Topiramate. A review of its pharmacodynamic and pharmacokinetic properties and clinical efficacy in the management of epilepsy.

Topiramate is a sulphamate-substituted monosaccharide derived from D-fructose and is structurally unrelated to other antiepileptic drugs. It acts by multiple mechanisms that suggest it may be effective in several types of epilepsy. In double-blind placebo-controlled trials, add-on therapy with topiramate 400 to 1000 mg/day reduces the seizure rate by > or = 50% in 35 to 52% of adult patients with resistant partial epilepsy (with or without secondarily generalised seizures) compared with 0 to 19% of placebo recipients; a 200 mg/day dosage was less effective. Topiramate has also been shown to be superior in efficacy to placebo in well controlled trials in patients with generalised tonic-clonic seizures, Lennox-Gastaut syndrome and in paediatric patients with partial epilepsy. Efficacy has been maintained for 7 years and some patients may also be satisfactorily treated with topiramate monotherapy. Further study is needed to follow up on the promising results of topiramate use in other paediatric epilepsies. Adverse CNS events are the most common untoward effects during topiramate therapy and are most likely to lead to withdrawal of the drug. However, most adverse events are mild to moderate in severity and lessen with continued drug therapy. In clinical trials, most adverse events which were dose limiting or led to discontinuation of treatment occurred during the titration phase. The overall incidence of adverse events may be reduced by slower upward dosage titration. In summary, topiramate appears to be a suitable agent for add-on therapy in adult patients with partial epilepsy. Preliminary reports support the use of add-on topiramate in adults with generalised epilepsy, in childhood epilepsies and in patients with Lennox-Gastaut syndrome, as well as the use of topiramate monotherapy in patients with partial epilepsy. Thus, topiramate can be considered an important new drug for the management of patients with refractory epilepsy.

Octreotide long-acting release (LAR). A review of its pharmacological properties and therapeutic use in the management of acromegaly.

Octreotide is a somatostatin analogue: a long-acting release (LAR) formulation of octreotide is designed for once-monthly intramuscular administration. As with native somatostatin, octreotide LAR exerts potent inhibitory effects on the secretion of growth hormone and on various peptides of the gastroenteropancreatic endocrine system. When patients with acromegaly who show a positive response to treatment with subcutaneous octreotide 300 to 600 micrograms/day are switched to octreotide LAR 20 or 30 mg, the resulting decrease in growth hormone levels is stable and sustained. Reductions in growth hormone levels to < 5 micrograms/L for about 4 weeks are seen in 86 to 100% of patients, to < 2 to 2.5 micrograms/L in 39 to 75% and to < 1 microgram/L in 24 to 40%. Levels of insulin-like growth factor-1 (IGF-1) decrease in parallel and are often normalised with repeated drug treatment. There is no evidence of tachyphylaxis with long term therapy (up to 34 months). Treatment with octreotide LAR improves facial appearance and soft tissue thickening, and eliminates or reduces the incidence of symptoms such as headache, fatigue, arthralgia and excessive perspiration. Tumour shrinkage has been noted in some, but not all, patients receiving octreotide LAR, although this has not been widely evaluated in clinical studies. Overall, octreotide LAR is well tolerated, and the mild to moderate gastrointestinal events experienced by up to 50% of patients are of short duration and often subside with continued drug administration. The incidence of gallbladder abnormalities (sediment, sludge, microlithiasis and gallstones) increases in patients receiving long term therapy with subcutaneous octreotide, although most patients remain asymptomatic. The incidence of gallbladder abnormalities in patients receiving octreotide LAR compares favourably with that during subcutaneous administration. Glycaemic control is not usually altered during octreotide LAR treatment. In summary, octreotide continues to be the principal pharmacological option for most patients with acromegaly. Octreotide LAR offers the convenience of once-monthly administration compared with daily subcutaneous drug administration. In addition, the good efficacy and tolerability profile of octreotide LAR should enhance patient compliance and acceptability of octreotide therapy and contribute to an improvement in patient quality of life.

Ketorolac. A reappraisal of its pharmacodynamic and pharmacokinetic properties and therapeutic use in pain management.

Ketorolac is a nonsteroidal anti-inflammatory drug (NSAID) with strong analgesic activity. The analgesic efficacy of ketorolac has been extensively evaluated in the postoperative setting, in both hospital inpatients and outpatients, and in patients with various other acute pain states. After major abdominal, orthopaedic or gynaecological surgery or ambulatory laparoscopic or gynaecological procedures, ketorolac provides relief from mild to severe pain in the majority of patients and has similar analgesic efficacy to that of standard dosages of morphine and pethidine (meperidine) as well as less frequently used opioids and other NSAIDs. The analgesic effect of ketorolac may be slightly delayed but often persists for longer than that of opioids. Combined therapy with ketorolac and an opioid results in a 25 to 50% reduction in opioid requirements, and in some patients this is accompanied by a concomitant decrease in opioid-induced adverse events, more rapid return to normal gastrointestinal function and shorter stay in hospital. In children undergoing myringotomy, hernia repair, tonsillectomy, or other surgery associated with mild to moderate pain, ketorolac provides comparable analgesia to morphine, pethidine or paracetamol (acetaminophen). In the emergency department, ketorolac attenuates moderate to severe pain in patients with renal colic, migraine headache, musculoskeletal pain or sickle cell crisis and is usually as effective as frequently used opioids, such as morphine and pethidine, and other NSAIDs and analgesics. Subcutaneous administration of ketorolac reduces pain in patients with cancer and seems particularly beneficial in pain resulting from bone metastases. The acquisition cost of ketorolac is greater than that of morphine or pethidine; however, in a small number of studies, the higher cost of ketorolac was offset when treatment with ketorolac resulted in a reduced hospital stay compared with alternative opioid therapy. The tolerability profile of ketorolac parallels that of other NSAIDs; most clinically important adverse events affect the gastrointestinal tract and/or renal or haematological function. The incidence of serious or fatal adverse events reported with ketorolac has decreased since revision of dosage guidelines. Results from a large retrospective postmarketing surveillance study in more than 20,000 patients demonstrated that the overall risk of gastrointestinal or operative site bleeding related to parenteral ketorolac therapy was only slightly higher than with opioids. However, the risk increased markedly when high dosages were used for more than 5 days, especially in the elderly. Acute renal failure may occur after treatment with ketorolac but is usually reversible on drug discontinuation. In common with other NSAIDs, ketorolac has also been implicated in allergic or hypersensitivity reactions. In summary, ketorolac is a strong analgesic with a tolerability profile which resembles that of other NSAIDs. When used in accordance with current dosage guidelines, this drug provides a useful alternative, or adjuvant, to opioids in patients with moderate to severe pain.

Irbesartan. A review of its pharmacodynamic and pharmacokinetic properties and therapeutic use in the management of hypertension.

Irbesartan inhibits the activity of angiotensin II (AII) via specific, selective noncompetitive antagonism of the AII receptor subtype 1 (AT1) which mediates most of the known physiological activities of AII. In patients with mild to moderate hypertension, once daily administration of irbesartan 150 or 300 mg, with or without adjunctive antihypertensive agents, provides effective 24-hour BP control. Irbesartan reduced BP to a similar extent to enalapril and atenolol and to a significantly greater extent than losartan. The combination of irbesartan and hydrochlorothiazide resulted in additive antihypertensive effects. The drug is effective in the elderly and dosage adjustment is not required in these patients or in those with renal or hepatic failure. Preliminary studies evaluating the efficacy of irbesartan in patients with heart failure have produced encouraging results. Irbesartan is very well tolerated and neither the frequency nor the pattern of adverse events differed from those seen in placebo recipients, although headache was significantly more frequent with the latter. Similarly, the incidence of adverse events did not differ significantly between irbesartan and enalapril in patients who received either drug as monotherapy. Headache, upper-respiratory tract infection and musculoskeletal pain were the most common complaints. Thus, irbesartan is an effective therapy for patients with mild to moderate hypertension and had an adverse event profile similar to that of placebo in clinical trials. On this basis it would appear to be an effective therapeutic option in this indication.

Tacrolimus. An update of its pharmacology and clinical efficacy in the management of organ transplantation.

Tacrolimus (FK 506) has been evaluated as immunosuppressive therapy in patients with a variety of solid organ and other transplants. Extensive data have now confirmed its efficacy as primary or rescue therapy in renal and hepatic transplantation. In prospective and historically controlled studies of primary therapy, tacrolimus generally demonstrated greater efficacy than the conventional formulation of cyclosporin for preventing episodes of acute rejection and allowed reduction of corticosteroid use. Chronic rejection rates were also significantly lower with tacrolimus in a large randomised liver transplantation trial. However, patient and graft survival rates were similar in both treatment groups (although numerically larger in adults with liver transplants). In children, rejection rates and corticosteroid requirements were usually lower with tacrolimus and patient and graft survival were generally similar with the 2 immunosuppressants. The finding of reduced corticosteroid requirements with tacrolimus may be of particular benefit in prepubertal children, who are still growing. A small amount of evidence has also accumulated regarding the use of tacrolimus as primary therapy in patients who have undergone bone marrow or heart and/or lung transplantation. Data are not conclusive, particularly in children, but tacrolimus appears to be useful for treating patients who have undergone these organ transplantations and may be associated with a lower incidence of obliterative bronchiolitis than cyclosporin in the latter group. Potential efficacy has also been shown in a limited number of patients with pancreas or pancreas-kidney, pancreatic islet and intestinal or multivisceral transplants, and in children who have undergone heart or heart-lung transplantation. Tacrolimus also has a use as rescue therapy in bone marrow, heart, lung and pancreatic transplantation, but data are currently insufficient for conclusions to be made. However, these results support the need for further study in these populations. Adverse effects occurring during tacrolimus therapy are generally of the type common to all immunosuppressive regimens. However, diabetes mellitus, neurotoxicity and nephrotoxicity are more common in tacrolimus than cyclosporin recipients. Hyperlipidaemia, hypertension, hirsutism and gingival hyperplasia are more common with cyclosporin. In 2 large multicentre clinical trials (US liver and European renal), tacrolimus was discontinued more frequently during the first year because of adverse events. However, the tolerability of tacrolimus appears related to dosage, improving as the dose is reduced. Tacrolimus should be considered an effective primary immunosuppressant in renal and hepatic transplantation. The drug is also a useful agent for rescue therapy in patients experiencing rejection or poor tolerability to cyclosporin. Thus, tacrolimus provides the clinician with an effective option for patients requiring immunosuppression and, with a different tolerability and efficacy profile to cyclosporin, it will better allow the tailoring of therapy to meet the needs of individual patients.

Streptokinase. A pharmacoeconomic appraisal of its use in the management of acute myocardial infarction.

Thrombolytic therapy with streptokinase and other agents reduces mortality and is now well accepted as the mainstay of revascularisation options for most patients after an acute myocardial infarction. Streptokinase is as efficacious as alteplase (recombinant tissue plasminogen activator; rt-PA) when given as a 3-hour infusion, anistreplase, reteplase and saruplase in reducing mortality. However, in the Global Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded Coronary Arteries (GUSTO) trial, an accelerated alteplase regimen (1.5-hour infusion) plus intravenous heparin demonstrated a statistically significant 1% absolute mortality reduction compared with streptokinase plus heparin. Treatment with streptokinase is consistently clinically superior to conventional treatment and is cost effective: the marginal cost per year of life saved (cost/YLS) is less than $US/$Can20,000 (1990 or 1991 currency) assuming 5-year survival. In addition, streptokinase treatment is associated with fewer intensive care days and total days spent in hospital and a decrease in the use of intensive care services compared with conventional therapy. Importantly, the cost/YLS of treating older patients (70 to 80 years) with streptokinase is similar to that in younger patients (approximately $US22,000, 1990 currency). In 1 study, the cost of in-hospital treatment and associated 1-year follow-up costs did not differ significantly regardless of whether patients received streptokinase or anistreplase. In the most comprehensive cost-effectiveness analysis to date, GUSTO investigators determined that the incremental cost/YLS in patients who received the accelerated alteplase regimen instead of streptokinase was $US32,678 (1993 currency); the projected life expectancy was about 15 years. Thrombolytic therapy is generally more cost effective in patients at high risk than in those at low risk. The cost effectiveness of streptokinase is dependent on infarct location and time to treatment, but is more favorable in patients with anterior than inferior infarctions and those treated as soon as possible after symptom onset. There are as yet no comparative data to indicate a clinical benefit for one thrombolytic agent over another in patients treated more than 6 hours after symptom onset; therefore, in all likelihood, streptokinase will be preferred on the basis of cost minimisation. Streptokinase is associated with a slightly higher rate of severe bleeding than alteplase but a lower incidence of stroke. Although quality-of-life information comparing thrombolytics is unavailable, most patients who received streptokinase or alteplase rated their quality of life as high on the basis of results from time trade-off assessments and health surveys. In summary, streptokinase is undeniably cost effective compared with conventional treatment. It is up to individual healthcare systems to determine whether the mortality advantage and cost differential of the accelerated alteplase regimen over streptokinase, as seen in the GUSTO trial, are affordable and justifiable. However, it is important to realise that treatment options may be limited by healthcare resources; thus, streptokinase can be regarded as a cost-effective thrombolytic strategy which is both efficacious and affordable within the constraints of most healthcare budgets.

Secnidazole. A review of its antimicrobial activity, pharmacokinetic properties and therapeutic use in the management of protozoal infections and bacterial vaginosis.

Secnidazole is structurally related to the commonly used 5-nitroimidazoles metronidazole and tinidazole. These drugs share a common spectrum of activity against anaerobic micro-organisms and they appear particularly effective in the treatment of amoebiasis, giardiasis, trichomoniasis and bacterial vaginosis. Secnidazole is rapidly and completely absorbed after oral administration and has a longer terminal elimination half-life (approximately 17 to 29 hours) than commonly used drugs in this class. in patients with intestinal amoebiasis or giardiasis, clinical or parasistological cure rates of 80 to 100% are achieved after treatment with a single dose of secnidazole 2g (30 mg/kg in children), similar to the response rates achieved with multiple dosage regimens of metronidazole or tinidazole. Patients with hepatic amoebiasis appears to respond well to 5- to 7-day therapy with secnidazole, but the efficacy of this drug regimen requires further evaluation in larger numbers of patients. After administration of a single dose of secnidazole, parasitological eradication was achieved in approximately 92 to 100% of patients with urogenital trichomoniasis. Patients with bacteria vaginosis respond at least as well to a single dose of secnidazole as to single-dose tinidazole, or single- or 7-day treatment with metronidazole; clinical improvement and/or microbiological evidence of cure was attained in approximately 59 to 96% of patients. In the clinical trials reviewed, secnidazole was well tolerated; most adverse events were gastrointestinal in nature and did not require treatment intervention or withdrawal from therapy. In summary, available evidence suggests that secnidazole is as efficacious as other 5-nitroimidazole drugs in the treatment of protozoal infections and bacterial vaginosis. The convenience and ease of administration associated with single-dose therapy, combined with a good tolerability profile, make secnidazole a suitable option to other single-dose treatments and an attractive alternative to multiple dosage regimens with other drugs in this class.

Tretinoin. A review of its pharmacodynamic and pharmacokinetic properties and use in the management of acute promyelocytic leukaemia.

Tretinoin (all-trans retinoic acid), a vitamin A derivative, induces cellular differentiation in several haematological precursor cell lines and cells from patients with acute promyelocytic leukaemia. Drug treatment with tretinoin is associated with morphological and functional maturation of leukaemic promyelocytes and a progressive reduction in the occurrence of the characteristic t(15;17) chromosomal translocation. Recent therapeutic trials indicate that tretinoin induces remission in 64 to 100% of patients with acute promyelocytic leukaemia. In newly diagnosed patients, remission induction treatment with tretinoin followed by intensive chemotherapy resulted in a significant reduction in relapse rate and prolongation of event-free and overall survival compared with chemotherapy alone in 1 comparative trial. Tretinoin alone does not totally eradicate the leukaemic clone and consolidation chemotherapy is recommended as follow-up. The use of reverse transcription polymerase chain reaction (RT-PCR) provides a sensitive and specific technique to assist in prediction and monitoring of a patient's response to treatment and to help detect the presence of residual or recurrent disease. The use of tretinoin is potentially limited by the rapid and almost universal development of drug resistance and occurrence of the often severe retinoic acid syndrome. Useful strategies have been described to manage these effects but current and future efforts must be directed at elucidating the mechanisms involved and determining the optimum therapeutic management. In summary, results to date indicate that the combination of tretinoin and intensive chemotherapy is more effective than chemotherapy alone and appears to improve the prognosis of newly diagnosed patients with acute promyelocytic leukaemia. Further information on the relative efficacy of various induction and post-remission strategies in subsets of patients will help determine optimum use of this promising agent in the management of acute promyelocytic leukaemia.

Alteplase. A reappraisal of its pharmacology and therapeutic use in vascular disorders other than acute myocardial infarction.

Alteplase is the product of recombinant DNA technology and is chemically identical to endogenous tissue-type plasminogen activator: Plasminogen is converted to plasmin by alteplase, and fibrinolysis of blood thrombi is subsequently stimulated. Alteplase is now firmly established as a treatment of choice in the management of acute myocardial infarction. The efficacy of intravenous alteplase in the treatment of pulmonary thromboembolism has also been established and appears to be similar to that of streptokinase and urokinase in this indication and in arterial thrombotic occlusion. However, its use in this latter indication and in other vascular disorders has not been as extensively documented. Although trials demonstrating the efficacy of intravenous alteplase in patients with deep vein thrombosis and intra-arterial alteplase in patients with arterial thrombotic occlusion exist, reliable data on the efficacy of the fibrinolytic in ischaemic stroke and intracranial haemorrhage are scarce. Little clinical benefit is apparent in patients with unstable angina, although careful use may be warranted in those with definite pretreatment coronary thrombi. Of concern, there is a suggestion that general use of alteplase in patients with unstable angina may be associated with increased incidence of myocardial infarction. The incidence of major haemorrhage associated with alteplase therapy increases with increasing dose and appears to be similar to that seen with other fibrinolytic agents. Thus, further well-designed studies of the use of alteplase in ischaemic stroke and cerebral haemorrhage are required. However, a small subset of patients with unstable angina and definite pretreatment coronary thrombi may benefit from alteplase therapy. Further, preliminary data suggest efficacy in the therapy of deep vein thrombosis and arterial thrombotic occlusion, and alteplase has a proven place in the fibrinolytic treatment of pulmonary thromboembolism.

Alteplase. A reappraisal of its pharmacological properties and therapeutic use in acute myocardial infarction.

Alteplase (recombinant tissue-type plasminogen activator) stimulates the fibrinolysis of blood clots by converting plasminogen to plasmin. The efficacy of intravenous alteplase in the early treatment of patients with acute myocardial infarction has been unequivocally proven, and recent results from the GUSTO trial indicate a significant advantage in 30-day survival for alteplase in an accelerated dosage regimen (< or = 100mg infused over 90 minutes rather than 3 hours) over streptokinase. The advantage of the accelerated alteplase dosage regimen seems to be maintained for at least 1 year. The role of heparin as adjunctive therapy to thrombolysis remains to be fully defined but heparin administration appears to be more important in conjunction with alteplase than with streptokinase. Ideally, patients should receive alteplase as soon as possible after the onset of symptoms of acute myocardial infarction and, while therapy is most beneficial when administered early, survival is improved when the drug is administered up to 12 hours after symptom onset. The accelerated regimen of alteplase used in the GUSTO trial demonstrated a survival advantage in patients < or = 75 as well as those > 75 years of age which was at least as great as that seen with streptokinase. Similarly, alteplase reduces mortality in patients with both anterior and inferior infarctions; however, those with anterior wall infarctions show an improved outcome over those with inferior infarcts. On the basis of pharmacoeconomic analysis of GUSTO data, the accelerated alteplase regimen cost an estimated additional $US32,678 per year of life saved compared with a conventional streptokinase regimen. Cumulative 1-year costs were greater in patients who received the accelerated alteplase regimen but survival was significantly greater than in patients who received streptokinase. No difference in quality of life was evident in patients who received either treatment. The incidence of major haemorrhage associated with alteplase therapy appears to be similar to that seen with other fibrinolytic agents, increasing with increasing dose; however, the risk of stroke, particularly haemorrhagic stroke, is higher with alteplase than with streptokinase. Thus, alteplase has become firmly established as a first-line option in the management of acute myocardial infarction. On the basis of accumulated evidence, the greatest risk reduction with alteplase therapy may be in certain high risk groups, such as those with anterior infarcts, selected elderly patients and those who present late after symptom onset.

Transnasal butorphanol. A review of its pharmacodynamic and pharmacokinetic properties, and therapeutic potential in acute pain management.

Butorphanol is a synthetic opioid agonist-antagonist analgesic with a pharmacological and therapeutic profile that has been well established since its launch as a parenteral formulation in 1978. The introduction of a transnasal formulation of butorphanol represents a new and noninvasive presentation of an analgesic for moderate to severe pain. This route of administration bypasses the gastrointestinal tract, and this is an advantage for a drug such as butorphanol that undergoes significant first-pass metabolism after oral administration. The onset of action and systemic bioavailability of butorphanol following transnasal delivery are similar to those after parenteral administration. The analgesic efficacy of transnasal butorphanol was generally superior to that of placebo in clinical trials in patients with moderate to severe postoperative pain or migraine headache. Results from single trials indicate that transnasal butorphanol provides pain relief comparable to that of intramuscular pethidine (meperidine) in postsurgical pain and comparable to or greater than intramuscular methadone in migraine headache. Moderate to severe musculoskeletal pain also appears to be responsive to transnasal butorphanol on the basis of results from 1 small noncomparative study. Tolerability of transnasal butorphanol parallels that of the injectable form, with somnolence, dizziness, nausea and/or vomiting reported most frequently. Thus, transnasal butorphanol is a novel formulation of an established analgesic which appears suitable for the short term treatment of moderate to severe pain, especially in an ambulatory setting. Transnasal butorphanol is likely to provide an alternative to oral opioid analgesics, particularly in the presence of nausea or vomiting, or to parenteral opioids when the oral route of administration is not appropriate.

Rifaximin. A review of its antibacterial activity, pharmacokinetic properties and therapeutic potential in conditions mediated by gastrointestinal bacteria.

Rifaximin is a derivative of rifamycin which acts by inhibiting bacterial ribonucleic acid (RNA) synthesis. It is virtually unabsorbed after oral administration; thus it is used primarily to treat local conditions within the gastrointestinal tract. In vitro data indicate rifaximin possesses good activity against species of Staphylococcus, Streptococcus and Enterococcus but lesser activity against species of Enterobacteriaceae. Bacterial resistance during exposure to rifaximin has been reported but its clinical importance remains to be fully defined. Results of comparative trials demonstrate that rifaximin is similar in efficacy to neomycin and lactulose in patients with hepatic encephalopathy and appears to be better tolerated. In 1 study, cyclical administration of rifaximin for 15 days per month was associated with progressive improvement over a 3-month period. In patients with infectious diarrhoea, rifaximin induces more rapid improvement in stool consistency and decreased frequency of faecal evacuations when compared with placebo, and is similar in efficacy to neomycin. Available data suggest rifaximin may be of some use in acute diverticulitis, but its use for the prevention of inflammatory complications or for control of common symptoms of diverticulosis requires further study. Preoperative treatment with rifaximin as antibacterial prophylaxis in colorectal surgery shows some potential but should be further investigated. Overall, rifaximin may be useful as an alternative therapy in hepatic encephalopathy but more data are needed to better define its clinical potential in infectious diarrhoea, diverticular disease and as antibacterial prophylaxis prior to colorectal surgery.

Idebenone. A review of its pharmacodynamic and pharmacokinetic properties, and therapeutic use in age-related cognitive disorders.

Idebenone is a benzoquinone compound which has been investigated in elderly patients with dementia. Its precise mechanism(s) of action remains unknown, but in vitro and in vivo studies suggest the drug may diminish nerve cell damage due to ischaemia, correct neurotransmitter defects and/or cerebral metabolism and facilitate memory and learning. In the small number of studies available for evaluation, idebenone was generally superior to placebo and comparable with bifemelane, oxiracetam and nebracetam on the basis of a number of objective and subjective tests and rating scales in patients with mild to moderate cognitive decline. Clinical trial results indicate that patients with mild dementia seem more likely to respond than those with greater functional decline. The degree of benefit conferred by idebenone is often difficult to determine, but in those who respond, improvement is generally mild to moderate. Therapy with idebenone appears well tolerated for up to 2 years, and no changes in vital signs or laboratory values have been seen in clinical trials. In view of the lack of a proven agent to limit or halt the progression of dementia in the elderly, idebenone may warrant consideration in patients with mild cognitive dysfunction on the basis of preliminary evidence of predominantly mild improvement of functional status in some patients and good tolerability. However, further well designed studies, including comparisons with newer and commonly used agents, such as tacrine, are required to better define the role of idebenone in this complex area of treatment.