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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.

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.

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 ani mal 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.

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.

The Hantronic pneumatic tube system was installed for transporting animal blood specimens from animal accommodation to clinical laboratories for analysis. It provides a safe system that is convenient and effective, and allows for rapid analysis of blood following collection. There were no changes considered to be of importance in the mean erythrocyte, leucocyte and platelet counts of whole blood from mice, rats and dogs after transportation through the system.

HFA-134a, a chlorine-free hydrofluoroalkane, was administered for 1 h daily to beagle dogs by means of a system for inhalation by face mask. In this 1-yr study, animals received atmospheric air, air containing an additional 12% nitrogen, or air containing a nominal 12% HFA-134a for 376 or 377 days. HFA-134a was rapidly absorbed into and cleared from the blood. There were no treatment-related clinical signs or effects on body weight, food consumption, ophthalmoscopy, heart function, respiratory rate, pulse rate, haematology, blood biochemistry, urine analysis, or postmortem findings. HFA-134a was considered to be nontoxic and to provide a safe alternative to chlorofluorocarbons for use in pharmaceutical metered-dose inhaler formulations.

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.

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.

The performance of a prototype AVL MS8 VET impedance haematology analyser was compared with that of a Technicon H*1 flow cytometry haematology analyser using blood from dogs and cats. Analysis was performed with the AVL MS8 VET on the day of blood collection and with the Technicon H*1 on the following day. Differences were noted in feline leucocyte and platelet counts and in canine and feline mean cell volume and mean cell haemoglobin concentration between analyses. The results indicate that the AVL MS8 VET is a reliable analyser for blood samples from dogs but may not be for those from cats. Attention is drawn to the importance of considering the type of analyser, calibration of the analyser, time of analysis after blood collection (effect of postal delay) and the effect of anticoagulants.

A haemolysis test has been evaluated as an alternative to the Draize eye test (Draize et al. 1944) for ocular irritancy. Haemolysis was seen with corrosive/ severe and severe/moderate eye irritants but was negligible with non-irritant substances.

A microcomputer-based system has been developed for administering metered dose aerosol formulations to dogs during toxicology studies. The apparatus comprises a thermistor bead mounted at the outlet of a dosing chamber that in turn is connected to an oropharyngeal tube. Attached to the inlet of the chamber is an actuator unit containing the aerosol. The actuator unit incorporates an operating plunger, a microswitch counting mechanism, a one-way valve, and an extract line connected to a vacuum pump. The signals from the thermistor bead and counting mechanism pass via a preamplifier control box to a computer. Also connected to the computer are a balance, a printer, and a monitor.The computer software was specially written for the system. Before starting a study the computer is programmed with details specific to the study. The system selects a dog to be dosed and weighs the aerosol pack. The dosing session commences when the oropharyngeal tube is placed into the dog's mouth. On completion of dosing,...

Summary 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 £11,500 to £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.

Myoclonic-Astatic Epilepsy (MAE) usually starts before five years of age and is associated with very frequent seizures and is highly resistant to treatment.To investigate the outcome of adjunctive topiramate (TPM) therapy in children with a diagnosis of MAE syndrome.In an outpatient setting, case notes of 27 children who received TPM were retrieved and analysed.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).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.

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.

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, 10000 or 50000 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 reduc tion 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.

1 Groups of 60 male and 60 female B6C3F1 mice or Han- Ibm 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 deliv ered 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 any 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 treat ment 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.