Drugs
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Review
Effects of beta-blockers on neurohormonal activation in patients with congestive heart failure.
The effect of beta-adrenoceptor antagonists (beta-blockers) on neurohormonal activation in patients with congestive heart failure has been the subject of study in numerous small clinical trials. Short term therapy with beta-blockers is associated with a variable acute neurohormonal response which may be determined by the pharmacology of the agent under study and the baseline characteristics of the patient population. ⋯ Agents with partial agonist activity appear to differ from pure antagonists, with some studies reporting evidence of increased neurohormonal activation. The mechanisms by which beta-blockers reduce neurohormonal activation and the clinical relevance of changes in adrenergic function to their use in the treatment of heart failure require further investigation.
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Budesonide, a topically active corticosteroid, has a broad spectrum of clinically significant local anti-inflammatory effects in patients with inflammatory lung diseases including persistent asthma. In infants and young children with persistent asthma, day- and night-time symptom scores, and the number of days in which beta2-agonist bronchodilators were required, were significantly lower during randomised, double-blind treatment with budesonide inhalation suspension 0.5 to 2 mg/day than placebo in 3 multicentre trials. Significantly fewer children discontinued therapy with budesonide inhalation suspension than with placebo because of worsening asthma symptoms in a study that included children who were receiving inhaled corticosteroids at baseline. ⋯ Hypothalamic-pituitary-adrenal axis function was not affected by short (12 weeks) or long (52 weeks) term treatment with nebulised budesonide. In conclusion, budesonide inhalation suspension is the most widely available nebulised corticosteroid, and in the US is the only inhaled corticosteroid indicated in children aged > or =1 year with persistent asthma. The preparation is suitable for use in infants, children and adults with persistent asthma and in infants and children with croup.
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Review
Inhaled salmeterol/fluticasone propionate combination: a review of its use in persistent asthma.
The long-acting beta2-agonist salmeterol and the corticosteroid fluticasone propionate are available as a combination inhalation device for the treatment of persistent asthma. Well designed studies in adults, adolescents and children aged > or =4 years, demonstrate that combined salmetero/fluticasone propionate 50/100, 50/250 and 50/500 microg administered via a dry powder inhaler (DPI) is clinically equivalent to concurrent delivery of the same dosages of the 2 drugs via separate DPIs. In adults and adolescents, combined salmeterol/fluticasone 50/100 and 50/250 microg twice daily produced rapid improvements in lung function that were consistently greater than those in patients receiving monotherapy twice daily salmeterol 50 microg, fluticasone propionate 100 or 250 microg or placebo in 2 well designed studies. Recipients of the combination had a significantly greater probability of completing 12 weeks of treatment than patients receiving monotherapy or placebo. The combination also produced significant improvements between baseline and end-point in all secondary outcome variables (morning and evening peak expiratory flow, daytime symptom scores, days and nights without asthma symptoms and requirements for as-needed beta-agonists) and health-related quality of life (QOL). Combination therapy was superior to monotherapy with salmeterol and placebo for all outcomes in both studies, and was superior to fluticasone propionate 100 microg for all but 1 outcome (nights without awakenings) in 1 study. Similar results were obtained in patients who had previously been using short acting beta2-agonists alone. Combined twice daily salmeterolfluticasone propionate 50/100 and 50/250 microg produced greater improvements in lung function than inhaled budesonide at higher dosages than fluticasone propionate in the combination. Combined salmeterol/fluticasone propionate 50/250 microg produced similar improvements in lung function to concurrent budesonide 800 microg plus formoterol 12 microg when given twice daily for 12 weeks. In another 12-week trial, combined salmeterol/fluticasone propionate 50/100 microg was more effective than oral montelukast 10 mg/day plus fluticasone propionate 100 microg twice daily in patients with suboptimally controlled asthma. Salmeterol/fluticasone is more cost effective than monotherapy with fluticasone propionate or budesonide. The most frequent adverse events associated with salmeterol/fluticasone propionate are headache, throat irritation, hoarseness and candidiasis. ⋯ Combined salmeterol/fluticasone propionate is as effective as the 2 drugs given concurrently via separate inhalers and significantly more effective than either drug given alone at the same nominal dosage. The combination is also significantly more effective than montelukast plus fluticasone propionate or monotherapy with inhaled budesonide. Furthermore, the combination is more cost effective than inhaled corticosteroid monotherapy.
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Ropivacaine is a long-acting, enantiomerically pure (S-enantiomer) amide local anaesthetic with a high pKa and low lipid solubility which blocks nerve fibres involved in pain transmission (Adelta and C fibres) to a greater degree than those controlling motor function (Abeta fibres). The drug was less cardiotoxic than equal concentrations of racemic bupivacaine but more so than lidocaine (lignocaine) in vitro and had a significantly higher threshold for CNS toxicity than racemic bupivacaine in healthy volunteers (mean maximum tolerated unbound arterial plasma concentrations were 0.56 and 0.3 mg/L, respectively). Extensive clinical data have shown that epidural ropivacaine 0.2% is effective for the initiation and maintenance of labour analgesia, and provides pain relief after abdominal or orthopaedic surgery especially when given in conjunction with opioids (coadministration with opioids may also allow for lower concentrations of ropivacaine to be used). The drug had efficacy generally similar to that of the same dose of bupivacaine with regard to pain relief but caused less motor blockade at low concentrations. Lumbar epidural administration of 20 to 30ml ropivacaine 0.5% provided anaesthesia of a similar quality to that achieved with bupivacaine 0.5% in women undergoing caesarean section, but the duration of motor blockade was shorter with ropivacaine. For lumbar epidural anaesthesia for lower limb or genitourinary surgery, comparative data suggest that higher concentrations of ropivacaine (0.75 or 1.0%) may be needed to provide the same sensory and motor blockade as bupivacaine 0.5 and 0.75%. In patients about to undergo upper limb surgery, 30 to 40ml ropivacaine 0.5% produced brachial plexus anaesthesia broadly similar to that achieved with equivalent volumes of bupivacaine 0.5%, although the time to onset of sensory block tended to be faster and the duration of motor block shorter with ropivacaine. Ropivacaine had an adverse event profile similar to that of bupivacaine in clinical trials. Several cases of CNS toxicity have been reported after inadvertent intravascular administration of ropivacaine, but only 1 case of cardiovascular toxicity has been reported to date. The outcome of these inadvertent intravascular administrations was favourable. ⋯ Ropivacaine is a well tolerated regional anaesthetic with an efficacy broadly similar to that of bupivacaine. However, it may be a preferred option because of its reduced CNS and cardiotoxic potential and its lower propensity for motor block.
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Neuropathic pain, a form of chronic pain caused by injury to or disease of the peripheral or central nervous system, is a formidable therapeutic challenge to clinicians because it does not respond well to traditional pain therapies. Our knowledge about the pathogenesis of neuropathic pain has grown significantly over last 2 decades. Basic research with animal and human models of neuropathic pain has shown that a number of pathophysiological and biochemical changes take place in the nervous system as a result of an insult. ⋯ There is potential for phenobarbital, clonazepam, valproic acid, topiramate, pregabalin and tiagabine to have antihyperalgesic and antinociceptive activities based on result in animal models of neuropathic pain, but the efficacy of these drugs in the treatment of human neuropathic pain has not yet been fully determined in clinical trials. The role of anticonvulsant drugs in the treatment of neuropathic pain is evolving and has been clearly demonstrated with gabapentin and carbamazepine. Further advances in our understanding of the mechanisms underlying neuropathic pain syndromes and well-designed clinical trials should further the opportunities to establish the role of anticonvulsants in the treatment of neuropathic pain.