Months Of Remission Research Articles

Bouncing back: is the bipolar rebound phenomenon peculiar to lithium? A retrospective naturalistic study

In bipolar disorder the discontinuation of lithium prophylaxis is associated with early episode precipitation. Is this ;rebound' phenomenon peculiar to lithium? This naturalistic retrospective case note review investigated the frequency of immediate recurrence after discontinuation of any prophylactic treatment. Bipolar patients who stopped at least one medication after at least 6 months of remission were studied. A total of 310 case notes were examined in a systematic search. A total of 53 cases of discontinuation in 48 subjects were found. Discontinued medications included lithium, valproate, carbamazepine, typical and atypical antipsychotics and antidepressants. Recurrence occurred within 3 months of medication withdrawal in 39 cases (74%). Over half of the discontinuation episodes involved lithium: recurrence occurred in 86% of these cases. In the groups stopping other prophylactic agents, a majority of subjects suffered recurrence: anticonvulsants (89%), antipsychotics (64%) and antidepressants (58%). However, these groups were small and the clarity of the data was undermined by the simultaneous withdrawal of other agents. Manic and hypomanic episodes were the most common form of recurrences. Depressive episodes occurred proportionately most frequently following antidepressant withdrawal. More than half of recurrences required hospital admission. This study provides preliminary naturalistic evidence that early episode recurrence in bipolar disorder is not peculiar to lithium withdrawal but may occur following withdrawal of medication from all classes recommended in prophylaxis. These findings, if replicated, have important implications for clinical practice and for research.

Acute renal failure, gastrointestinal bleeding, and cardiac arrhythmia after administration of arsenic trioxide for acute promyelocytic leukemia

The case of a patient who developed acute renal failure, gastrointestinal bleeding, and cardiac arrhythmia after receiving arsenic trioxide for the treatment of acute promyelocytic leukemia (APL) is described. An 84-year-old Caucasian woman with a history of osteoarthritis sought medical attention for relapse of her APL, which had initially been diagnosed approximately 30 months earlier. Complete remission was accomplished with three cycles of i.v. daunorubicin for 3 days and oral tretinoin for 28 days. After 19 months in remission, she was noted to have increased bruising and blood test values consistent with APL relapse. Two additional trials of oral tretinoin were unsuccessful, and arsenic trioxide was initiated at a daily dosage of 0.15 mg/kg of actual body weight. Less than 24 hours after receiving arsenic trioxide, the patient had "bile-like emesis" and her hemoglobin level decreased. Upper gastrointestinal bleeding was suspected and managed aggressively with transfusions of platelets and fresh frozen plasma and i.v. desmopressin. She became anuric, and her serum creatinine level more than doubled. Hemodialysis was started due to a sudden increase in potassium and fluid overload that did not respond to i.v. furosemide. One hour after hemodialysis, the patient was found pulseless and unresponsive by nursing staff. The cardiac arrest team rapidly responded and noted atrial fibrillation with a fast ventricular rate. Postresuscitation, the patient was transferred to the intensive care unit. Despite aggressive life-support therapy, the patient remained unresponsive. An 84-year-old woman developed acute renal failure, gastrointestinal bleeding, and cardiac arrhythmia after receiving arsenic trioxide for the treatment of APL.

Comparison of monotherapy effect of phenytoin, carbamazapine and valproic acid in pediatric general tonic clonic and partial epilepsy

Background Problems on epilepsy do not only depend on thedisease itself but also on management and drug regimens. Drugselection is very important to yield optimal treatment effect andto prevent side effects due to long-term therapy.Objective To determine whether there are any different effectsof monotherapy of phenytoin, carbamazapine, and valproic acidon pediatric general tonic clonic and partial epilepsy.Methods We conducted a historical cohort study on one monthuntil 18-years old children diagnosed as general tonic clonic orparsial epilepsy treated with phenytoin, carbamazapine, or valproicacid routinely for more than two years in Sardjito Hospital fromJanuary 2000 until May 2007. The sample size of each group was41. The main outcome was the time of 12-month remission,whereas the secondary outcomes were withdrawal from treatment,time to remission, side effects and cure rates.Results Valproic acid increased the possibility to achieve 12-monthremission (RR 2.66; 95%CI 1.06;6.65) compared to phenytoin,whereas carbamazapine did not (RR 1.47; 95%CI 0.66;3.28).Survival analysis showed that valproic acid was better thancarbamazapine (P=0.042) and phenytoin (P=0.007). There wereno significant differences among groups in the result of withdrawalfrom treatment, time to remission, and cure variables. The sideeffects of valproic acid seemed less than those of others.Conclusions Valproic acid increases the possibility of 12-monthremission compared to carbamazapine and phenytoin asmonotherapy in pediatric general tonic clonic and partial epilepsywithout increasing side effects. Carbamazapine has similar effectsof therapy to phenytoin.

Effects of levetiracetam on EEG abnormalities in juvenile myoclonic epilepsy

A multicenter, prospective, long-term, open-label study to evaluate the effects of levetiracetam on electroencephalogram (EEG) abnormalities and photoparoxysmal response (PPR) of patients affected by juvenile myoclonic epilepsy (JME). Forty-eight patients with newly diagnosed JME (10) or resistant/intolerant (38) to previous antiepileptic drugs (AEDs) were enrolled. After an 8-week baseline period, levetiracetam was titrated in 2 weeks to 500 mg b.i.d. and then increased to up to 3,000 mg/day. Efficacy parameters were based on the comparison and analysis of EEG interictal abnormalities classified as spikes-and-waves, polyspikes-and-waves, and presence of PPR. Secondary end point was evaluation of EEG and PPR changes as predictive factors of 12-month seizure freedom. Overall, mean dose of levetiracetam was 2,208 mg/day. Mean study period was 19.3 +/- 11.5 months (range 0.3-38). During the baseline period, interictal EEG abnormalities were detected in 44/48 patients (91.6%) and PPR was determined in 17/48 (35.4%) of patients. After levetiracetam treatment, 27/48 (56.2%) of patients compared to 4/48 (8.3%) in the baseline period (p < 0.0001) had a normal EEG. Thirteen of 17 (76.4%) (p < 0.0003) patients showed suppression of PPR. Cumulative probability of days with myoclonia (DWM) 12-month remission was significantly higher (p < 0.05) in patients with a normal (normalized) EEG after levetiracetam treatment compared to those with an unchanged EEG. Levetiracetam appeared to be effective in decreasing epileptiform EEG abnormalities, and suppressing the PPR in JME patients. This effect, along with a good efficacy and tolerability profile in this population further supports a first-line role for levetiracetam in the treatment of JME.

Deficit schizophrenia: Concept and validity

Byline: Sandeep. Grover, Parmanand. Kulhara First effort to distinguish and characterise psychotic illnesses was made by Emil Kraepelin,[sup] [1] who on the basis of observations of longitudinal course, categorised psychotic illnesses into 'dementia praecox' and 'manic-depressive psychosis'. Many attempts were subsequently made to further characterise schizophrenia (dementia praecox), which culminated in the realisation that it is a heterogeneous disorder that has significant variability in clinical profiles, course and outcome. By 1980, to reduce the heterogeneity of this complex disorder, researchers tried to identify homogeneous subtypes in the hope to facilitate the identification of links between symptoms and putative neurobiological basis of aetiology. The division of symptoms as positive or negative and categorisation of schizophrenia as positive and negative subtypes[sup] [2] and type I and type II[sup] [3] became popular. However, researchers noticed that negative symptoms as described by Crow were not inherent to the disorder alone, but may also be due to neuroleptic medications, depression and environmental factors. This ushered in the concept of primary and secondary negative symptoms. To better understand primary negative symptoms and in a quest to homogenise a separate subtype of schizophrenia, Carpenter et al.[sup] [4] gave the concept of deficit and non-deficit schizophrenia. Concept of Deficit Schizophrenia According to Carpenter et al. ,[sup] [4] the term 'deficit symptoms' should be used to refer specifically to those negative symptoms that are present as enduring traits. According to these authors, deficit symptoms may be present during and in-between episodes of exacerbation of positive symptoms. These deficit symptoms occur regardless of the patient's medication status and are not specifically responsive to anticholinergic drugs or antipsychotic drug withdrawal. It was further conceptualised that the presence of poor premorbid adjustment preceding initial psychotic episode may be manifestations of the deficit syndrome. In contrast, in non-deficit type of schizophrenia, negative symptoms may be present but demonstrate greater fluctuation, lack of persistence and temporal association with possible underlying causes like dysphoric states, drug status, etc. The patient with deficit symptoms may also have changes in symptom intensity and superimposed secondary negative symptoms, but a core of primary and enduring negative symptoms must be present. According to Carpenter et al. ,[sup] [4] this approach to deficit symptoms requires clinical judgment based on longitudinal observation rather than a cross-sectional assessment to establish the presence or absence of the symptoms. To further stress their concept, they operationalised the diagnostic criteria for deficit schizophrenia, which is shown in [Table 1]. Carpenter et al. conceptualised that those patients who met only criterion 1 can be designated as schizophrenia without negative symptoms . Patients, who meet criteria 1 and 2 and possibly 4, but not criterion 3, can be designated as schizophrenia with secondary negative symptoms . Only those patients who satisfy all four criteria should be designated as schizophrenia with deficit syndrome . Those patients meeting criteria 1, 2 and 3, but not criterion 4, could either be schizophrenia with primary, non-enduring negative symptoms though these patients with passage of time may satisfy full criteria for schizophrenia with deficit syndrome and thus become schizophrenia with deficit syndrome . To further distinguish deficit syndrome from primary, non-enduring negative symptoms, the authors[sup] [4] suggested certain conditions for those patients who meet criteria 1, 2 and 3, but not criterion 4 for schizophrenia with deficit syndrome. It was recommended that patients who had two or more prior periods of primary negative symptom (criteria 1, 2 and 3 for schizophrenia with deficit syndrome) followed by at least 3 months of remission of negative symptoms and where the current period of primary negative symptoms is of duration of 4 months or less should be considered to have primary deficit state. …

The Association Between Polymorphisms in RLIP76 and Drug Response in Epilepsy

Approximately 30% of patients with epilepsy are resistant to treatment with anti-epileptic drugs (AEDs). The ABC drug transporter proteins are hypothesized to mediate drug resistance in epilepsy. More recently, a non-ABC putative transporter, RLIP76, has also been proposed to be involved in the mechanism of pharmacoresistance. One previous association study of six polymorphisms in RLIP76 failed to find any association with drug resistance in a retrospective cohort of epilepsy patients. We aimed to look for an association with outcomes reflecting drug response in a larger prospective cohort, with gene-wide coverage. We investigated the role of common polymorphisms in RLIP76 in epilepsy pharmacoresistance by genotyping 23 common RLIP76 polymorphisms in a prospective cohort of 503 epilepsy patients, from the standard and new anti-epileptic drugs (SANAD) prospective study of new and old AEDs. A total of 13 of these were tested for association with four outcomes reflecting response to drugs: time to first seizure, time to 12-month remission, time to withdrawal due to inadequate seizure control, and time to withdrawal due to unacceptable adverse drug events. No significant associations, allowing for multiple testing, were found in the whole cohort. There was also no effect in a subgroup of patients on carbamazepine, which is thought to be a RLIP76 substrate, although two polymorphisms were associated with time to first seizure (p = 0.007). We failed to demonstrate any association between RLIP76 polymorphisms and four different measures of drug response in the larger cohort, but a subgroup analysis of patients receiving carbamazepine suggested an association that should be investigated further. Our data suggest that common variants in RLIP76 are unlikely to contribute to epilepsy drug response.

Definitions of recovery and outcomes of major depression: results from a 10‐year follow‐up

Furukawa TA, Fujita A, Harai H, Yoshimura R, Kitamura T, Takahashi K. Definitions of recovery and outcomes of major depression: results from a 10-year follow-up.ObjectiveConsensus operational definitions for symptomatic remission and recovery of a major depressive episode have been proposed but only irregularly followed.MethodWe examined the predictive validity of different definitions of recovery in a multi-center 10-year follow-up study of an inception cohort of untreated unipolar major depressive episodes (n = 95). Time to recovery and time to recurrence after recovery were estimated by Kaplan–Meier survival analyses for alternative definitions requiring 2, 4, 6 or 12 months of remission to declare recovery.ResultsThe median time to recovery was 3.0, 4.0, 4.0 and 12.0 months respectively. The index episode lasted longer than 24 months in 9.4%, 9.2%, 12.6% and 24.5%. The median time to subthreshold recurrence was 16.0, 32.0, 42.0 and 74.0 months.ConclusionEither 4- or 6-month duration of remission defined a change point before which the episode was continuous and after which the recurrence was reasonably unlikely.Significant outcomes Requiring two months of remission is probably too short to declare recovery because a subthreshold recurrence occurs in more than half of the cohort within a year and a half.If we require 4 or 6 months before we declare recovery, the median time to recovery is 4 months and that to subthreshold recurrence is nearly 3 years.Requiring 12 months of remission before declaring recovery would make the episode discontinuous yet long and inflate the rate of chronicity.Limitations The sample size was relatively small and the confidence intervals were accordingly wide.This was a naturalistic study and the treatments were not controlled.Validity of alternative definitions of remission requires a separate study.

The benefit of active drug trials is dependent on aetiology in refractory focal epilepsy

Background:Earlier studies have shown that aetiology makes a difference in the outcome of epilepsy, but there is a paucity of follow-up studies to evaluate the possibilities of achieving seizure freedom...

Likelihood of seizure remission in an adult population with refractory epilepsy

We aimed to determine the likelihood of remission and its clinical predictors in adult patients meeting a strict definition of refractory epilepsy. We also wanted to investigate the influence of treatment regimen on remission. A total of 246 patients with treatment refractory epilepsy (having at least 1 seizure per month and having not responded positively to at least 2 antiepileptic drugs) were identified in 2000 and followed for 3 years. We used Kaplan-Meier methods to estimate the rate of achieving a 6-month terminal seizure remission and Cox regression analysis to evaluate clinical predictors for seizure remission. The estimated 6-month terminal seizure remission rate was 19% (95% confidence interval, 14-26%) for all cases and 14% (95% confidence interval, 10-21%) when limited to those treated only with medication. Negative predictors for remission included a history of status epilepticus, younger age at intractability, number of failed drug therapies, and presence of mental retardation. No specific drug was significantly associated with remission, and frequently, no clear intervention led to terminal remission. Fifteen percent (approximately 5% per year) of a drug refractory epilepsy population obtained a 6-month terminal seizure remission. Our results signify that no matter how many antiepileptic drug therapies have failed, there is always hope of a meaningful seizure remission in this population. Furthermore, we have elucidated four clinical predictors that can aid the epileptologist in prognostication.

A randomised controlled trial examining the longer-term outcomes of standard versus new antiepileptic drugs. The SANAD trial

To compare clinicians' choice of one of the standard epilepsy drug treatments (carbamazepine or valproate) versus appropriate comparator new drugs. A clinical trial comprising two arms, one comparing new drugs in carbamazepine and the other with valproate. A multicentre study recruiting patients with epilepsy from hospital outpatient clinics. Patients with an adequately documented history of two or more clinically definite unprovoked epileptic seizures within the last year for whom treatment with a single antiepileptic drug represented the best therapeutic option. Arm A was carbamazepine (CBZ) versus gabapentin (GBP) versus lamotrigine (LTG) versus oxcarbazepine (OXC) versus topiramate (TPM). Arm B valproate (VPS) versus LTG versus TPM. Time to treatment failure (withdrawal of the randomised drug for reasons of unacceptable adverse events or inadequate seizure control or a combination of the two) and time to achieve a 12-month remission of seizures. Time from randomisation to first seizure, 24-month remission of seizures, incidence of clinically important adverse events, quality of life (QoL) outcomes and health economic outcomes were also considered. Arm A recruited 1721 patients (88% with symptomatic or cryptogenic partial epilepsy and 10% with unclassified epilepsy). Arm B recruited 716 patients (63% with idiopathic generalised epilepsy and 25% with unclassified epilepsy). In Arm A LTG had the lowest incidence of treatment failure and was statistically superior to all drugs for this outcome with the exception of OXC. Some 12% and 8% fewer patients experienced treatment failure on LTG than CBZ, the standard drug, at 1 and 2 years after randomisation, respectively. The superiority of LTG over CBZ was due to its better tolerability but there is satisfactory evidence indicating that LTG is not clinically inferior to CBZ for measures of its efficacy. No consistent differences in QoL outcomes were found between treatment groups. Health economic analysis supported LTG being preferred to CBZ for both cost per seizure avoided and cost per quality-adjusted life-year gained. In Arm B for time to treatment failure, VPS, the standard drug, was preferred to both TPM and LTG, as it was the drug least likely to be associated with treatment failure for inadequate seizure control and was the preferred drug for time to achieving a 12-month remission. QoL assessments did not show any between-treatment differences. The health economic assessment supported the conclusion that VPS should remain the drug of first choice for idiopathic generalised or unclassified epilepsy, although there is a suggestion that TPM is a cost-effective alternative to VPS. The evidence suggests that LTG may be a clinical and cost-effective alternative to the existing standard drug treatment, CBZ, for patients diagnosed as having partial seizures. For patients with idiopathic generalised epilepsy or difficult to classify epilepsy, VPS remains the clinically most effective drug, although TPM may be a cost-effective alternative for some patients. Three new antiepileptic drugs have recently been licensed in the UK for the treatment of epilepsy (levetiracetam, zonisamide and pregabalin), therefore these drugs should be compared in a similarly designed trial.

Now We Know the Drug of First Choice—Or Do We?

The SANAD Study of Effectiveness of Carbamazepine, Gabapentin, Lamotrigine, Oxcarbazepine, or Topiramate for Treatment of Partial Epilepsy: An Unblinded Randomised Controlled Trial. Marson AG, Al-Kharusi AM, Alwaidh M, Appleton R, Baker GA, Chadwick DW, Cramp C, Cockerell OC, Cooper PN, Doughty J, Eaton B, Gamble C, Goulding PJ, Howell SJ, Hughes A, Jackson M, Jacoby A, Kellett M, Lawson GR, Leach JP, Nicolaides P, Roberts R, Shackley P, Shen J, Smith DF, Smith PE, Smith CT, Vanoli A, Williamson PR; SANAD Study group. Lancet 2007;369(9566):1000–1015. BACKGROUND: Carbamazepine is widely accepted as a drug of first choice for patients with partial onset seizures. Several newer drugs possess efficacy against these seizure types but previous randomised controlled trials have failed to inform a choice between these drugs. We aimed to assess efficacy with regards to longer-term outcomes, quality of life, and health economic outcomes. METHODS: SANAD was an unblinded randomised controlled trial in hospital-based outpatient clinics in the UK. Arm A recruited 1,721 patients for whom carbamazepine was deemed to be standard treatment, and they were randomly assigned to receive carbamazepine, gabapentin, lamotrigine, oxcarbazepine, or topiramate. Primary outcomes were time to treatment failure, and time to 12-months remission, and assessment was by both intention to treat and per protocol. This study is registered as an International Standard Randomised Controlled Trial, number ISRCTN38354748. FINDINGS: For time to treatment failure, lamotrigine was significantly better than carbamazepine (hazard ratio [HR] 0·78 [95% CI 0·63–0·97]), gabapentin (0·65 [0·52–0·80]), and topiramate (0·64 [0·52–0·79]), and had a non-significant advantage compared with oxcarbazepine (1·15 [0·86–1·54]). For time to 12-month remission carbamazepine was significantly better than gabapentin (0·75 [0·63–0·90]), and estimates suggest a non-significant advantage for carbamazepine against lamotrigine (0·91 [0·77–1·09]), topiramate (0·86 [0·72–1·03]), and oxcarbazepine (0·92 [0·73–1·18]). In a per-protocol analysis, at 2 and 4 years the difference (95% CI) in the proportion achieving a 12-month remission (lamotrigine-carbamazepine) is 0 (–8 to 7) and 5 (–3 to 12), suggesting non-inferiority of lamotrigine compared with carbamazepine. INTERPRETATION: Lamotrigine is clinically better than carbamazepine, the standard drug treatment, for time to treatment failure outcomes and is therefore a cost-effective alternative for patients diagnosed with partial onset seizures. The SANAD Study of Effectiveness of Valproate, Lamotrigine, or Topiramate for Generalised and Unclassifiable Epilepsy: An Unblinded Randomised Controlled Trial. Marson AG, Al-Kharusi AM, Alwaidh M, Appleton R, Baker GA, Chadwick DW, Cramp C, Cockerell OC, Cooper PN, Doughty J, Eaton B, Gamble C, Goulding PJ, Howell SJ, Hughes A, Jackson M, Jacoby A, Kellett M, Lawson GR, Leach JP, Nicolaides P, Roberts R, Shackley P, Shen J, Smith DF, Smith PE, Smith CT, Vanoli A, Williamson PR; SANAD Study group. Lancet 2007;369(9566):1016–1026. BACKGROUND: Valproate is widely accepted as a drug of first choice for patients with generalised onset seizures, and its broad spectrum of efficacy means it is recommended for patients with seizures that are difficult to classify. Lamotrigine and topiramate are also thought to possess broad spectrum activity. The SANAD study aimed to compare the longer-term effects of these drugs in patients with generalised onset seizures or seizures that are difficult to classify. METHODS: SANAD was an unblinded randomised controlled trial in hospital-based outpatient clinics in the UK. Arm B of the study recruited 716 patients for whom valproate was considered to be standard treatment. Patients were randomly assigned to valproate, lamotrigine, or topiramate between Jan 12, 1999, and Aug 31, 2004, and follow-up data were obtained up to Jan 13, 2006. Primary outcomes were time to treatment failure, and time to 1-year remission, and analysis was by both intention to treat and per protocol. This study is registered as an International Standard Randomised Controlled Trial, number ISRCTN38354748. FINDINGS: For time to treatment failure, valproate was significantly better than topiramate (hazard ratio 1·57 [95% CI 1·19–2·08]), but there was no significant difference between valproate and lamotrigine (1·25 [0·94–1·68]). For patients with an idiopathic generalised epilepsy, valproate was significantly better than both lamotrigine (1·55 [1·07–2·24] and topiramate (1·89 [1·32–2·70]). For time to 12-month remission valproate was significantly better than lamotrigine overall (0·76 [0·62–0·94]), and for the subgroup with an idiopathic generalised epilepsy 0·68 (0·53–0·89). But there was no significant difference between valproate and topiramate in either the analysis overall or for the subgroup with an idiopathic generalised epilepsy. INTERPRETATION: Valproate is better tolerated than topiramate and more efficacious than lamotrigine, and should remain the drug of first choice for many patients with generalised and unclassified epilepsies. However, because of known potential adverse effects of valproate during pregnancy, the benefits for seizure control in women of childbearing years should be considered.

Comparative Monotherapy Trials and the Clinical Treatment of Epilepsy

Comparison of Levetiracetam and Controlled-Release Carbamazepine in Newly Diagnosed Epilepsy. Brodie MJ, Perucca E, Ryvlin P, Ben-Menachem E, Meencke HJ; Levetiracetam Monotherapy Study Group. Neurology 2007;68(6):402–408. OBJECTIVE: We report the results of a prospective study of the efficacy and tolerability of levetiracetam, a new antiepileptic drug witha unique mechanism of action, in comparison with controlled-release carbamazepine as first treatment in newly diagnosed epilepsy. METHODS: Adults with 2 partial or generalized tonic–clonic seizures in the previous year were randomly assigned to levetiracetam (500 mg twice daily, n = 288) or controlled-release carbamazepine (200 mg twice daily, n = 291) in a multicenter, double-blind, noninferiority, parallel-group trial. If a seizure occurred within 26 weeks of stabilization, dosage was increased incrementally to a maximum of levetiracetam 1,500 mg twice daily or carbamazepine 600 mg twice daily. Patients achieving the primary endpoint (6-month seizure freedom) continued on treatment for a further 6-month maintenance period. RESULTS: At per-protocol analysis, 73.0% (56.6%) of patients randomized to levetiracetam and 72.8% (58.5%) receiving controlled-release carbamazepine were seizure free at the last evaluated dose (adjusted absolute difference 0.2%, 95% CI – 7.8% to 8.2%) for 6 months (1 year). Of all patients achieving 6-month (1-year) remission, 80.1% (86.0%) in the levetiracetam group and 85.4% (89.3%) in the carbamazepine group did so at the lowest dose level. Withdrawal rates for adverse events were 14.4% with levetiracetam and 19.2% with carbamazepine. CONCLUSIONS: Levetiracetam and controlled-release carbamazepine produced equivalent seizure freedom rates in newly diagnosed epilepsy at optimal dosing in a setting mimicking clinical practice. This trial has confirmed in a randomized, double-blind setting previously uncontrolled observations that most people with epilepsy will respond to their first-ever antiepileptic drug at low dosage.

Once- or Twice-Daily MMX™ Mesalamine for the Maintenance of Remission of Mild or Moderate Ulcerative Colitis

Purpose: Mesalamine with MMX Multi Matrix System® (MMX) technology (LIALDA™, also known as MEZAVANT™ XL in the UK and Ireland, and as MEZAVANT™ elsewhere) is a novel, high-strength formulation of 5-aminosalicylate (5-ASA; 1.2 g per tablet), designed to release 5-ASA throughout the colon. An analysis of combined data from two randomized, phase III trials (SPD476–301 and -302) demonstrated the efficacy of MMX mesalamine for improving remission rates in patients with active, mild (Ulcerative Colitis Disease Activity Index [UC-DAI] score 4-<6) or moderate ulcerative colitis (UC-DAI score 6–10). In a subsequent 12-month extension study (SPD476–303), in patients achieving remission, MMX mesalamine 2.4 g/day was shown to be efficacious for maintenance of remission. Here, data from study 303 were analyzed to assess the efficacy of MMX mesalamine for the maintenance of remission in patients with either mild or moderate ulcerative colitis. Methods: Patients were randomized to receive MMX mesalamine 2.4 g/day (given once daily [QD]) or 2.4 g/day (1.2 g given twice daily [BID]). Data were analyzed to assess remission rates by baseline disease severity. Remission at 12 months was defined as a modified UC-DAI score of ≤1 calculated as: rectal bleeding and stool frequency scores of 0, a combined Physician's Global Assessment and sigmoidoscopy score of ≤1, no mucosal friability, and ≥1-point reduction in sigmoidoscopy score from baseline. Results: In the efficacy population (N = 451), 12-month remission rates were 70.5% (117/166) for patients with mild disease at baseline, and 64.2% (183/285) for patients with moderate disease at baseline. Remission rates were not significantly different in patients receiving MMX mesalamine 2.4 g/day QD or BID for mild disease (69.0 vs 72.2%, P= 0.653) or moderate disease (61.4 vs 66.7%, P= 0.352). Conclusion: MMX mesalamine 2.4 g/day, given QD or BID, is efficacious for the maintenance of remission of both mild and moderate ulcerative colitis.

Long-Term Remission Rates in Patients with Mild-to-Moderate Ulcerative Colitis Who Require an MMX™ Mesalamine Dose Increase To Induce Initial Remission

Purpose: MMX Multi Matrix System® (MMX) mesalamine (LIALDA™[ US] MEZAVANT™ XL [UK and Ireland] and MEZAVANT™[ elsewhere]), is a novel high-strength, once-daily 5-aminosalicylic acid therapy that has been shown to be efficacious for the induction and maintenance of remission of mild-to-moderate ulcerative colitis (UC) in a phase III clinical trial program. Here we examine long-term remission rates in patients who required a MMX mesalamine dose escalation to induce remission. Methods: In two placebo-controlled, phase III clinical trials (SPD476–301 and -302), patients with active, mild-to-moderate UC received MMX mesalamine 2.4 or 4.8 g/day for up to 8 weeks to induce remission. Those patients not in remission at the end of these trials could opt to receive a further 8 weeks’ treatment with MMX mesalamine 4.8 g/day (as part of a two-phase, open-label trial [SPD476–303]). Patients who achieved remission in these studies could choose to receive MMX mesalamine 2.4 g/day maintenance therapy for 12 months (second phase of study 303). In this retrospective analysis, we determined 12-month remission rates for (a) patients who received MMX mesalamine 2.4 g/day as induction therapy and then entered the maintenance study directly; and (b) patients who received 2.4 g/day plus a further 8 weeks of high-dose MMX mesalamine therapy before entering the maintenance phase (2.4 g/day). Results: Seventy-nine patients received MMX mesalamine 2.4 g/day in studies 301 and 302 and entered the maintenance phase directly. A total of 53 patients received MMX mesalamine 2.4 g/day for 8 weeks, plus a further 8 weeks’ MMX mesalamine 4.8 g/day and then entered the 12-month maintenance phase of study 303. Twelve-month remission rates were 73.4% for patients who directly entered the maintenance phase, and 50.9% for those who entered via the 8-week extension phase. Conclusion: In this analysis, in patients initially treated with MMX mesalamine 2.4 g/day, the requirement for further treatment at a higher dose to achieve remission was associated with reduced long-term remission rates. These patients may represent a difficult-to-treat subgroup who may require a higher maintenance dose of MMX mesalamine. Further studies are needed to test this hypothesis.

MMX™ Mesalamine Is Effective for the Maintenance of Ulcerative Colitis Remission in Both Left-Sided and Extensive Disease

Purpose: A combined analysis of two phase III, placebo-controlled studies (SPD476–301 and -302) has demonstrated mesalamine with MMX Multi Matrix System® (MMX) technology (LIALDA™, also known as MEZAVANT™ XL in the UK and Ireland, and as MEZAVANT™ elsewhere; hereafter referred to as MMX mesalamine) to be efficacious for the induction of remission of active, mild-to-moderate ulcerative colitis (UC), in patients with left-sided (distal to the splenic flexure) or extensive (involving the transverse colon) disease. In a subsequent 12-month extension study (SPD476–303), MMX mesalamine 2.4 g/day has demonstrated efficacy for maintenance of UC remission. Here we present a post-hoc analysis of 12-month remission rates with MMX mesalamine therapy in patients with a medical history of either left-sided or extensive UC. Methods: Patients were randomized to MMX mesalamine 2.4 g/day given once daily (QD) or 1.2 g given twice daily (BID) for 12 months. Remission was defined as a modified Ulcerative Colitis Disease Activity Index score ≤1, calculated as: scores of 0 for rectal bleeding and stool frequency, a combined Physician's Global Assessment and sigmoidoscopy score of ≤1, no mucosal friability, and a sigmoidoscopy score reduction of ≥1 from baseline. Results: In total, 451 patients were included in the efficacy population. Of the 450 with known extent of disease, 67.0% (233/348) and 64.7% (66/102) of patients with left-sided or extensive disease, respectively, were in remission at month 12. The results were similar with once- or twice-daily treatment in patients with left-sided (QD = 65.5%, BID = 68.4%, P= 0.570) or extensive disease (QD = 60.4%, BID = 68.5%, P= 0.393). Conclusion: MMX mesalamine 2.4 g/day is effective for the maintenance of remission of mild-to-moderate UC in both left-sided and extensive disease.

Therapeutic monitoring of antiepileptic drugs for epilepsy

The aim of drug treatment for epilepsy is to prevent seizures without causing adverse effects. To achieve this, drug dosages need to be individualised. Measuring antiepileptic drug levels in body fluids (therapeutic drug monitoring) is frequently used to optimise drug dosage for individual patients. To review the evidence regarding the effects of therapeutic drug monitoring upon outcomes in epilepsy. We searched the Cochrane Epilepsy Group Specialised Register (September 2006), the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2005, Issue 4), MEDLINE (January 1966 to April 2005) and EMBASE (1974 to May 2005). No language restrictions were imposed. We checked the reference lists of retrieved articles for additional reports of relevant studies. Randomised controlled trials comparing the outcomes of antiepileptic drug monotherapy guided by therapeutic drug monitoring with drug treatment without the aid of therapeutic drug monitoring. We based this review on published aggregate data. The main outcomes measured were the proportions of patients achieving a 12-month remission from seizures, reporting adverse effects, and being withdrawn from the treatment they had been randomised to receive. Only one study met the inclusion criteria for the review. In this open study, 180 patients with newly-diagnosed, untreated epilepsy were randomised to treatment with the antiepileptic drug selected by their physician either with or without therapeutic drug serum level monitoring as an aid to dosage adjustments. The antiepileptic drugs used were carbamazepine, valproate, phenytoin, phenobarbital and primidone. A 12-month remission from seizures was achieved by 60% of the patients randomised to therapeutic drug monitoring (intervention group) and by 61% in the control group. A total of 56% in the intervention group and 58% in the control group were seizure free during the last 12 months of follow up. Adverse effects were reported by 48% in the intervention group and 47% of the control group patients. Of those randomised to therapeutic drug monitoring, 62% completed the two-year follow up compared with 67% of the control group. We found no clear evidence to support routine antiepileptic drug serum concentration measurement with the aim of reaching predefined target ranges for the optimisation of treatment of patients with newly-diagnosed epilepsy with antiepileptic drug monotherapy. However, this does not exclude the possible usefulness of therapeutic drug monitoring of specific antiepileptic drugs during polytherapy, in special situations or in selected patients, although evidence is lacking.

The SANAD study of effectiveness of carbamazepine, gabapentin, lamotrigine, oxcarbazepine, or topiramate for treatment of partial epilepsy: an unblinded randomised controlled trial

Carbamazepine is widely accepted as a drug of first choice for patients with partial onset seizures. Several newer drugs possess efficacy against these seizure types but previous randomised controlled trials have failed to inform a choice between these drugs. We aimed to assess efficacy with regards to longer-term outcomes, quality of life, and health economic outcomes. SANAD was an unblinded randomised controlled trial in hospital-based outpatient clinics in the UK. Arm A recruited 1721 patients for whom carbamazepine was deemed to be standard treatment, and they were randomly assigned to receive carbamazepine, gabapentin, lamotrigine, oxcarbazepine, or topiramate. Primary outcomes were time to treatment failure, and time to 12-months remission, and assessment was by both intention to treat and per protocol. This study is registered as an International Standard Randomised Controlled Trial, number ISRCTN38354748. For time to treatment failure, lamotrigine was significantly better than carbamazepine (hazard ratio [HR] 0.78 [95% CI 0.63-0.97]), gabapentin (0.65 [0.52-0.80]), and topiramate (0.64 [0.52-0.79]), and had a non-significant advantage compared with oxcarbazepine (1.15 [0.86-1.54]). For time to 12-month remission carbamazepine was significantly better than gabapentin (0.75 [0.63-0.90]), and estimates suggest a non-significant advantage for carbamazepine against lamotrigine (0.91 [0.77-1.09]), topiramate (0.86 [0.72-1.03]), and oxcarbazepine (0.92 [0.73-1.18]). In a per-protocol analysis, at 2 and 4 years the difference (95% CI) in the proportion achieving a 12-month remission (lamotrigine-carbamazepine) is 0 (-8 to 7) and 5 (-3 to 12), suggesting non-inferiority of lamotrigine compared with carbamazepine. Lamotrigine is clinically better than carbamazepine, the standard drug treatment, for time to treatment failure outcomes and is therefore a cost-effective alternative for patients diagnosed with partial onset seizures.

The SANAD study of effectiveness of valproate, lamotrigine, or topiramate for generalised and unclassifiable epilepsy: an unblinded randomised controlled trial

Valproate is widely accepted as a drug of first choice for patients with generalised onset seizures, and its broad spectrum of efficacy means it is recommended for patients with seizures that are difficult to classify. Lamotrigine and topiramate are also thought to possess broad spectrum activity. The SANAD study aimed to compare the longer-term effects of these drugs in patients with generalised onset seizures or seizures that are difficult to classify. SANAD was an unblinded randomised controlled trial in hospital-based outpatient clinics in the UK. Arm B of the study recruited 716 patients for whom valproate was considered to be standard treatment. Patients were randomly assigned to valproate, lamotrigine, or topiramate between Jan 12, 1999, and Aug 31, 2004, and follow-up data were obtained up to Jan 13, 2006. Primary outcomes were time to treatment failure, and time to 1-year remission, and analysis was by both intention to treat and per protocol. This study is registered as an International Standard Randomised Controlled Trial, number ISRCTN38354748. For time to treatment failure, valproate was significantly better than topiramate (hazard ratio 1.57 [95% CI 1.19-2.08]), but there was no significant difference between valproate and lamotrigine (1.25 [0.94-1.68]). For patients with an idiopathic generalised epilepsy, valproate was significantly better than both lamotrigine (1.55 [1.07-2.24] and topiramate (1.89 [1.32-2.70]). For time to 12-month remission valproate was significantly better than lamotrigine overall (0.76 [0.62-0.94]), and for the subgroup with an idiopathic generalised epilepsy 0.68 (0.53-0.89). But there was no significant difference between valproate and topiramate in either the analysis overall or for the subgroup with an idiopathic generalised epilepsy. Valproate is better tolerated than topiramate and more efficacious than lamotrigine, and should remain the drug of first choice for many patients with generalised and unclassified epilepsies. However, because of known potential adverse effects of valproate during pregnancy, the benefits for seizure control in women of childbearing years should be considered.

Levetiracetam in clinical practice: Long-term experience in patients with refractory epilepsy referred to a tertiary epilepsy center

Objective For the treatment of patients with chronic refractory epilepsies, development of new antiepileptic drugs is crucial. Three regulatory trials have demonstrated that add-on levetiracetam is efficacious in patients with localization-related epilepsy. However, results from these highly controlled short-term clinical trials cannot simply be extrapolated to everyday clinical practice. Therefore, more information is needed about the long-term profile of a new antiepileptic drug in clinical practice. Method We analyzed all patients who had been treated with levetiracetam in the Epilepsy Centre Kempenhaeghe from the introduction of the drug in early 2001 up to a final assessment point, at the end of 2003, using a medical information system. Results In total, 301 patients were included. One hundred thirty-eight patients (45.8%) discontinued LEV treatment during the 24-month follow-up period. Reasons for discontinuation were lack of efficacy in 15.9% of patients, adverse events in 6.0% of patients, and a combination of lack of efficacy and adverse events in 16.3% of patients. By Kaplan–Meier survival analysis, the continuation rate was 65.6% after 1 year and 45.8% after 2 years. About 15% of patients in this highly refractory group had a 3-month remission, whereas 10% of patients became seizure-free for longer periods. The most frequently reported side effects at the time of discontinuation were mood disorders, tiredness, and sleepiness. Variables predicting (dis)continuation of levetiracetam treatment could not be identified. Conclusion Levetiracetam is a new antiepileptic drug that appears to be a useful add-on treatment in patients with refractory epilepsy. Its side effect profile is mild, with mood disorders being the most dominant adverse event.

Comparison of levetiracetam and controlled-release carbamazepine in newly diagnosed epilepsy

We report the results of a prospective study of the efficacy and tolerability of levetiracetam, a new antiepileptic drug with a unique mechanism of action, in comparison with controlled-release carbamazepine as first treatment in newly diagnosed epilepsy. Adults with > or =2 partial or generalized tonic-clonic seizures in the previous year were randomly assigned to levetiracetam (500 mg twice daily, n = 288) or controlled-release carbamazepine (200 mg twice daily, n = 291) in a multicenter, double-blind, noninferiority, parallel-group trial. If a seizure occurred within 26 weeks of stabilization, dosage was increased incrementally to a maximum of levetiracetam 1,500 mg twice daily or carbamazepine 600 mg twice daily. Patients achieving the primary endpoint (6-month seizure freedom) continued on treatment for a further 6-month maintenance period. At per-protocol analysis, 73.0% (56.6%) of patients randomized to levetiracetam and 72.8% (58.5%) receiving controlled-release carbamazepine were seizure free at the last evaluated dose (adjusted absolute difference 0.2%, 95% CI -7.8% to 8.2%) for > or =6 months (1 year). Of all patients achieving 6-month (1-year) remission, 80.1% (86.0%) in the levetiracetam group and 85.4% (89.3%) in the carbamazepine group did so at the lowest dose level. Withdrawal rates for adverse events were 14.4% with levetiracetam and 19.2% with carbamazepine. Levetiracetam and controlled-release carbamazepine produced equivalent seizure freedom rates in newly diagnosed epilepsy at optimal dosing in a setting mimicking clinical practice. This trial has confirmed in a randomized, double-blind setting previously uncontrolled observations that most people with epilepsy will respond to their first-ever antiepileptic drug at low dosage.