The combined use of disease activity and infliximab serum trough concentrations for early prediction of (non-)response to infliximab in rheumatoid arthritis.

AIM: Early prediction of (non-)response to infliximab therapy can improve therapeutic benefit by avoiding unnecessary periods of high disease activity during ineffective therapy. This prospective cohort study therefore aimed to study the predictive value of (1) disease activity alone and (2) infliximab serum trough concentrations in addition to disease activity 6 weeks after start of treatment for achieving low disease activity after 6 months. METHODS: Disease activity and infliximab serum trough concentrations were assessed in all rheumatoid arthritis (RA) patients at 2, 6 and 26 weeks after initiation of infliximab therapy. Receiver operating characteristic (ROC) curves and Youden indices were used to calculate specificity for prediction of good response after 6 months while aiming for maximum sensitivity. RESULTS: Fifty-seven consecutive RA patients starting with infliximab therapy were included. After 6 months, 15 (26%, 95 % CI 15, 38%) patients reached good European League against Rheumatism (EULAR) response. A disease activity score <4.2 at 6 weeks after initiation of therapy was a moderate predictor for reaching EULAR response after 6 months (sensitivity 100%, specificity 49%). Infliximab serum trough concentrations (>2.5 mg l(-1)) as predictor complimentary to disease activity (<4.2) slightly increased the specificity from 49% to 54% without changing the sensitivity (100%). As 39% of the patients did not fulfill at least one of these criteria at week 6, these patients could already be switched to another therapy after 6 weeks. CONCLUSIONS: The combination of disease activity and infliximab serum trough concentrations could be a fair predictor to identify early (after 6 weeks) patients who have insufficient response after 6 months of therapy.

Anti-infliximab antibodies are already detectable in most patients with rheumatoid arthritis halfway through an infusion cycle: an open-label pharmacokinetic cohort study.

BACKGROUND: This study in patients with rheumatoid arthritis (RA) treated with infliximab describes prospectively the course of (anti)infliximab levels within an infusion cycle to assess at what moment patients develop low/no infliximab trough levels and/or detectable anti-infliximab levels. METHODS: Infliximab treated RA patients were included in this descriptive open-label cohort study. During one infusion cycle (anti-)infliximab levels were assessed just before and one hour after infusion, and subsequently at 50%, 75% and at the end of the infusion cycle (pre-infusion). RESULTS: 27 patients were included. The median infliximab levels decreased from 77.0 mg/l (p25-p75: 65-89) one hour after the infusion to pre-infusion levels of 0.0 mg/l (p25-p75: 0.0-3.1). In 7 (26%) patients pre-infusion anti-infliximab antibodies were detected; these antibodies were already present halfway through the infusion cycle in 5 of the 7 individuals. Patients with detectable pre-infusion anti-infliximab antibodies have significantly more often low/no infliximab levels (< 1 mg/l) halfway trough the infusion cycle (in 5/7 patients) compared to patients without detectable pre-infusion anti-infliximab antibodies (0/20 patients, p < 0.001). CONCLUSIONS: Most anti-infliximab forming patients have detectable anti-infliximab antibodies halfway through an infusion cycle, which implies that these patients are exposed to nontherapeutical infliximab levels during more than half of their infusion cycle. As none of the patients without anti-infliximab antibodies had no/low-infliximab levels halfway through the infusion cycle, the presence of pre-infusion anti-infliximab antibodies seems a sensitive and specific predictor for no/low infliximab-levels.

The impact of side effects on long-term retention in three new antiepileptic drugs.

OBJECTIVE: To determine long-term retention, percentage of patients withdrawing because of adverse events, percentage of patients achieving seizure freedom, safety profile of the new anti-epileptic drugs lamotrigine, levetiracetam and topiramate. METHODS: All patients treated with lamotrigine, levetiracetam or topiramate in the Epilepsy Centre were identified. Each drug was analyzed from introduction of the drug in the Netherlands up to a final assessment point 2 years later. RESULTS: Data from 1066 patients were included: 336 for lamotrigine, 301 for levetiracetam, 429 for topiramate. Two-year retention rates were 69.2% (lamotrigine), 45.8% (levetiracetam), 38.3% (topiramate); (LTG vs. LEV at p<0.001; LTG vs. TPM at p<0.001; LEV vs. TPM at p=0.005). Seizure freedom rates were lowest for lamotrigine and highest for levetiracetam. Adverse events played a role in drug discontinuation in 154/429 patients (35.9%) on topiramate, 52/336 patients (15.5%) on lamotrigine (p<0.001), 68/301 patients (22.5%) on levetiracetam (p<0.001). Mood and general CNS-effects are common in patients on lamotrigine and levetiracetam, and neurocognitive side effects are most prevalent in patients on topiramate. A positive effect on cognition is frequently noted in patients on lamotrigine. CONCLUSION: A drug that is only modestly efficacious but has a favourable safety profile may look better than a drug that is more efficacious but produces clinically meaningful adverse events. Therefore, a drug's retention rate is mainly determined by its side effect profile. As a consequence, retention rate was highest for lamotrigine and lowest for topiramate. Intermediate retention rates were seen with levetiracetam use.

Influence of chemical structure on hypersensitivity reactions induced by antiepileptic drugs: the role of the aromatic ring.

OBJECTIVE: Antiepileptic drugs (AEDs) can cause various 'idiosyncratic' hypersensitivity reactions, i.e. the mechanism by which AEDs induce hypersensitivity is unknown. The aim of this study was to assess whether the presence of an aromatic ring as a commonality in chemical structures of AEDs can explain symptoms of hypersensitivity. METHODS: Between January 1985 and January 2007, all adverse drug reactions (ADRs) reported to the Netherlands Pharmacovigilance Centre Lareb related to AEDs as suspected drugs were included in this study. ADRs were analysed using a case/non-case design. Cases were defined as those patients with ADRs involving symptoms of hypersensitivity. Non-cases were patients with all other ADR reports. Symptoms of hypersensitivity were classified according to the Gell and Coombs classification (type I-IV) and the organ involved (e.g. cutaneous, hepatic). AEDs were classified as aromatic anticonvulsant if their chemical structure contained at least one aromatic ring. All other AEDs were classified as non-aromatic. We assessed the strength of the association between aromatic AEDs versus non-aromatic AEDs and reported hypersensitivity reactions with logistic regression analysis and expressed these as reporting odds ratios (RORs). RESULTS: In total, 303 cases of hypersensitivity associated with the use of AEDs were reported. Aromatic AEDs were suspected in 64.4% of these reports versus 41.3% (574/1389) of the non-hypersensitivity reports. A significant ROR of 2.15 (95% CI 1.63, 2.82) was found for aromatic AEDs and all hypersensitivity reactions. Aromatic AEDs were significantly associated with immunoglobin E-mediated type I hypersensitivity reactions (ROR 2.15; 95% CI 1.23, 3.78) and T-cell-mediated type IV reactions (ROR 6.06; 95% CI 3.41, 10.75). Type II and III reactions did not show an association. Cutaneous symptoms represented 39.9% of the hypersensitivity-related ADRs. Aromatic AEDs were significantly associated with cutaneous hypersensitivity reactions (ROR 5.81; 95% CI 3.38, 9.99). CONCLUSION: This study confirms that the presence of an aromatic ring as a common feature in chemical structures of AEDs partly explains apparent 'idiosyncratic' hypersensitivity reactions. Symptoms of hypersensitivity were reported twice as frequently with aromatic AEDs than with non-aromatic AEDs. Strong associations for aromatic AEDs versus non-aromatic AEDs were found for T-cell-mediated (type IV) reactions, as well as for cutaneous reactions.

Drug treatment-related factors of inadequate seizure control.

To optimize seizure control it is important to identify modifiable factors. We conducted a case-control study to explore to what extent drug treatment-related factors are associated with seizures. Eighty-six patients with epilepsy were evaluated: 45 cases (recently experienced a seizure) and 41 controls (seizure-free for at least 2 months). There was a significant association between low AED serum concentration and seizures (odds ratio (OR)=8.9, 95% confidence interval (CI)=1.7-47.8), compliance was not associated with seizures (OR=0.9, 95% CI=0.2-4.0), and changes in medication (mainly non-AEDs) were more frequently observed in the case group than in the control group (OR=4.1, 95% CI=0.9-18.3). These findings indicate that patients with low AED serum levels have a nine times higher risk of seizures compared with patients with therapeutic AED levels and that changes in medication regimens in patients with epilepsy should be made with care.

Aggregated N-of-1 trials for unlicensed medicines for small populations: an assessment of a trial with ephedrine for myasthenia gravis.

BACKGROUND: Inexpensive medicines with a long history of use may currently be prescribed off-label for rare indications. Reimbursement is at the discretion of health insurance companies, and may be unpredictable. The example addressed was ephedrine as add-on treatment for myasthenia gravis. Stakeholders from academia, a patient organization, the Dutch National Health Care Institute (NHCI) and Dutch Medicines Evaluation Board (MEB) advised on the trial design. The NHCI and MEB agreed to provide scientific advice on the suitability of the evidence generated by the trial, for regulatory decisions. This paper describes the feasibility of the trial and the utility of its aggregated results. RESULTS: The trialists experienced the trial as feasible. Retrospective interviews showed that the trial as performed was acceptable to patients. The treatment effect in the primary outcome measure, muscle strength, was statistically significant when inferred to the population level, though the effect size was modest. Secondary outcomes were statistically significant in a preplanned, fixed effects analysis within the four patients. The NHCI advised that it could potentially make reimbursement decisions based on the Fitting Evidence framework, should the trialists decide to apply for reimbursement. The MEB advised that for a licensing decision, the N-of-1 design is a last-resort option for demonstrating treatment benefit in a rare disease. N-of-1 trials alone do not provide enough evidence on potential risk. The MEB found the current trial inconclusive. It suggested doing a 2-armed trial of longer duration, possibly with a different outcome measure (postponement of corticosteroid use). It suggested engaging a consultancy or commercial sponsor, should the trialists decide to seek market authorization of the drug. CONCLUSIONS: In theory, evidence from aggregated N-of-1 trials is suitable for use in licensing and reimbursement decisions. The current example illustrates differences in interpretation of N-of-1 results by health authorities. In the era of personalized medicine, consensus is required on the interpretation of data from study designs geared to small groups. Demonstrating effectiveness of inexpensive medicines in small populations may require involvement of non-commercial parties, to preserve affordability.

Ephedrine treatment for autoimmune myasthenia gravis.

We studied the effect and safety of ephedrine as add-on treatment for patients with myasthenia gravis with acetylcholine receptor antibodies (AChR MG), who do not sufficiently respond to standard treatment. Four patients with AChR MG were included in a placebo-controlled, double-blind, and randomised, multiple crossover series of n-of-1 trials. Each n-of-1 trial consisted of 3 cycles, in which two 5-day intervention periods were followed by 2 days washout. In each cycle, ephedrine 50 mg daily in 2 doses was compared with placebo in the alternate treatment period. Primary outcome was a change in QMG score. Add-on treatment with ephedrine compared with placebo improved QMG score by 1.0 point (95% confidence interval 0.21-1.79), which was significant for the group of trial patients as well as for the population treatment effect. Ephedrine also showed a significant trial average treatment effect for all secondary outcomes, improving MG Composite by 2.7, MG-ADL by 1.0 and VAS score for muscle strength by 1.1. Adverse events were mild and included palpitations, tremor and restlessness. Although all ECGs were normal, ephedrine prolonged the corrected QT interval. Ephedrine as add-on treatment for myasthenia gravis resulted in a small but consistent reduction of symptoms and weakness in patients with moderate disease severity.

Non-compliance on the part of the professional community with a national guideline: an argumentative policy analysis.

In 1997, the National Health Insurance Board of the Netherlands (CVZ) introduced a guideline for the use of a new anti-epileptic drug, Lamotrigine. The goal was to limit the use of this relatively expensive drug to patients with difficult-to-treat epilepsy. A survey had shown that only a minority of neurologists were familiar with the guideline, and even fewer applied it in practice. In the present study, interviews were held with stakeholders to obtain a better understanding of why this policy measure failed. The results indicate that the problem definitions of policy maker and practicing neurologists differed widely, and that the policy measure was conflicting with certain professional beliefs. In such cases, the theory of argumentative policy predicts that policy is unlikely to succeed, unless policy makers take actions to ensure a greater congruence in interpretative frames between them and their target population.

Effect of low-dose ritonavir (100 mg twice daily) on the activity of cytochrome P450 2D6 in healthy volunteers.

OBJECTIVE: In the treatment of human immunodeficiency virus infection, the protease inhibitor ritonavir is used in a low dose (100 mg twice daily) to inhibit cytochrome P450 (CYP) 3A4 and thereby increase plasma concentrations of coadministered protease inhibitors. When applied in a therapeutic dose (600 mg twice daily), ritonavir also inhibits CYP2D6. The effect of low-dose ritonavir on CYP2D6 is unknown and was investigated in this study. METHODS: This was a 1-arm, 2-period, fixed-order study in 13 healthy male volunteers who were extensive metabolizers of CYP2D6. The first period examined baseline CYP2D6 activity by evaluating the pharmacokinetics of a single dose of desipramine and by metabolic phenotyping with dextromethorphan. During the second period, participants took ritonavir, 100 mg twice daily, for 2 weeks, followed by repeat assessment of desipramine pharmacokinetics and the dextromethorphan metabolic phenotype in the presence of ritonavir. RESULTS: Low-dose ritonavir (100 mg twice daily) significantly increased the exposure to single-dose desipramine, as reflected in a geometric mean ratio (with ritonavir/without ritonavir) of 1.26 (95% confidence interval, 1.13-1.40) for the desipramine area under the concentration versus time curve from time 0 to infinity (P < .001). Coadministration of low-dose ritonavir did not significantly affect the dextromethorphan/dextrorphan urinary metabolic ratio and did not convert any extensive metabolizer to a poor metabolizer. CONCLUSIONS: Low-dose ritonavir (100 mg twice daily) exerts a modest inhibitory effect on the activity of CYP2D6 in extensive metabolizers, as assessed with desipramine as the index substrate. This effect was not apparent with the dextromethorphan/dextrorphan metabolic ratio as an indicator for CYP2D6 activity. It is expected that the effect of low-dose ritonavir on CYP2D6 will not require standard dose reductions for CYP2D6 substrates.

Improving the process of antibiotic therapy in daily practice: interventions to optimize timing, dosage adjustment to renal function, and switch therapy.

BACKGROUND: Timely administration of the first dose, dosage adjustment to renal function, switch from intravenous to oral administration, and streamlining are important aspects of rational antibiotic prescription. The goals of this study were to investigate all of these variables, compare them with predefined quality standards, and implement improvement with specific interventions. METHODS: At the departments of internal medicine, surgery, and neurology and the emergency department of a tertiary referral university medical center, all consecutive patients receiving therapeutic antibiotics were enrolled. Dosages, timing of first doses, dosing intervals, administration routes, and adjustment of the chosen drug to clinical data were investigated. After the preintervention period, barriers to change were identified, followed by specific interventions and a postintervention measurement. RESULTS: In the preintervention and postintervention periods, 247 and 250 patients were enrolled, receiving 563 and 598 antibiotic prescriptions, respectively. The mean time from the order to first dose at the wards improved from 2.7 to 1.7 hours in potentially severe cases (P =.003). Dosage adjustment to renal function remained unchanged at 45% vs 52% (P =.09) of cases where necessary. Switching of therapy from intravenous to oral improved from 46% to 62% (P =.03) and was performed a mean of 1.6 days earlier (P =.002). Streamlining was performed correctly in most cases, and thus no interventions were necessary. CONCLUSIONS: Timing of antibiotic therapy and switch therapy may be improved with a combination of interventions. To improve poor adjustment of dosing to renal function, other strategies are needed. In our setting, streamlining was already correct in most cases.

Authors' response to the letter from Kalleian Eserian et al.

This letter is a response to the comments of Kalleian Eserian et al. on our study relating to the accuracy, precision and sustainability of six tablet splitters and a kitchen knife as an alternative to breaking paracetamol 500mg tablets by hand. We would like to inform the readers of International Journal of Pharmaceutics that our study focused on splitting tablets with a mechanical tool rather than breaking tablets by hand. Although publications on hand breaking tablets were not cited for this reason, we are familiar with the conclusions of these publications. This is especially true for the publications that were written by direct colleagues from the department of the corresponding author e.g., Van Santen et al. and Van der Steen et al.

Ephedrine as add-on therapy for patients with myasthenia gravis: protocol for a series of randomised, placebo-controlled n-of-1 trials.

INTRODUCTION: Myasthenia gravis (MG), a rare neuromuscular disease, is often initially treated using acetylcholinesterase inhibitors. Patients who do not respond adequately depend on the use of corticosteroids or other immunosuppressive medication, but these may have serious side effects. Clinical observations suggest that ephedrine can diminish, postpone or even prevent the need for immunosuppressive therapy when added to acetylcholinesterase inhibitors or low-dose prednisone. In the Netherlands, ephedrine is not licensed for MG nor is reimbursement guaranteed. MG is a rare condition, and ephedrine might be indicated only in a subset of patients. Thus, randomised controlled trials comparing large groups are difficult to conduct. We, therefore, aim to aggregate data from a small series of n-of-1 trials (also known as single patient trials) to assess the effect of ephedrine as add-on treatment for MG. METHODS AND ANALYSIS: Single-centre, placebo-controlled, double-blind, randomised, multiple crossover n-of-1 studies in 4 adult patients with generalised MG who show inadequate improvement on pyridostigmine and/or immunosuppressive drugs. Each n-of-1 trial has 3 cycles of two 5-day intervention periods. TREATMENT: 25 mg ephedrine or placebo, twice daily. MAIN OUTCOME MEASURE: Quantitative Myasthenia Gravis (QMG) test. STATISTICAL ANALYSIS: fixed effects linear model for QMG for all patients combined. SECONDARY OUTCOME MEASURES: Clinical: effects on MG-Composite and MG-Activities of Daily Living (MG-ADL) scales; QMG at individual level; adverse events. Acceptability of trial design: number of patients eligible and enrolled; number of treatment cycles completed; patients' and caregivers' experiences. ETHICS AND DISSEMINATION: This study was approved by the Medical Ethics Committee of Leiden University Medical Center, No. P14.108. Results of the trial will be reported in a peer-reviewed publication. Regulatory stakeholders will comment on the suitability of the trial for market authorisation and reimbursement purposes. TRIAL REGISTRATION NUMBER: This study is registered under EudraCT number 2014-001355-23, protocol no. 40960, V.1.0, registration date 27 March 2014.

The influence of efavirenz on the pharmacokinetics of a twice-daily combination of indinavir and low-dose ritonavir in healthy volunteers.

OBJECTIVE: This study evaluated the effect of multiple-dose efavirenz on the steady-state pharmacokinetics of the combination of indinavir (800 mg) and low-dose ritonavir (100 mg) twice a day, in which ritonavir is used to increase indinavir plasma concentrations. METHODS: Eighteen healthy male volunteers participated in this multiple-dose, 1-arm, 2-period interaction study. They took a combination of 800 mg indinavir and 100 mg ritonavir with food for 15 days. From days 15 to 29, a once-daily administration of 600 mg efavirenz was added to the combination. Pharmacokinetics of indinavir and ritonavir on days 15 and 29 were compared. RESULTS: Fourteen volunteers completed the study. The addition of efavirenz resulted in significant reductions (P <.01) in indinavir area under the curve (AUC, -25%), trough concentration (C(min), -50%), and maximum concentration (C(max), -17%). All indinavir C(min) levels on day 29 remained equivalent to or above the mean C(min) value described for the regimen of 800 mg indinavir three times a day, without ritonavir (0.15 mg/L). Changes in ritonavir AUC, C(min), and C(max) were -36%, -39%, and -34%, respectively. Pharmacokinetics of efavirenz on day 29 were comparable with published data. CONCLUSIONS: The addition of efavirenz to a combination of 800 mg indinavir and 100 mg ritonavir twice daily results in significant decreases in AUC, C(max), and especially C(min) of indinavir. The dose of indinavir or ritonavir should be increased to maintain similar indinavir drug levels after addition of efavirenz to the indinavir-ritonavir combination. Dose modifications may not be needed in antiretroviral-naive human immunodeficiency virus-infected patients if the reference C(min) of the regimen of 800 mg indinavir 3 times a day is considered to be adequate.

Administration of indinavir and low-dose ritonavir (800/100 mg twice daily) with food reduces nephrotoxic peak plasma levels of indinavir.

BACKGROUND: The objective of this study was to compare indinavir peak plasma (Cmax) values after administration of indinavir/ritonavir 800/100 mg on an empty stomach or with food. High indinavir Cmax values have been associated with indinavir-related nephrotoxicity. METHODS: This was an open-label, randomized, two-treatment, two-period, cross-over pharmacokinetic study performed at steady state. HIV-infected patients who had been using indinavir/ritonavir 800/100 mg twice daily for at least 4 weeks were randomized to take this combination with a light breakfast (two filled rolls and 130 ml of fluid) on a first study day, and without food on a second day, or in the reverse order. The pharmacokinetics of indinavir and ritonavir were assessed after plasma and urine sampling during 12 h. RESULTS: Data for nine patients were evaluated. Administration of indinavir/ritonavir 800/100 mg on an empty stomach resulted in a higher indinavir Cmax [geometric mean (GM) ratio - fasting/fed and 95% confidence interval (CI): 1.28 (1.08-1.52), P=0.01] and a trend to a shorter indinavir tmax (P=0.07) compared to administration with food. The mode of administration of indinavir/ritonavir did not affect plasma indinavir Cmax and AUC values, parameters that have been associated with the antiviral efficacy of indinavir, nor the urinary excretion of indinavir. CONCLUSIONS: Administration of indinavir/ritonavir 800/100 mg on an empty stomach results in a higher indinavir Cmax compared to ingestion with a light meal. Stated the other way round, intake with a light meal reduces indinavir Cmax, which probably reflects a food-induced delay in the absorption of indinavir. It is recommended to administer indinavir/ritonavir 800/100 mg with food, as a possible means to prevent indinavir-related nephrotoxicity in patients who start or continue with this regimen.

Therapeutic drug monitoring: an aid to optimising response to antiretroviral drugs?

Therapeutic drug monitoring (TDM) has been proposed as a means to optimise response to highly active antiretroviral therapy (HAART) in HIV infection. Protease inhibitors (PIs) and the non-nucleoside reverse transcriptase inhibitors (NNRTIs) efavirenz and nevirapine satisfy many criteria for TDM. Nucleoside reverse transcriptase inhibitors (NRTIs) are not suitable candidates for TDM, since no clear plasma concentration-effect relationships have been established for these drugs. Several important limitations to the application of TDM for antiretroviral drugs should be recognised, including uncertainty about the best pharmacokinetic predictor of response and insufficient validation of target concentrations for individual PIs and NNRTIs. Data from two clinical trials support the use of TDM in treatment-naive HIV-infected patients who start with an indinavir- or nelfinavir-based regimen. TDM either prevented virological failures (presumably by preventing the development of resistance) or treatment discontinuations due to concentration-related toxicity. Application of routine TDM in other patient groups (treatment-experienced patients) or for drugs other than indinavir or nelfinavir (NNRTIs, other PIs, combination of PIs) is speculative at this moment. However, TDM can be used in selected patient groups (children, pregnant women, patients with renal or hepatic dysfunction) to confirm adequate drug concentrations, and for management of drug-drug interactions.TDM in treatment-experienced patients may be optimally used in conjunction with resistance testing. The integration of pharmacological and virological measures in the inhibitory quotient (IQ) needs to be standardised and elaborated further. TDM should be accompanied by careful assessment of adherence and can itself help identify non-adherence, although a drug concentration only reflects the last few drug doses taken by a patient. Additional clinical trials are needed before routine TDM can be adopted as standard of care in the treatment of HIV infection.

The accuracy, precision and sustainability of different techniques for tablet subdivision: breaking by hand and the use of tablet splitters or a kitchen knife.

INTRODUCTION: Tablets are frequently subdivided to lower the dose, to facilitate swallowing by e.g. children or older people or to save costs. Splitting devices are commonly used when hand breaking is difficult or painful. METHODS: Three techniques for tablet subdivision were investigated: hand breaking, tablet splitter, kitchen knife. A best case drug (paracetamol), tablet (round, flat, uncoated, 500 mg) and operator (24-year student) were applied. Hundred tablets were subdivided by hand and by three devices of each of the following types: Fit & Healthy, Health Care Logistics, Lifetime, PillAid, PillTool, Pilomat tablet splitter; Blokker kitchen knife. The intra and inter device accuracy, precision and sustainability were investigated. The compliance to (adapted) regulatory requirements was investigated also. RESULTS: The accuracy and precision of hand broken tablets was 104/97% resp. 2.8/3.2% (one part per tablet considered; parts right/left side operator). The right/left accuracies of the splitting devices varied between 60 and 133%; the precisions 4.0 and 29.6%. The devices did not deteriorate over 100-fold use. Only hand broken tablets complied with all regulatory requirements. CONCLUSION: Health care professionals should realize that tablet splitting may result in inaccurate dosing. Authorities should undertake appropriate measures to assure good function of tablet splitters and, where feasible, to reduce the need for their use.

Controlled release of morphine from a poloxamer 407 gel.

Treatment of painful ulcers is discouraging. Topical morphine has been described as a useful therapeutic adjunct in some patients. In the development of a new analgesic product, we studied the in vitro release characteristics of a new topical formulation containing 0.5% (w/w) morphine-HCl in a poloxamer 407 (P407) based gel. A diffusion cell was used for measurement of in vitro release characteristics. The donor compartment (DC) and the receptor compartment (RC) were separated by a 5000 Da cellulose acetate membrane. The morphine-HCl release from this developed P407 based gel followed zero-order kinetics with a constant release of 150 µg cm(-2)h(-1). Our results support the use of this P407 gel as a sustained release topical formulation in the pharmacological treatment of painful ulcers. Future research welcomes a formulation with release characteristics leading to less frequent application.

[Pitfalls in the treatment of neuropathic pain in patients with cancer]. / Valkuilen in de behandeling van neuropathische pijn bij patiënten met kanker.

Three patients with cancer experienced severe side-effects after starting anti-neuropathic pain therapy. All patients, 1 woman and 2 men aged between 69 and 71, fell or had problems with balance. These side-effects diminished after reducing the doses or stopping the medication. It seems that side-effects in patients with cancer are more common and more severe than in other populations with neuropathic pain, such as patients with diabetic neuropathy or postherpetic neuralgia. There is little research into the treatment of neuropathic pain in patients with cancer. In this patient group it is advisable to monitor the patient at least once a week for an optimal treatment and to prevent severe side-effects, especially in the first weeks after starting the treatment.

Adherence rates and associations with nonadherence in patients with rheumatoid arthritis using disease modifying antirheumatic drugs.

OBJECTIVE: Nonadherence in patients with rheumatoid arthritis (RA) using disease modifying antirheumatic drugs (DMARD) may result in unnecessarily high levels of disease activity and function loss. The aim of this descriptive study was to assess adherence rates with self-report measures in a large random population, and to identify potential risk factors for nonadherence. METHODS: A randomly selected sample of 228 patients with RA using DMARD was invited for a standardised interview. For each medicine, the patients were asked about adherence, consumption and perceived (side) effects. After the interview, the patients received self-report questionnaires to assess adherence [Compliance Questionnaire on Rheumatology (CQR) and the Medication Adherence Scale (MARS)], coping, beliefs about medicines, satisfaction about medicine information, and physical functioning. Subsequently, associations between adherence and demographics, clinical characteristics, and patient attitudes were examined. RESULTS: Depending on the instrument used, 68% (CQR) and 60% (MARS) of the patients were adherent to DMARD. Nonadherence was not associated with demographic and clinical characteristics, satisfaction about information, medication concerns, and coping styles. The disease duration, the number of perceived side-effects, and beliefs about the necessity of the medicine were weakly associated with adherence. CONCLUSION: In this large study with a random RA population, 32%-40% of the patients did not adhere to their DMARD prescription. As none of the possible risk factors was strongly related to adherence, no general risk factor seems to be powerful enough as a possible screening tool or target for adherence-improving interventions. This implies that nonadherence barriers should be assessed on an individual basis.

A cost-effectiveness decision model for antiepileptic drug treatment in newly diagnosed epilepsy patients.

OBJECTIVE: To establish cost-effectiveness of antiepileptic drug (AED) treatment strategies of newly diagnosed patients with epilepsy. METHODS: A decision analysis was carried out comparing effectiveness and treatment cost of six treatment strategies comprising carbamazepine (CBZ), lamotrigine (LTG), and valproate (VPA) as first-line and second-line drugs. Three outcome groups were defined: complete success, partial success, and failure. Data on seizure control and failure due to adverse effects were derived from the literature. Data on resource use and costs were collected for each outcome group by means of a patient survey. RESULTS: Cost data were obtained from 71 patients. Cost increased from complete success to failure outcome groups. The probability of obtaining complete success varied from 64% (VPA-CBZ strategy) to 74% (LTG-VPA strategy). The strategy LTG-VPA was more effective than the least expensive strategy CBZ-VPA, but at higher costs per additional effectively treated patient. Probabilistic sensitivity analysis confirmed these findings to be robust. Subsequent analysis showed that changing inclusion criteria used in the selection of the studies from the literature had a major effect on cost-effectiveness ratios of the various strategies. The probability that LTG first-line therapy is the most cost-effective option remains small, even defining a high cost-effectiveness threshold. Nevertheless, LTG second-line strategies can be cost-effective depending on the willingness to pay for patient improvement. CONCLUSIONS: Only a few studies satisfied our inclusion criteria for employment in our decision model. Our model supports the use of conventional AEDs as first-line options for patients with newly diagnosed epilepsy. LTG second-line therapy is likely to be the most cost-effective option in case society is willing to pay more than Euro 6000 for an additional successfully treated patient. This study also illustrates that, with the data presently available, the outcome of decision analysis for AED treatment choice depends on the inclusion criteria used to select trials. Prospective real-life studies are needed in which first- and second-line treatment strategies are compared with respect to both effectiveness and costs.