Drugs
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General anaesthesia has become, thanks to recently developed drugs, monitoring devices and delivery systems, a very well tolerated method of making the great surgical opportunities of the last few years available to all ages of patient. With a balanced and rational use of drug profiles, general anaesthesia allows even frail and very ill patients a margin of tolerability inconceivable just a few years ago. For the vast majority of patients, the risk from the general anaesthetic technique is so small it can be considered negligible. ⋯ The currently available drugs and their place in anaesthetic practice are also assessed. Recent developments in the area of total intravenous anaesthesia and monitoring for potential awareness using bispectral analysis suggest that this technique should now be included in the choice of anaesthetic. Recommendations are made on both the selection of the technique, and the appropriate agents for a given group of patients.
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Review Comparative Study
Topotecan: a review of its efficacy in small cell lung cancer.
Topotecan, a water soluble semisynthetic derivative of camptothecin, has demonstrated antineoplastic activity in a wide range of cell culture and xenograft systems and is currently approved for second-line therapy in ovarian and small cell lung cancer (SCLC). The drug inhibits replication of rapidly dividing cells by disrupting the normal function of the nuclear enzyme topoisomerase I. The efficacy of topotecan is related to exposure time and the recommended regimen is 1.5 mg/m2 as a 30-minute intravenous infusion, daily for 5 days, repeated every 21 days. In phase II trials of topotecan in SCLC (usually with the 1.5mg/m2, 5 day regimen) the overall response rate in refractory patients (those who had relapsed < or =90 days after first-line therapy) was low at 2 to 11%, whereas in sensitive patients (those relapsing > or =90 days after first-line therapy) the overall response rate was 14 to 37%. Topotecan was compared with combined cyclophosphamide/doxorubicin(adriamycin)/vincristine (CAV) therapy in patients with relapsed, sensitive (relapsed > or =60 days after first-line therapy) SCLC. The response rates were 24.3% and 18.3% and, respectively, for the topotecan- and CAV-treated groups, and no significant differences were detected when primary efficacy endpoints (response rates and duration) were compared. However, the results of a symptom-specific questionnaire for SCLC did suggest that topotecan offered superior control of some symptoms. SCLC is usually treated with combinations of cytotoxic drugs, and topotecan is showing promise when partnered with paclitaxel and platinum compounds. The efficacy of an oral formulation of topotecan is also being investigated; preliminary results are encouraging and suggest similar efficacy to intravenous formulations, but with less frequent neutropenia. The tolerability and compliance advantages of oral topotecan may make this the route of choice in the future. Noncumulative anaemia, neutropenia and thrombocytopenia are the dose-limiting adverse effects associated with topotecan. CAV and topotecan therapy had similar suppressive effects on neutrophils in patients with SCLC, but the incidences of grade 3 or 4 anaemia and grade 4 thrombocytopenia were significantly higher in topotecan-treated patients. Non-haematological adverse events in SCLC patients treated with topotecan or CAV were similar and most were grade 1 or 2. Gastrointestinal disturbances were common in both groups, as were alopecia and fatigue. ⋯ In a large randomised comparative study, topotecan was as effective as CAV in treating relapsed SCLC. The response rate was modest and further comparative and drug-combination studies are required to accurately position topotecan within the schedule of available drugs used to treat SCLC, particularly in relation to first-line therapy. However, recurrent SCLC is extremely intractable to therapy and topotecan is a valuable extension to the limited range of treatment options for SCLC.
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Review Comparative Study
Deferiprone: a review of its clinical potential in iron overload in beta-thalassaemia major and other transfusion-dependent diseases.
Patients with beta-thalassaemia and other transfusion-dependent diseases develop iron overload from chronic blood transfusions and require regular iron chelation to prevent potentially fatal iron-related complications. The only iron chelator currently widely available is deferoxamine, which is expensive and requires prolonged subcutaneous infusion 3 to 7 times per week or daily intramuscular injections. Moreover, some patients are unable to tolerate deferoxamine and compliance with the drug is poor in many patients. Deferiprone is the most extensively studied oral iron chelator to date. Non-comparative clinical studies mostly in patients with beta-thalassaemia have demonstrated that deferiprone 75 to 100 mg/kg/day can reduce iron burden in regularly transfused iron-overloaded patients. Serum ferritin levels are generally reduced in patients with very high pretreatment levels and are frequently maintained within an acceptable range in those who are already adequately chelated. Deferiprone is not effective in all patients (some of whom show increases in serum ferritin and/or liver iron content, particularly during long term therapy). This may reflect factors such as suboptimal dosage and/or severe degree of iron overload at baseline in some instances. Although few long term comparative data are available, deferiprone at the recommended dosage of 75 mg/kg/day appears to be less effective than deferoxamine; however, compliance is superior with deferiprone, which may partly compensate for this. Deferiprone has additive, or possibly synergistic, effects on iron excretion when combined with deferoxamine. The optimum dosage and long term efficacy of deferiprone, and its effects on survival and progression of iron-related organ damage, remain to be established. The most important adverse effects in deferiprone-treated patients are arthropathy and neutropenia/agranulocytosis. Other adverse events include gastrointestinal disturbances, ALT elevation, development of antinuclear antibodies and zinc deficiency. With deferiprone, adverse effects occur mostly in heavily iron-loaded patients, whereas with deferoxamine adverse effects occur predominantly when body iron burden is lower. ⋯ Deferiprone is the most promising oral iron chelator under development at present. Further studies are required to determine the best way to use this new drug. Although it appears to be less effective than deferoxamine at the recommended dosage and there are concerns regarding its tolerability, it may nevertheless offer a therapeutic alternative in the management of patients unable or unwilling to receive the latter drug. Deferipone also shows promise as an adjunct to deferoxamine therapy in patients with insufficient response and may prove useful as a maintenance treatment to interpose between treatments.
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There is now considerable clinical trial data to support the use of beta-blockers in patients with congestive heart failure (CHF) due to systolic left ventricular dysfunction. A substantial database has accumulated over the last 20 years supporting the benefits of these agents on ventricular function and clinical status. In addition, morbidity and mortality benefits have been suggested, specifically with the non-selective vasodilating agent, carvedilol. ⋯ Furthermore, it would now appear unethical to deprive suitable NYHA Class II-III CHF patients of beta-blockers as part of the design of such studies. In conclusion, beta-blockers have now become the most extensively studied class of agents in the treatment of CHF, with a database of over 6000 patients in placebo-controlled studies, and ongoing clinical and mechanistic studies. Despite this, further questions remain regarding the use of these agents in CHF, including their role in the extreme elderly, in patients with diabetes mellitus and in patients with renal impairment.
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Review Comparative Study
Tranexamic acid: a review of its use in surgery and other indications.
Tranexamic acid is a synthetic derivative of the amino acid lysine that exerts its antifibrinolytic effect through the reversible blockade of lysine binding sites on plasminogen molecules. Intravenously administered tranexamic acid (most commonly 10 mg/kg followed by infusion of 1 mg/kg/hour) caused reductions relative to placebo of 29 to 54% in postoperative blood losses in patients undergoing cardiac surgery with cardiopulmonary bypass (CPB), with statistically significant reductions in transfusion requirements in some studies. Tranexamic acid had similar efficacy to aprotinin 2 x 10(6) kallikrein inhibitory units (KIU) and was superior to dipyridamole in the reduction of postoperative blood losses. Transfusion requirements were reduced significantly by 43% with tranexamic acid and by 60% with aprotinin in 1 study. Meta-analysis of 60 trials showed tranexamic acid and aprotinin, unlike epsilon-aminocaproic acid (EACA) and desmopressin, to reduce significantly the number of patients requiring allogeneic blood transfusions after cardiac surgery with CPB. Tranexamic acid was associated with reductions relative to placebo in mortality of 5 to 54% in patients with upper gastrointestinal bleeding. Meta-analysis indicated a reduction of 40%. Reductions of 34 to 57.9% versus placebo or control in mean menstrual blood loss occurred during tranexamic acid therapy in women with menorrhagia; the drug has also been used to good effect in placental bleeding, postpartum haemorrhage and conisation of the cervix. Tranexamic acid significantly reduced mean blood losses after oral surgery in patients with haemophilia and was effective as a mouthwash in dental patients receiving oral anticoagulants. Reductions in blood loss were also obtained with the use of the drug in patients undergoing orthotopic liver transplantation or transurethral prostatic surgery, and rates of rebleeding were reduced in patients with traumatic hyphaema. Clinical benefit has also been reported with tranexamic acid in patients with hereditary angioneurotic oedema. Tranexamic acid is well tolerated; nausea and diarrhoea are the most common adverse events. Increased risk of thrombosis with the drug has not been demonstrated in clinical trials. ⋯ Tranexamic acid is useful in a wide range of haemorrhagic conditions. The drug reduces postoperative blood losses and transfusion requirements in a number of types of surgery, with potential cost and tolerability advantages over aprotinin, and appears to reduce rates of mortality and urgent surgery in patients with upper gastrointestinal haemorrhage. Tranexamic acid reduces menstrual blood loss and is a possible alternative to surgery in menorrhagia, and has been used successfully to control bleeding in pregnancy.