The efficacy and safety of bucillamine as a second-line DMARD in the treatment of rheumatoid arthritis: a retrospective cohort study

Abstract

We investigated the efficacy and safety of bucillamine administered as a second-line DMARD compared to administration as a first-line DMARD in the treatment of rheumatoid arthritis (RA). We conducted a retrospective cohort study and reviewed medical records of 86 patients with active RA who began to receive bucillamine at Yokohama Minami Kyosai Hospital between January 1998 and July 2004. The efficacy of treatments was compared based on rates of achievement of 20, 50, and 70% improvement in ACR core set 6 months after initiation of the therapy. In the group administered bucillamine as a first-line DMARD (18 patients), 44.4, 22.2, and 11.1% of patients achieved ACR 20, 50, 70, respectively, while 56.5, 34.1, and 19.5% achieved ACR 20, 50, 70, respectively, in the group administered bucillamine following switching from MTX (46 patients), and 53.3, 33.3, and 13.3% achieved ACR 20, 50, and 70, respectively, in the group administered bucillamine following switching from Sulfasalazine (SSZ) (15 patients). The rates of achievements of ACR 20, 50, 70 did not differ statistically between the three groups and there was no increase in risk of serious adverse effects related to previous DMARDs. The usefulness of bucillamine as a second-line DMARD was demonstrated.     

Biosimilarity for Follow-on Biologics

With dramatic increased spending on biologics and approaching patent expirations for existing biological products, there is a need to consolidate thinking on the regulatory approval pathway of biosimilars. However, biologics have much greater complexity by nature. The traditional paradigm currently used for generic chemical drugs, where bioequivalence is the focus, cannot be extrapolated to biologics. In the biosimilars scenario, the comparability of pharmacokinetic and pharmacodynamic parameters, and the comparability of efficacy and safety from clinical trials are the keys for the success of follow-on biologics. Developing sensitive bioanalytical methods to detect small, meaningful differences is critical. This article proposes a novel reference-scaled method to evaluate the comparability of pharmacokinetics parameters, and illustrates the method using a study comparing a test drug to a reference drug in a cancer study.     

Patients Have Treatment Preferences: A Multicentre,Double-blind,Crossover Study Comparing Rabeprazole and Omeprazole

Summary

It is increasingly common practice to change patients from one medication in a drug class to another, often as part of a general formulary change. The underlying assumption and accepted wisdom is that all compounds within a class are identical. To our knowledge, there has been no published investigation into the patients' views on such changes or on the individual medications. These views may be affected by positive side-effects, not normally sought in clinical trials, as well as negative side-effects, which are always reported. The objectives of this study were to determine whether patients whose primary symptoms were already controlled by a proton pump inhibitor (PPI) could distinguish between rabeprazole and omeprazole; to determine the incidence of positive, as well as negative, side-effects; to elicit patients' opinions on changing medication within a class, and on the importance of certain characteristics of medication. The design was a double-blind, double-dummy, randomised, crossover trial, set in five general practice research centres in the UK and Ireland. 240 eligible patients were randomised to receive daily treatment, first for 4 weeks with omeprazole 20mg/day, and then for 4 weeks with rabeprazole 20mg/day, or in the reverse order. Each phase of 4 weeks was separately assessed by patients through questionnaires and by non-directed questioning about positive and negative side-effects. At the end of the 8 weeks, patients compared the two medications in seven treatment characteristics. Patients were further asked their attitude to changing medication within a class. Data were collected by a web-based electronic data capture system. Results showed that the majority of patients could be switched to another PPI therapy, predictably without noticeable difference in maintenance of primary symptom control. About one-quarter to one-half of patients were able to express a preference for one or other of the treatments dependent on the variable assessed. For 'absence of unwanted side-effects' and 'presence of positive side-effects' a statistically significant difference in favour of rabeprazole was detected (p?=?0.0467 and p?=?0.0188, respectively). In terms of the total treatment preference score, the primary outcome variable, there was no statistically significant difference between the two PPIs (p?=?0.0754). This finding is mainly attributable to the two PPIs providing similar relief of primary symptoms, as expected. These three scores mask the findings for the other variables assessed. However, there were numerically more patients (10 vs. 3) who reported 'marked' positive side-effects on rabeprazole. On direct questioning, patients indicated that tablets (rabeprazole) were more easily swallowed than capsules (omeprazole) (p?<?0.0001), but less easily handled than capsules (p?=?0.0003). These analyses may however have been confounded by the fact that the omeprazole medication had to be over-encapsulated to allow blinding for this double-dummy, blinded study. There was no difference in tolerability between rabeprazole and omeprazole, with 52.6% and 51% of patients reporting at least one adverse event, respectively. Of the patients controlled and maintained on omeprazole before the study, 33.9% reported adverse events on omeprazole during the study and seven discontinued the study for that reason. Patients thought the most important drug characteristics for treating this condition were rapid and lasting control of pain. Most (83.6%) would be willing to try an alternative medication within a drug class. In conclusion, most patients already controlled by a PPI would be willing to try another. An individual patient may have a strong preference for one PPI over another, and this difference may be important if treatment is to be long term.     

Developmental changes in lateralized inhibition of symmetric movements in children with and without Developmental Coordination Disorder

The present study investigates developmental changes in selective inhibition of symmetric movements with a lateralized switching task from bimanual to unimanual tapping in typically developing (TD) children and with Developmental Coordination Disorder (DCD) from 7 to 10 years old. Twelve right-handed TD children and twelve gender-matched children with DCD and probable DCD produce a motor switching task in which they have (1) to synchronize with the beat of an auditory metronome to produce bimanual symmetrical tapping and (2) to selectively inhibit their left finger's tapping while continuing their right finger's tapping and conversely. We assess (1) the development of the capacity to inhibit the stopping finger (number of supplementary taps after the stopping instruction) and (2) the development of the capacity to maintain the continuing finger (changes in the mean tempo and its variability for the continuing finger's tapping) and (3) the evolution of performance through trials. Results indicate that (1) TD children present an age-related increase in the capacity to inhibit and to maintain the left finger's tapping, (2) DCD exhibits persistent difficulties to inhibit the left finger's tapping, and (3) both groups improve their capacity to inhibit the left finger's movements through trials. In conclusion, the lateralized switching task provides a simple and fine tool to reveal differences in selective inhibition of symmetric movements in TD children and children with DCD. More theoretically, the specific improvement in selective inhibition of the left finger suggests a progressive development of inter-hemispheric communication during typical development that is absent or delayed in children with DCD.     

Clinical and economic issues associated with switching between triptans in clinical practice

ABSTRACT

Seven oral triptans are now generally available for the acute treatment of migraine, and physicians may sometimes feel under pressure to switch patients from one triptan to another for non-clinical reasons. This commentary article provides advice on what information should be taken into account by the physician before they consider switching one triptan for another.

We review recommendations on switching triptans from international guidelines for migraine management and relate these to data from a recently published study on the economic implications of switching triptans in the UK. Controlled clinical studies reveal that most of the oral triptans have broadly similar efficacy profiles. Switching triptans can therefore only be recommended if the patient experiences problems such as lack of efficacy or intolerable side effects following repeated use of the initial triptan. The retrospective database study revealed that most patients who had their triptan switched were subsequently switched again during a 15 month review period, most usually back to their original triptan. Overall, switching a patient's triptan led to increased costs (analysed as costs of medication and the GP consultation) to the healthcare provider.

These data indicate that patients should only be switched from one triptan for another for clinical reasons and not for perceived economic reasons, i.e. cost of the medication.     

Contrasting baseline-dependent effects of amphetamine,chlorpromazine and scopolamine on response switching in the pigeon

Both amphetamine and scopolamine increase low rates and reduce high rates of responding. It has been suggested that the dependence of the effects of these drugs on control rate may be due to their non-specific disruptive cue properties rather than to specific pharmacological actions. To examine whether this possible non-specific disruption also applied to response-choice, pigeons were trained under a schedule in which 30 key-peck responses were required. This fixed-ratio could be completed by responding in any order on either or both of two keys, and then the first switch between the two keys was reinforced by the presentation of food. Under control conditions, the probability of the birds switching between the keys increased as the ratio progressed, resulting in performance which could be analysed in a manner analogous to rate-dependent analyses of responding under fixed-interval (FI) schedules. The birds were then treated with amphetamine (0.4–3.2 mg/kg), chlorpromazine (1.0–30 mg/kg) and scopolamine (0.01–0.10 mg/kg). Amphetamine increased switching at all baselines, to probabilities greater than chance (i.e.P. switch >0.5). Scopolamine resulted in response choice converging towards chance, whereas chlorpromazine reduced switching when the baseline probabilities were high. Thus: i) amphetamine increases switching in pigeons as it has previously been shown to do in rats, and this effect is not due to regression towards random choice, ii) the opposite effect of a reduction in switching can occur after chlorpromazine treatment, and iii) whereas the effects of amphetamine and scopolamine on response rate may be similar, the effects of the two drugs on response choice are dissociable, with only scopolamine resulting in a randomisation of performance.     

普通变异型免疫缺陷症的Ig类别及其亚类转换障碍——Ⅰ:体外观察

采用美洲商陆(PWM)或EB病毒(EBV)体外诱导26例常见变异型免疫缺陷病(CVI)外周血淋巴细胞产生免疫球蛋白(Ig)及其亚类的能力,结果显示所有病例均不能产生全部Ig及其亚类     

Tratamiento de la psoriasis en placas moderada a grave con fármacos biológicos: análisis del sobrecoste de la intensificación temporal frente a cambio a otro biológico en caso de fracaso secundario

IntroductionIn the event of failure of maintenance therapy with biologic agents for moderate to severe plaque psoriasis, the possible approaches are to switch to another agent or escalate the dose (generally by increased dosing frequency). Knowledge of the economic impact of the 2 alternatives would be extremely useful for therapeutic decision making.ObjectiveThe present analysis aimed to determine the moment in which the annualized additional cost of escalation exceeds a specified cost overrun.Materials and methodsBased on the purchase cost (average wholesale price) of approved biologics for the treatment of moderate to severe psoriasis, the number of weeks of escalation of the initial biologic until the annualized cost of dose escalation ran €1000 over the cost of switching to another biologic was calculated for a typical patient weighing 80 kg.ResultsAccording to this model, switching to another biologic is always cost effective, with adalimumab followed by ustekinumab the best choices in this respect. Ustekinumab allows for a longer trial escalation period (2 to 4 injections) before the cost overrun threshold is reached, whereas the threshold is reached in a single infusion if a patient is on infliximab.ConclusionThe study does not take into account the differential efficacy of the various biologic therapies as rescue treatment for failure of maintenance therapy given the lack of scientific evidence. The results nevertheless show substantial differences in the period during which treatment can be intensified before reaching the preset cost overrun.     

Expression of Activation-Induced Cytidine Deaminase Gene in B Lymphocytes of Patients with Common Variable Immunodeficiency

Objective

Common variable immunodeficiency (CVID) is a heterogeneous disorder characterized by reduced serum level of IgG, IgA or IgM and recurrent bacterial infections. Class switch recombination (CSR) as a critical process in immunoglobulin production is defective in a group of CVID patients. Activation-induced cytidine deaminase (AID) protein is an important molecule involving CSR process. The aim of this study was to investigate the AID gene mRNA production in a group of CVID patients indicating possible role of this molecule in this disorder.

Methods

Peripheral blood mononuclear cells (PBMC) of 29 CVID patients and 21 healthy controls were isolated and stimulated by CD40L and IL-4 to induce AID gene expression. After 5 days AID gene mRNA production was investigated by real time polymerase chain reaction.

Findings

AID gene was expressed in all of the studied patients. However the mean density of extracted AID mRNA showed higher level in CVID patients (230.95±103.04 ng/ml) rather than controls (210.00±44.72 ng/ml; P=0.5). CVID cases with lower level of AID had decreased total level of IgE (P=0.04) and stimulated IgE production (P=0.02); while cases with increased level of AID presented higher level of IgA (P=0.04) and numbers of B cells (P=0.02) and autoimmune disease (P=0.02).

Conclusion

Different levels of AID gene expression may have important roles in dysregulation of immune system and final clinical presentation in CVID patients. Therefore investigating the expression of AID gene can help in classifying CVID patients.