Benefit-risk assessment of ciclosporin withdrawal in renal transplant recipients.

Ciclosporin is associated with significant toxicity, including nephrotoxicity, and with an increased risk of cardiovascular events. Many attempts have been made to wean patients from ciclosporin. Before the availability of new immunosuppressive drugs, the acute rejection rate observed after ciclosporin withdrawal did not permit the widespread use of withdrawal regimens even though meta-analysis did not show that they adversely affected patient or graft survival. Nevertheless, maintenance therapy with azathioprine and corticosteroids has not become routine practice. The introduction of mycophenolate mofetil and subsequently sirolimus has increased the number of clinical studies of the effects of ciclosporin withdrawal. In stable patients, this withdrawal is associated with a small but significant increase in the incidence of acute rejection episodes. Declining renal function and other forms of ciclosporin-related toxicity have improved. However, this improvement was also observed when ciclosporin was only reduced (and not withdrawn), which did not increase the risk of acute rejection. More precise definition of the patients who could benefit from ciclosporin-withdrawal may help to optimise the immunosuppressive regimen in this setting. In patients with chronic allograft deterioration, ciclosporin withdrawal together with mycophenolate mofetil introduction has been shown to improve renal function significantly in many small studies, and a large prospective randomised study. For the time being, ciclosporin withdrawal is a good therapeutic option for patients with declining renal function and signs of chronic ciclosporin nephrotoxicity on renal biopsy. Finally, recent preliminary studies have reported the results of complete avoidance of calcineurin inhibitors after renal transplantation. These results are promising as regards the incidence of acute rejection, renal function and safety, but need confirmation in larger trials with a longer follow-up. Nevertheless, it has become clear that the concept of an immunosuppressive regimen with little or no nephrotoxicity after renal transplantation is more and more important and plays a crucial part in tailoring immunosuppression to the needs of specific patient populations.     

Benefit-risk assessment of raloxifene in postmenopausal osteoporosis.

Raloxifene, a nonsteroidal benzothiophene, is a second-generation selective estrogen receptor modulator (SERM) that is an antiresorptive agent. Raloxifene is a non-hormonal agent that binds to the estrogen receptor and results in estrogen agonist effects on bone and the cardiovascular system and estrogen antagonist effects on endometrial and breast tissue. Raloxifene has diverse pharmacodynamic properties due to its differential interactions with the estrogen receptor and tissue selectivity. Raloxifene was the first SERM to be approved for the prevention and treatment of postmenopausal osteoporosis. In this review, we conducted a systematic search of the literature for trials that evaluated the following outcomes: bone density, fractures, quality of life, cardiovascular outcomes, safety and adverse events. Raloxifene at the approved dosage of 60 mg/day increased lumbar spine bone density by 2.5% relative to control after 2 years of therapy. A large fracture prevention trial confirmed that treatment with raloxifene 60 mg/day for 3 years decreased the relative risk of incident vertebral fractures by 30-50% in women with prevalent fractures or osteoporosis. Extraskeletal effects of raloxifene include a reduction in total cholesterol and low density lipoprotein cholesterol levels. Assessment of the safety profile revealed that raloxifene was not associated with endometrial hyperplasia and that there was a 72% reduction in the incidence of invasive breast cancer in raloxifene-treated postmenopausal women with osteoporosis. Adverse events associated with raloxifene included an increase in the absolute risk of venous thromboembolism and an increase in the risk of hot flashes and leg cramps. In comparison to other osteoporosis therapies, raloxifene has a lesser impact on bone mineral density, a similar effect on the occurrence of vertebral fractures, but no effect on the frequency of non-vertebral fractures. Raloxifene can be recommended for the prevention of vertebral fractures in women with osteopenia/osteoporosis who are not at high risk of non-vertebral fractures and who do not have a past history of venous thromboembolism.     

Benefit-risk assessment of treatments for heparin-induced thrombocytopenia.

Patients with heparin-induced thrombocytopenia (HIT) are at high risk of thrombosis and should be treated with alternative anticoagulant therapy to reduce complications. The current treatment of choice is one of the approved direct thrombin inhibitors, argatroban or lepirudin. These drugs have been proven to be safe and effective in multicentre clinical trials where dosage regimens have been established for prophylaxis and treatment of thrombosis. Argatroban has also been tested and approved for use in invasive cardiology procedures in the HIT patient. Dosage regimens for other clinical uses, such as cardiac surgery, have not yet been established for either drug. The safety and effectiveness of the thrombin inhibitors is dependent on their use according to established guidelines. Other treatment options that may be effective for the patient with HIT include dextran, plasmapheresis, intravenous gammaglobulin and aspirin (acetylsalicylic acid). Although used historically, these options have not been tested in rigorous clinical trials. For life- and limb-threatening thrombosis, thrombolytic agents and/or surgery may provide benefit. Because the risk of bleeding is high from these procedures, they should be performed only by an experienced practitioner. Several studies have shown that patients with HIT requiring continued anticoagulation are best managed with a warfarin derivative initiated while under full anticoagulation with a thrombin inhibitor. There is a risk of skin necrosis and bleeding if guidelines for dose administration and monitoring of warfarin are not followed. Subsequent use of heparin or a low molecular weight heparin after resolution of the clinical episode of HIT can be hazardous, particularly within the first 3 months. If laboratory testing is negative, heparin may be cautiously reinstituted for short-term use (1-2 hours) with monitoring for platelet count decrease and thromboembolism. The pregnant patient with HIT requiring anticoagulation represents a particular challenge, where there is no drug of choice at present. Although today there are realistic treatment options for the patient with HIT, the morbidity and mortality associated with this disease have not been eliminated. Awareness and early treatment of HIT remain important components of the clinical care for patients exposed to heparins. Future therapeutic developments based on a better understanding of the pathophysiology of HIT may further improve clinical outcomes. Despite some limitations, the current treatment options for patients with HIT provide unparalleled benefit compared with the treatment options available only a few years ago.     

Benefit-risk assessment of irinotecan in advanced colorectal cancer.

Irinotecan exerts its cytotoxic activity through inhibition of the nuclear enzyme topoisomerase I. It has been approved in most countries worldwide for treatment of patients with advanced colorectal cancer (CRC). Activity is seen in previously untreated patients and in patients refractory to fluorouracil treatment, whether it is given alone or in combination with other cytotoxic drugs. Irinotecan was first developed in patients refractory to fluorouracil. Activity in terms of tumour responses and patient benefit was seen in several phase II trials that used either a weekly or a three-weekly schedule. In two randomised trials (irinotecan vs best supportive care, and irinotecan vs an infused fluorouracil-based regimen), irinotecan prolonged median survival by approximately 2.5 months without any deterioration in quality-of-life. It was later studied in previously untreated patients with advanced CRC in combination with fluorouracil/folinic acid (leucovorin). In three large randomised trials, median time to tumour progression was prolonged by approximately 2.5 months and overall survival by about 2.5 months compared with fluorouracil/folinic acid alone. Tumour responses were also seen more frequently in the irinotecan arm (35-40% vs 20%). Again, quality-of-life scores were not deteriorated by the addition of irinotecan. Irinotecan has many acute adverse effects. The most prominent and dose limiting being diarrhoea and neutropenia. With irinotecan monotherapy, diarrhoea was seen in 80% of patients and severe grade 3 to 4 diarrhoea occurred in 30-40% of the patients. The severity of diarrhoea can be diminished by preventive actions. Less risk of diarrhoea is generally seen when irinotecan is combined with fluorouracil. Neutropenia is generally short-lived, but may be severe if diarrhoea is also present. This has been noticed particularly when irinotecan has been given in combination with a bolus fluorouracil/folinic acid regimen. Other toxicities include acute cholinergic-like symptoms, nausea and vomiting, and alopecia. In spite of these adverse effects, irinotecan has been accepted as an important first-line treatment for patients with advanced CRC, in combination with, preferably, an infused fluorouracil-based regimen, and has been approved for use as monotherapy in the second-line indication.     

Benefit-risk assessment of antileukotrienes in the management of asthma.

Antileukotrienes are a relatively new class of anti-asthma drugs that either block leukotriene synthesis (5-lipoxygenase inhibitors) like zileuton, or antagonise the most relevant of their receptors (the cysteinyl leukotriene 1 receptor [CysLT1]) like montelukast, zafirlukast or pranlukast. Hence, their major effect is an anti-inflammatory one. With the exception of pranlukast, the other antileukotrienes have been studied and marketed in the US and Europe for long enough to establish that they are useful drugs in the management of asthma. Their effects, significantly better than placebo, seem more pronounced in subjective measurements (i.e. symptoms scores or quality-of-life tests) than in objective parameters (i.e. forced expiratory volume in 1 second or peak expiratory flow rate). Also, there is some evidence that these drugs work better in some subsets of patients with certain genetic polymorphisms - probably related to their leukotriene metabolism - or patients with certain asthma characteristics. There are a small number of comparative studies only, and with regard to long-term asthma control differences between the agents have not been evaluated. Nevertheless, their overall effect appears comparable with sodium cromoglycate (cromolyn sodium) or theophylline, but significantly less than low-dose inhaled corticosteroids. Antileukotrienes have been shown to have a degree of corticosteroid-sparing effect, but salmeterol appears to perform better as an add-on drug. Montelukast is probably the most useful antileukotriene for continuous treatment of exercise-induced asthma, performing as well as salmeterol without inducing any tolerance. All antileukotrienes are taken orally; their frequency of administration is quite different ranging from four times daily (zileuton) to once daily (montelukast). Antileukotrienes are well tolerated drugs, even though zileuton intake has been related to transitional liver enzyme elevations in some cases. Also Churg-Strauss syndrome (a systemic vasculitis), has been described in small numbers of patients taking CysLT1 antagonists. It is quite probable that this disease appears as a consequence of an 'unmasking' effect when corticosteroid dosages are reduced in patients with severe asthma once CysLT1 antagonists are introduced, but more data are needed to definitely establish the mechanism behind this effect. Overall, however, the benefits of antileukotrienes in the treatment of asthma greatly outweigh their risks.     

Benefit-risk assessment of rofecoxib in the treatment of osteoarthritis.

NSAIDs are widely used to treat pain and inflammation in osteoarthritis. Their use in this indication is generally intermittent and fluctuates with the intensity of the disease. Nonetheless, success of the therapy is frequently limited by injury to the gastrointestinal mucosa and complications such as bleeding, ulceration and perforation. A careful and detailed evaluation of these aspects in regard to the newly introduced NSAIDs is of considerable clinical importance. This review focuses on the NSAID rofecoxib, one of the selective cyclo-oxygenase (COX)-2 inhibitors, which are claimed to be as effective as nonselective NSAIDs with better gastrointestinal tolerability. Indeed, phase II, phase III and epidemiological studies have revealed that the efficacy of rofecoxib is comparable to that of conventional NSAIDs but with lower gastrointestinal toxicity, although this advantage may not be demonstrable in every patient. In patients treated with low-dose aspirin (acetylsalicylic acid) for cardiovascular prophylaxis, celecoxib (another selective COX-2 inhibitor) seems to have no obvious advantages over conventional NSAIDs, and similar conclusions may be applied to rofecoxib. A comparison of NSAID therapy +/- concomitant low-dose aspirin was not a primary outcome in this trial with celecoxib and there is thus a need for further studies which compare the gastrointestinal risk of a selective COX-2 inhibitor plus aspirin versus a conventional NSAID. Recent debate has emerged regarding the cardiovascular safety of rofecoxib. Although there is evidence both for and against higher cardiovascular risk with rofecoxib, a retrospective cohort study recently published suggested that there is no increased risk of acute myocardial infarction in the short-term when compared with non-selective NSAIDs. The renal toxicity of rofecoxib has been thoroughly investigated. Clinical studies revealed renal effects of rofecoxib similar to those of conventional NSAIDs. Since adverse effects increase with the degree of renal impairment, monitoring of renal function should be carried out in patients at risk. Although there are still insufficient data concerning certain important adverse effects of rofecoxib, this drug is becoming an important alternative in the therapy of osteoarthritis, especially in high-risk patients. Clinicians need to weigh up the benefits and risks of rofecoxib on a case-by-base basis.     

Benefit-risk assessment of zaleplon in the treatment of insomnia.

Insomnia is a heterogeneous, highly prevalent condition that is associated with a high level of psychiatric, physical, social and economic morbidity. The treatment of insomnia involves pharmacological and non-pharmacological interventions. The mainstay of pharmacological treatment of insomnia has been the benzodiazepines, the introduction of which represented a significant improvement over the barbiturates and chloral hydrate. Although benzodiazepines have been shown to be efficacious in treating insomnia, they have also been associated with a number of adverse effects including tolerance, dependence, withdrawal and abuse potential, impairment in daytime cognitive and psychomotor performance (including an increased risk of accidents and falls), adverse effects on respiration and the disruption of normal sleep architecture with reduction in both slow wave sleep and rapid eye movement. In the last decade, the treatment of insomnia has been supplemented by the introduction of a number of non-benzodiazepine hypnotics including zolpidem, zopiclone and, most recently, zaleplon. Zaleplon possesses a unique pharmacological profile, with an ultra-short half-life of about 1 hour, and selective binding to the BZ1(omega1) receptor subtypes of the GABA(A) receptor. This unique pharmacological profile predicts a number of pharmacodynamic properties that account for a unique benefit-risk profile. Consistent with these predictions, zaleplon has been shown in a number of studies to be efficacious in promoting sleep initiation, but less so in promoting sleep maintenance. The adverse effects associated with zaleplon have been shown to be more rapidly resolved and/or lesser in magnitude than those associated with benzodiazepines (including triazolam) and the longer acting non-benzodiazepine hypnotics (zolpidem and zopiclone). This improved risk profile includes: the effects of zaleplon on psychomotor and cognitive performance; tolerance, withdrawal and rebound; respiratory depression; sleep architecture; and other treatment-emergent adverse effects. The unique benefit-risk profile of this agent may be particularly suitable for certain patients with insomnia and provides yet another option in the management of this impairing condition.     

Benefit-risk assessment of long-acting beta2-agonists in asthma.

The use of a regular long-acting beta2-adrenoceptor agonists (beta2-agonists; LABA) is now established in asthma guidelines as the preferred option for second-line controller therapy in addition to inhaled corticosteroids. This has been driven by data showing beneficial effects of LABAs on exacerbation rates, in turn suggesting a putative corticosteroid-sparing effect. As LABAs are devoid of any clinically meaningful anti-inflammatory activity in vivo, their effects on exacerbations are presumably due to a diurnal stabilising effect on airway smooth muscle. LABAs have marked effects on symptoms and lung function, and this may make it difficult to assess anti-inflammatory control with inhaled corticosteroids when used in a combination inhaler such as fluticasone propionate/salmeterol or budesonide/formoterol. The use of fixed-dose combination inhalers is in many respects counter-intuitive to conventional teaching regarding flexible dosage titration with inhaled corticosteroids. It would therefore seem prudent first to gain optimal control of inflammation with inhaled corticosteroids before considering adding a LABA. Increasing the dosage of inhaled corticosteroids will have a relatively greater effect on exacerbations than on symptoms and lung function, whereas the converse applies when adding a LABA. Another option is to add a leukotriene receptor antagonist, which confers additional anti-inflammatory activity and is as effective on exacerbations as adding a LABA. Despite in vitro and ex vivo data showing a ligand-independent effect of LABAs on glucocorticoid receptor activation, clinical data do not indicate any relevant synergy between LABAs and inhaled corticosteroids when used together in the same inhaler. In particular, there is no evidence of potentiation by LABAs of the in vivo anti-inflammatory activity of inhaled corticosteroids that would suggest any genuine corticosteroid-sparing activity. Nonetheless, the data support the additive effects of inhaled corticosteroids and LABAs when used together due to their separate effects on inflammation and smooth muscle, respectively.Tolerance with LABAs is a predictable pharmacological phenomenon that occurs despite concomitant therapy with inhaled corticosteroids. Moreover, cross-tolerance also develops to short-acting beta2-agonists used for protection against bronchoconstrictor stimuli as a result of LABA-induced down-regulation, desensitisation and prolonged occupancy of beta2-adrenoceptors. The exact role of beta2-adrenoceptor polymorphism in determining tolerance with LABAs requires further prospective clinical studies evaluating long-term effects on outcomes such as exacerbations in patients with relevant genotypes and haplotypes. The next decade will provide challenging issues for clinicians with respect to defining further the role of LABAs as add-on controller therapy, particularly in evaluating the long-term effects of combination inhalers on inflammatory outcomes and airway remodelling.     

Benefit-risk assessment of the levonorgestrel intrauterine system in contraception.

The levonorgestrel-releasing intrauterine system (IUS) is a long-acting, fully reversible method of contraception. It is one of the most effective forms of contraception available, and combines the advantages of both hormonal and intrauterine contraception. The levonorgestrel-releasing IUS also gives the users many non-contraceptive benefits: the amount of menstrual bleeding and the number of days of menstrual bleeding are reduced, which makes it suitable for the treatment of menorrhagia (heavy menstrual blood loss). Dysmenorrhoea (painful menstruation) and premenstrual symptoms are also relieved. In addition, the levonorgestrel-releasing IUS provides protection for the endometrium during hormone replacement therapy. The local release of levonorgestrel into the uterine cavity results in a strong uniform suppression of the endometrial epithelium as the epithelium becomes insensitive to estradiol released from the ovaries. This accounts for the reduction in menstrual blood loss. All possible patterns of bleeding are seen among users of the levonorgestrel-releasing IUS; however, most of the women who experience total amenorrhoea continue to ovulate. The first months of use are often characterised by irregular, scanty bleeding, which in most cases resolves spontaneously. The menstrual pattern and fertility return to normal soon after the levonorgestrel-releasing IUS is removed. The contraceptive efficacy is high with 5-year failure rates of 0.5-1.1 per 100 users. The absolute number of ectopic pregnancies is low, as is the rate per 1000 users. The levonorgestrel-releasing IUS is equally effective in all age groups and the bodyweight of the user is not associated with failure of the method. In Western cultures continuance rates among users of the levonorgestrel-releasing IUS are comparable with those of other long-term methods of contraception. Premature removal of the device is most often associated with heavy menstrual bleeding and pain, as with other long-term methods of contraception, and is most common in the youngest age group. When adequately counselled about the benign nature of oligo- or amenorrhoea, most women are very willing to accept life without menstruation. The risk of premature removal can be markedly diminished with good pre-insertion counselling, which also markedly increases user satisfaction. User satisfaction is strongly associated with the information given at the time of the levonorgestrel-releasing IUS insertion. Thus, the benefits of the levonorgestrel-releasing IUS make it a very suitable method of contraception for most women.     

A benefit-risk assessment of basiliximab in renal transplantation.

Interleukin-2 (IL-2) and its receptor (IL-2R) play a central role in T lymphocyte activation and immune response after transplantation. Research on the biology of IL-2R allowed the identification of key signal transduction pathways involved in the generation of proliferative and antiapoptotic signals in T cells. The alpha-chain of the IL-2R is a specific peptide against which monoclonal antibodies have been raised, with the aim of blunting the immune response by means of inhibiting proliferation and inducing apoptosis in primed lymphocytes. Indeed, basiliximab, one of such antibodies, has proved to be effective in reducing the episodes of acute rejection after kidney and pancreas transplantation. The use of basiliximab was associated with a significant reduction in the incidence of any treated rejection episodes after kidney transplantation in the two major randomised studies (placebo 52.2% vs basiliximab 34.2% at 6 months, European study; placebo 54.9% vs basiliximab 37.6% at 1 year, US trial). Basiliximab and equine antithymocyte globulin (ATG) administration resulted in a similar rate of biopsy-proven acute rejection at 6 months (19% for both) and at 12 months (19% and 20%, respectively). The use of basiliximab appears not to be associated with an increased incidence of adverse events as compared with placebo in immunosuppressive regimens, including calcineurin inhibitors, mycophenolate mofetil or azathioprine and corticosteroids, and its safety profile is superior to ATG. Moreover, a similar occurrence of infections is noted in selected studies (65.5% after basiliximab vs 65.7% of controls), including cytomegalovirus infection (17.3% vs 14.5%), and cytokine-release syndrome is not observed. Finally, economic analysis demonstrated lower costs of overall treatment in patients treated with basiliximab. Therefore, the use of basiliximab entails a very low risk, allows safe reduction of corticosteroid dosage and reduces the short- and mid-term rejection rates. However, the improvement in the long-term survival of kidney grafts in patients treated according to modern immunosuppressive protocols is still to be demonstrated. These conclusions are based on a systematic review of the scientific literature, indexed on Medline database, concerning the mechanism of action, therapeutic activity, safety and pharmacoeconomic evaluation of basiliximab in renal transplantation.     

Benefit-risk assessment of telithromycin in the treatment of community-acquired pneumonia.

The purpose of this review is to assess the benefits and risks associated with the use of the ketolide antibacterial telithromycin, currently licensed for the treatment of adults with mild to moderate community-acquired pneumonia (CAP). Telithromycin is active against both the major (Streptococcus pneumoniae, Haemophilus influenzae and Moraxella catarrhalis) and atypical/intracellular (Chlamydophila pneumoniae, Legionella pneumophila and Mycoplasma pneumoniae) CAP pathogens. It is associated with a low potential to select for resistance and has maintained its in vitro activity against isolates of respiratory pathogens in countries where it has been in clinical use for several years. In randomized clinical trials, telithromycin has demonstrated efficacy comparable to the established antibacterial classes (macrolides, fluoroquinolones and beta-lactams) in the treatment of CAP.The safety profile of telithromycin is broadly similar to that of other antibacterials used to treat CAP. The most common adverse events are gastrointestinal adverse effects and headache; these are generally mild to moderate in severity and reversible. Telithromycin appears to be well tolerated by adult patients in all age groups, including those with co-morbid conditions. In common with other antibacterials, telithromycin has the potential to affect the corrected QT interval; the concomitant use of cisapride or pimozide with telithromycin is contraindicated, while telithromycin should be avoided in patients receiving Class IA or Class III antiarrhythmic drugs. Visual disturbances (usually transient) have occurred in a small proportion of patients treated with telithromycin; it is recommended that activities such as driving are minimized during treatment. Telithromycin is contraindicated in patients with myasthenia gravis. Hepatic dysfunction may occur in some patients taking telithromycin; rare cases of acute hepatic failure and severe liver injury, including deaths, have been reported. As telithromycin is an inhibitor of the cytochrome P450 (CYP) 3A4 system, coadministration of telithromycin with drugs metabolized by this pathway may require dose adjustments (e.g. with benzodiazepines) or a temporary hiatus in the use of the coadministered drug (e.g. HMG-CoA reductase inhibitors) metabolized by CYP3A4. Telithromycin may potentiate the effects of oral anticoagulants; careful monitoring is recommended in patients receiving telithromycin and oral anticoagulants simultaneously.Although serious and sometimes fatal events have occurred in patients receiving telithromycin therapy, current data indicate that telithromycin offers an acceptable benefit risk ratio in the treatment of mild to moderate CAP.     

Benefit-risk assessment of infliximab in the treatment of rheumatoid arthritis.

In the last decade, there have been substantial advances in the treatment of rheumatoid arthritis with the addition of several new disease-modifying agents to the therapeutic armamentarium. Biological agents targeting tumour necrosis factor (TNF) represent one such important addition. Infliximab, a chimeric anti-TNF monoclonal antibody, has shown remarkable promise in alleviating the signs and symptoms of rheumatoid arthritis in addition to retarding radiographic disease progression when used in combination with methotrexate. In its pivotal phase III trial, the addition of infliximab to patients with methotrexate-refractory disease was associated with substantial clinical benefit. Using American College of Rheumatology criteria for improvement, one-half of patients receiving infliximab (3 mg/kg every 8 weeks) plus methotrexate showed at least 20% improvement compared with only 20% of those receiving placebo plus methotrexate (p < 0.001) with over one-half of eventual responders obtaining criteria for improvement by the second week of observation. Although its use has been met with much deserved enthusiasm, recent reports have highlighted several potential serious adverse effects associated with infliximab (and other TNF antagonists), including infusion reactions, congestive heart failure, drug-induced lupus, and CNS demyelination. In addition, recent reports have cited the potential for reactivation of mycobacterial and fungal infection in patients receiving infliximab, mandating appropriate tuberculosis screening prior to drug initiation. Although the frequency of serious drug-related toxicity (requiring discontinuation of the agent) appears to be quite low, these reports underscore the need for caution and close surveillance with the administration of TNF inhibitors, particularly given that strategies aimed at preventing toxicity remain unproven. Despite its potential for toxicity, infliximab remains a valuable alternative for patients with rheumatoid arthritis.     

Benefit-risk assessment of levetiracetam in the treatment of partial seizures.

Levetiracetam is a novel antiepileptic drug that has been demonstrated as being effective in the management of partial seizures. It is rapidly and completely absorbed after oral administration and it is predominantly eliminated as unchanged drug in the urine. Its metabolism is independent of the cytochrome P450 enzyme system, nor does it induce cytochrome P450 enzymes. As a result of its pharmacokinetic features, levetiracetam has not been demonstrated to interact with other drugs in either direction. In double-blind, placebo-controlled trials, all the levetiracetam dosages tested were effective, including 1000 mg/day, 2000 mg/day and 3000 mg/day. The ineffective dose is not known. Efficacy seemed to be maintained in long-term studies, with no evidence of tolerance. In major double-blind, placebo-controlled trials discontinuation rates because of adverse events were 6.9-10.9% for levetiracetam-treated patients (all doses) compared with 5.3-8.6% for placebo-treated patients. The most common adverse events that differed between treatment groups and placebo control groups were somnolence, asthenia, dizziness and, in the US study, infection. Since levetiracetam was marketed, behavioural effects have been reported, namely irritability, agitation, anger and aggressive behaviour. These adverse effects are more likely in learning disabled individuals, those with prior psychiatric history and those with symptomatic generalised epilepsy. Overall, the risk has been estimated at 12-15%. Laboratory parameters overall seem to be not significantly affected by levetiracetam, although slight trends to lower white and red blood cell counts were detected in the studies. No organ toxicity has been described so far, with patient exposures exceeding 500,000. In summary, levetiracetam exhibits a very favourable safety profile in patients with partial onset seizures. Whereas somnolence, asthenia and dizziness were the most prominent adverse effects in clinical trials, behavioural adverse effects have generally been the most common reason for drug discontinuation in clinical practice.     

Benefit-risk assessment of ropivacaine in the management of postoperative pain.

Ropivacaine is a long-acting amide-type local anaesthetic, released for clinical use in 1996. In comparison with bupivacaine, ropivacaine is equally effective for subcutaneous infiltration, epidural and peripheral nerve block for surgery, obstetric procedures and postoperative analgesia. Nevertheless, ropivacaine differs from bupivacaine in several aspects: firstly, it is marketed as a pure S(-)-enantiomer and not as a racemate, and secondly, its lipid solubility is markedly lower. These features have been suggested to significantly improve the safety profile of ropivacaine, and indeed, numerous studies have shown that ropivacaine has less cardiovascular and CNS toxicity than racemic bupivacaine in healthy volunteers.Extensive clinical data have demonstrated that epidural 0.2% ropivacaine is nearly identical to 0.2% bupivacaine with regard to onset, quality and duration of sensory blockade for initiation and maintenance of labour analgesia. Ropivacaine also provides effective pain relief after abdominal or orthopaedic surgery, especially when given in conjunction with opioids or other adjuvants. Nevertheless, epidurally administered ropivacaine causes significantly less motor blockade at low concentrations. Whether the greater degree of blockade of nerve fibres involved in pain transmission (Adelta- and C-fibres) than of those controlling motor function (Aalpha- and Abeta-fibres) is due to a lower relative potency compared with bupivacaine or whether other physicochemical properties or stereoselectivity are involved, is still a matter of intense debate.Recommended epidural doses for postoperative or labour pain are 20-40 mg as bolus with 20-30 mg as top-up dose, with an interval of >or=30 minutes. Alternatively, 0.2% ropivacaine can be given as continuous epidural infusion at a rate of 6-14 mL/h (lumbar route) or 4-10 mL/h (thoracic route).Preoperative or postoperative subcutaneous wound infiltration, during cholecystectomy or inguinal hernia repair, with ropivacaine 100-175 mg has been shown to be more effective than placebo and as effective as bupivacaine in reducing wound pain, whereby the vasoconstrictive potency of ropivacaine may be involved. Similar results were found in peripheral blockades on upper and lower limbs. Ropivacaine shows an identical efficacy and potency to that of bupivacaine, with similar analgesic duration over hours using single shot or continuous catheter techniques.In summary, ropivacaine, a newer long-acting local anaesthetic, has an efficacy generally similar to that of the same dose of bupivacaine with regard to postoperative pain relief, but causes less motor blockade and stronger vasoconstriction at low concentrations. Despite a significantly better safety profile of the pure S(-)-isomer of ropivacaine, the increased cost of ropivacaine may presently limit its clinical utility in postoperative pain therapy.     

Benefit-risk assessment for binary diagnostic tests

ABSTRACT

In diagnostic device evaluation, it is important to have an integrated benefit-risk (BR) assessment for safety and effectiveness, which is not same as the assessment for drugs and therapeutic devices. Correct diagnosis does not lead to direct clinical outcome such as longer survival, release of symptoms, tumor shrinkage, etc.; but leads to the proper treatment in time while incorrect diagnosis may result in serious consequences of unnecessary tests and wrong treatments. Some common measures used in evaluating the accuracy of a diagnostic device include sensitivity, specificity, positive predictive value and negative predictive value. Here, we propose a BR measure by incorporating information about true-positive and true-negative cases (correct diagnosis) and false-positive and false-negative cases (incorrect diagnosis) for facilitating the necessary decision-making. Three decision rules are discussed depending on the purpose of the clinical study. Different statistical models are developed for estimating the BR measure for data obtained from different sampling schemes (cross-sectional and case–control sampling). The construction of confidence intervals (CIs) for the proposed BR measure is based on (i) the asymptotic normality of the maximum likelihood estimators (MLEs), and (ii) parametric bootstrap re-sampling technique. The performance of these CIs is evaluated by intensive Monte-Carlo simulations which reveal that both CIs perform reasonably well. Finally, the proposed methodology is applied to two clinical trial datasets.     

Benefit-risk assessment of tolterodine in the treatment of overactive bladder in adults.

Overactive bladder is associated with symptoms of urgency, with or without urge incontinence, usually with daytime frequency and nocturia in the absence of local pathological factors. Muscarinic receptor antagonists (antimuscarinics) are the first-line pharmacotherapy. Tolterodine, a competitive, nonselective antimuscarinic specifically developed for the treatment of overactive bladder, demonstrated tissue selectivity for the bladder over the parotid gland in an animal model. As of March 5, 2003, the immediate-release (IR) formulation had been approved in 72 countries and the extended-release (ER) formulation had been approved in 28 countries, and tolterodine had been administered to 5 million patients. This review evaluates the benefit-risk profile of tolterodine in the treatment of adults with overactive bladder, summarising clinical trial and postmarketing surveillance data.Tolterodine has been found to significantly reduce micturition frequency, urgency perception and the number of episodes of urge incontinence and increase the volume voided per micturition. Dry mouth, an antimuscarinic class effect, is the most commonly reported adverse effect but is mostly mild to moderate in severity. Serious adverse effects are reported infrequently. Based on summary and review of postmarketing surveillance and clinical trial safety data received by the market authorization holder and contained in the Periodic Safety Update Reports for tolterodine, several monitored serious events of the gastrointestinal tract (e.g. ileus or haemorrhage), nervous system (e.g. syncope, convulsions and memory disorders) and cardiovascular system (e.g. ventricular arrhythmia, atrial fibrillation, palpitations, bradycardia, transient ischaemic attacks and hypertension) were not considered related to tolterodine. QT or corrected QT (QTc) prolongation was not observed in any of the five cases of verified ventricular arrhythmia in patients administered tolterodine; there is insufficient evidence to indicate that tolterodine causes ventricular arrhythmia or extrasystoles or any specific type of cardiac rhythm abnormality. The safety profile of tolterodine is similar in patients aged > or =65 years and in younger adults. Clinically relevant drug interactions are limited to cytochrome P450 3A4 inhibitors, such as ketoconazole, and co-administration with such agents warrants a tolterodine dosage decrease.In addition, tolterodine IR 2mg twice daily is similar in efficacy to oxybutynin IR 5mg three times daily, and tolterodine ER 4 mg once daily is similar in efficacy to oxybutynin ER 10mg once daily. Dry mouth occurred less frequently with tolterodine than oxybutynin, and moderate to severe dry mouth occurred more than three times less frequently. Based on the low frequency of adverse events, the absence of unexpected adverse events and the very low frequency of serious adverse events, we conclude that tolterodine is a well tolerated treatment for overactive bladder in adults, in whom it should be considered as first-line therapy.     

Benefit-risk assessment of transdermal fentanyl for the treatment of chronic pain.

Transdermal fentanyl is effective and well tolerated for the treatment of chronic pain caused by malignancy and non-malignant conditions when administered according to the manufacturer's recommendations. Compared with oral opioids, the advantages of transdermal fentanyl include a lower incidence and impact of adverse effects (constipation, nausea and vomiting, and daytime drowsiness), a higher degree of patient satisfaction, improved quality of life, improved convenience and compliance resulting from administration every 72 hours, and decreased use of rescue medication. Transdermal fentanyl is a useful analgesic for cancer patients who are unable to swallow or have gastrointestinal problems. Transdermal fentanyl forms a depot within the upper skin layers before entering the microcirculation. Therapeutic blood levels are attained 12-16 hours after patch application and decrease slowly with a half-life of 16-22 hours following removal. Patients with chronic pain should be titrated to adequate relief with short-acting oral or parenteral opioids prior to the initiation of transdermal fentanyl in order to prevent exacerbations of pain or opioid-related adverse effects. Transdermal fentanyl can then be initiated based on the 24-hour opioid requirement once adequate analgesia has been achieved. The prolonged elimination of transdermal fentanyl can become problematic if patients develop opioid-related adverse effects, especially hypoventilation. Adverse effects do not improve immediately after patch removal and may take many hours to resolve. Patients who experience opioid-related toxicity associated with respiratory depression should be treated immediately with an opioid antagonist such as naloxone and closely monitored for at least 24 hours. Because of the short half-life of naloxone, sequential doses or a continuous infusion of the opioid antagonist may be necessary. Transdermal fentanyl should be administered cautiously to patients with pre-existing conditions such as emphysema that may predispose them to the development of hypoventilation. Transdermal fentanyl is indicated only for patients who require continuous opioid administration for the treatment of chronic pain that cannot be managed with other medications. It is contraindicated in the management of acute and postoperative pain, as pain may decrease more rapidly in these circumstances than fentanyl blood levels can be adjusted, leading to the development of life-threatening hypoventilation. Cognitive and physical impairments such as confusion and abnormal co-ordination can occur with transdermal fentanyl. Therefore, patients should be instructed to refrain from driving or operating machinery immediately following the initiation of transdermal fentanyl, or after any dosage increase. Patients may resume such activities once the absence of these potential adverse effects is documented.     

HPLC法检测肾移植病人全血中西罗莫司的药物浓度

目的 :建立测定全血中西罗莫司含量的方法。 方法 :采用HPLC法 ,色谱柱为 :YMC PackODS A(15 0mm× 4 .6mm ,5 μm) ,预柱为AlltimaC18(7.5mm× 4 .6mm ,5 μm)。流动相为乙腈∶四氢呋喃∶水 =5 5∶5∶4 0 ;检测波长为 2 78nm ,流速为 1.5ml/min ,柱温 :5 0℃。 32 去甲氧基西罗莫司为内标。 结果 :西罗莫司及内标 32 去甲氧基西罗莫司的保留时间分别为 10 .1、12 .1min ,全血定量线性范围 :2 .4 9～ 76 .36ng/ml,最低检测浓度为 1.98ng/ml,方法回收率为 99.93%～ 10 5 .90 % ,日内、日间RSD <7.4 0 %。 结论 :本方法准确、可靠 ,适用于临床对西罗莫司的血药浓度监测。