorithms. The Markov process incorporated 18 health states, representing a range of outcomes across the treatments. Utility values were derived from a survey of 83 parents of children with ADHD, and treatment efficacy and safety were based on a review of controlled clinical trials and literature, and validated by international experts. Costs and outcomes were estimated using Monte Carlo simulation over 1-year. RESULTS: Atomoxetine was a cost-effective treatment across the whole ADHD population, with incremental cost-effectiveness ratios ranging from pound 11,500 to pound 15,900 per QALY, compared with alternative pharmacotherapies, which are within UK and rest of Europe acceptability limits. Higher utility values achieved treating ADHD with atomoxetine, compensate for the relatively higher acquisition cost compared with stimulants. CONCLUSIONS: Atomoxetine is cost-effective and may have advantages over stimulants, including benefits to HRQL and no abuse liability and is the only treatment in the UK licensed for continued treatment into adulthood in adolescents who have shown a response from treatment.

Topiramate in the treatment of myoclonic-astatic epilepsy in children: a retrospective hospital audit.

BACKGROUND: Myoclonic-Astatic Epilepsy (MAE) usually starts before five years of age and is associated with very frequent seizures and is highly resistant to treatment. AIM: To investigate the outcome of adjunctive topiramate (TPM) therapy in children with a diagnosis of MAE syndrome. SUBJECTS AND METHODS: In an outpatient setting, case notes of 27 children who received TPM were retrieved and analysed. RESULTS: Records of 6 children with MAE, who were experiencing 2-8 atonic seizures daily before starting TPM were studied. Improvement was noted after addition of TPM (mean dose at steady-state 7.4+/-2.5mg/kg/day) to the regimen of 1-3 anti-epileptic drugs they were receiving concurrently. All but one child improved following the titration period: one had 50-80% improvement in the frequency of atonic seizures and three had over 80% improvement. However, one child who showed over 80% improvement and was free of atonic seizures, later developed increased frequency of other seizure types. In one child there was no significant improvement. Improvement has been sustained for over 6 months in three patients and over 4 months in one; three have continued TPM. TPM was stopped in three patients (reduction in seizure control/no improvement). CONCLUSIONS: This study supports the efficacy of TPM in controlling atonic seizures in MAE and indicates that it should be considered as an add-on drug in the management of this 'difficult-to-treat' epileptic syndrome.

Itch: scratching more than the surface.

In origin, itch can be cutaneous ("pruritoceptive", e.g. dermatitis), neuropathic (e.g. multiple sclerosis), neurogenic (e.g. cholestasis), mixed (e.g. uraemia) or psychogenic. Although itch of cutaneous origin shares a common neural pathway with pain, the afferent C-fibres subserving this type of itch are a functionally distinct subset: they respond to histamine, acetylcholine and other pruritogens, but are insensitive to mechanical stimuli. Histamine is the main mediator for itch in insect bite reactions and in most forms of urticaria, and in these circumstances the itch responds well to H(1)-antihistamines. However, in most dermatoses and in systemic disease, low-sedative H(1)-antihistamines are ineffective. Opioid antagonists relieve itch caused by spinal opioids, cholestasis and, possibly, uraemia. Ondansetron relieves itch caused by spinal opioids (but not cholestasis and uraemia). Other drug treatments for itch include rifampicin, colestyramine and 17-alpha alkyl androgens (cholestasis), thalidomide (uraemia), cimetidine and corticosteroids (Hodgkin's lymphoma), paroxetine (paraneoplastic itch), aspirin and paroxetine (polycythaemia vera) and indometacin (some HIV+ patients). If the remedies specified fail, paroxetine and mirtazapine should be considered. Ultraviolet B therapy, particularly narrow-band UVB, may be superior to drug treatment for itch in uraemia.

Risperidone compared with olanzapine in a naturalistic clinical study in Ireland: a cost analysis.

BACKGROUND: Risperidone and olanzapine are thought to have similar clinical effects. This study was designed to compare costs of treatment. AIM: To compare costs of treatment with risperidone or olanzapine in a naturalistic setting. METHOD: The Irish Risperidone Olanzapine Drug Outcomes studies in Schizophrenia (RODOS) programme was a retrospective review of medical notes and prescription charts in 396 inpatients with schizophrenia or schizoaffective disorder. The main outcome measure was cost of inpatient drug treatment. RESULTS: There was no statistical difference in length of hospital stay between risperidone-treated and olanzapine-treated patients (mean duration of stay 37.8 and 40.5 days, p=0.90). Mean+/-SD doses of risperidone and olanzapine were 4.2+/-2.1 mg/day and 12.9+/-5.0 mg/day, respectively. Average daily cost of all inpatient drugs was significantly higher for olanzapine than for risperidone (i.e. IEP5.61 [7.12] vs IEP3.38 [4.29]; p<0.0001), as was mean total costs of all inpatient drugs (i.e. IEP114.8 [145.8] vs IEP62.0 [78.7]; p<0.0001). This partly reflected the mean, non-significant, longer treatment duration for olanzapine compared with risperidone (mean 30.0 vs 26.4 days; p=0.27). Concomitant neuroleptic use was similar for both groups (71% risperidone, 73% olanzapine; p=0.54). CONCLUSION: Risperidone was associated with significantly lower drug treatment costs.

Opioid drugs: a comparative survey of therapeutic and "street" use.

OBJECTIVES: The prescription of strong opioid analgesics for chronic non-cancer pain (CNCP) is described as controversial and can result in misidentification of patients as drug abusers or individuals with an addiction. This study compared the effects of opioid drugs on CNCP patients and "street" users. SUBJECTS/SETTING: The groups comprised 36 CNCP patients attending a pain clinic and 39 street users, recruited on London streets. DESIGN: CNCP patients were interviewed in a pain clinic and street users in a street setting. A questionnaire was used to assess drug craving, dose escalation, cessation of use, compulsion to use, effects on career, relationships and activities, experience of "highs," and problems due to intoxication. To assess physiological dependence, subjects answered questions on specific effects e.g. stomach pains, nausea/vomiting, cramps/aches, etc.). Efficacy was assessed in CNCP patients by determining analgesia and physical function. RESULTS: CNCP patients started therapy in the low dose range for oral morphine (

Improvement in quality of life for cancer patients treated with epoetin alfa.

Anaemia is a common complication of cancer and cancer therapies, and fatigue is one of the most common symptoms of anaemia, disrupting functional performance and reducing overall quality of life. The positive effects of treating renal patients with recombinant human erythropoietin are well documented. This case report series details the specific effects of fatigue on individual patients with cancer and their way of life, and describes their significant improvement in lifestyle following the reversal of anaemia using recombinant human erythropoietin, epoetin alfa.

Use of Bisphosphonates in the Treatment of Multiple Myeloma.

Bone pain is the single most common presenting complaint in myeloma. Although first-line chemotherapy has a marked effect on bone pain, skeletal disease frequently continues to progress throughout the course of the disease and the incidence of skeletal events remains high. The underlying pathology in myeloma constitutes mainly increased osteoclastic activity but also reduced osteoblastic activity. Any agent that inhibits osteoclast activity potentially provides some degree of skeletal protection although only the bisphosphonates have achieved widespread use. Bisphosphonates are potent inhibitors of osteoclast-mediated bone resorption and evidence of bone protection and modification of skeletal disease progression has been greatest with clodronate and pamidronate. The MRC VIth Myeloma Trial is, to date, by far the largest randomised placebo-controlled trial of bisphosphonates in myeloma. Current evidence suggests that bisphosphonate treatment should begin as early as possible and continue indefinitely, and probably should be considered for all patients with myeloma. The additional costs of clodronate therapy in the management of myeloma patients were around 17% higher than in controls which is moderate when considering the significant reductions in hypercalcaemic episodes and in vertebral and non-vertebral fractures.

HFA-134a (1,1,1,2-tetrafluoroethane): effects of inhalation exposure upon reproductive performance, development and maturation of rats.

1. HFA-134a was administered to AHA rats by snout-only inhalation for 1 h daily to assess the effects of treatment on reproduction and development. 2. In a fertility study, rats were exposed to atmospheres of 2500, 10,000 or 50,000 p.p.m. HFA-134a throughout gametogenesis, mating, pregnancy and lactation. 3. In a peri- and post-natal study, rats were exposed to HFA-134a from days 17 to 20 of pregnancy and days 1 to 21 post partum to atmospheres of 1800, 9900 or 64,400 p.p.m. 4. The only treatment-related effect was a slight reduction in body weight gain of males of the treated parental generation at 50,000 p.p.m. (fertility study). 5. In neither study were there any adverse effects of HFA-134a on the reproductive performance of treated animals or on the development, maturation or reproductive performance of up to two successive generations.

HFA-134a (1,1,1,2-tetrafluoroethane); lack of oncogenicity in rodents after inhalation.

1. Groups of 60 male and 60 female B6C3F1 mice or HanIbm Wistar rats were exposed to HFA-134a using snout-only inhalation exposure techniques for periods of one hour daily for at least 104 weeks. HFA-134a was delivered directly from cylinders at vapour concentrations of 2500, 15,000 and 75,000ppm for mice and from metered-dose inhalers at vapour concentrations of 2500, 10,000 and 50,000ppm for rats. 2. Intended dosages were achieved. 3. Evidence of absorption was found at each dose level and was dose related. 4. Neither species suffered treatment related effects on survival, clinical signs, body weights, haematology nor on the type, incidence, site or severity of gross lesions. 5. There was no effect of treatment on the type, incidence, site or severity of neoplasms in mice or rats. 6. There were no non-neoplastic findings related to treatment in mice. 7. HFA-134a was considered not to be oncogenic and to provide a safe alternative to chlorofluorocarbons for use in pharmaceutical metered-dose inhalers.

An overview of the toxicology of HFA-134a (1,1,1,2-tetrafluoroethane).

1. This paper reviews the results of preclinical toxicology studies on HFA-134a carried out by Glaxo Research and Development Ltd. 2. A comprehensive range of studies was conducted in animal models suitable for the type of investigation. 3. The inhalation route of administration was used in all in vivo studies (with the exception of local tolerance and sensitisation studies) as patients will be exposed only to vapour during actuation of metered-dose inhalers. Cell cultures used for in vitro studies were also exposed to the vapour. 4. There was no mortality of rodents or dogs at extremely high vapour concentrations (81%v/v) 5. HFA-134a was considered not to be toxic or oncogenic and to provide a safe alternative to chlorofluorocarbons for use in pharmaceutical metered-dose inhalers.

Review of the toxicology of beclomethasone dipropionate.

This paper reviews the published toxicity of beclomethasone dipropionate (BDP). BDP is a synthetic glucocorticosteroid which has a powerful local anti-inflammatory effect but little systemic action. It has been developed for both dermatological and inhaled applications. LD50 values and other acute studies indicated low toxicity. Findings published for repeat dose and reproductive toxicity studies embraced the known range of metabolic and physiological effects of glucocorticoids. For repeat dose studies, these included reduction in body weight gains, cushingoid syndrome in dogs, reductions in the numbers of lymphocytes and the weights of the tissues connected with the immune system, and hepatic glycogen deposition and fatty liver changes. In reproductive studies, there was an increase in the prevalence of cleft palate in mice and rabbits and in the number of dead foetuses, and ossification was retarded. Despite the route of administration, there was a general similarity of effects within and between species. All observations were characteristic of synthetic glucocorticoids and related to the intrinsic effects of these drugs.

Toxicity of a novel HMG-CoA reductase inhibitor in the common marmoset (Callithrix jacchus).

1. GR95030X, a potent inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, was administered daily to marmosets by gavage. In a Maximum Repeatable Dose (MRD) study, doses of up to 30 mg kg-1 day-1 were administered for 49 days. In a chronic study, animals received dosages equivalent to 0, 1, 2.5, 7.5 and 20 mg kg-1 day-1 for 204 or 205 days. Some animals were maintained without treatment for a recovery period of 29 or 30 days. 2. Clinical signs included poor coat condition, weakness with impaired coordination, lethargy and other behavioural changes. There was also alimentary disturbance, and some deaths occurred at doses of 20 mg kg-1 day-1 and above. 3. Adverse effects upon body weight were seen although some recovery was apparent after the cessation of treatment. 4. Serum cholesterol concentrations were reduced. Very large increases in serum ALT, AST and CK activities were recorded with CK-MM isoenzymes accounting for 80% or more of the total CK enzyme activity. 5. Treatment was associated with muscle fibre atrophy and a sarcolemmal response with little evidence of regeneration. Histological examination revealed vascular changes, glial proliferation and cell death in the brain, with no consistent distribution. Alveolar capillary congestion and alveolar proteinosis indicated that there may have been a reduction in cardiac function. 6. HMG-CoA reductase inhibitors have evident potential to cause myopathy in marmosets. This is believed to be the first report of such an effect.

A review of the toxicology of salbutamol (albuterol).

This paper reviews the published toxicology of salbutamol. Salbutamol is a relatively selective beta 2-adrenoreceptor stimulant with rapid, potent bronchodilator activity and only minor inotropic or chronotropic effects. It was not found to be mutagenic. LD50 values and other acute studies indicated low toxicity. Findings published for repeat dose studies were mainly uneventful. Tachycardia and flushing of the skin were observed in dogs. There were several findings peculiar to the rat--growth of the salivary gland, enlargement of the Harderian gland, an increase in colloid in the pituitary, and mesovarian leiomyomas. Increases in heart weights associated with inflammation, hypertrophy of muscle fibres, focal myocardial necrosis and fibrosis were seen in rats. Malformation, in the form of cleft palate, was reported in mice but not in rats or rabbits. These treatment related effects reported for salbutamol are not compound-related but rather are class-related. They are an expression of pharmacological activity brought about by the excessive beta stimulant action of high dosage with the drug.