Nabumetone: new preparation. Just another NSAID

(1) Nabumetone is a nonsteroidal antiinflammatory drug recently marketed in France. It has been available in other countries for about 15 years. Its licensed indications cover chronic inflammatory rheumatism and osteoarthritis. (2) The clinical file is bulky, but available trials in chronic inflammatory rheumatism involve only rheumatoid arthritis. (3) In rheumatoid arthritis (4 trials) and osteoarthritis (11 trials), nabumetone was no more effective than other nonsteroidal antiinflammatory drugs with which it was compared. (4) Clinical trial data, pharmacovigilance surveys and epidemiological studies suggest that nabumetone is among the antiinflammatory drugs with the least gastrointestinal adverse effects, but it has not yet been shown that they are less frequent than those of diclofenac, etodolac, ibuprofen or sulindac.     

Open-label extension studies: do they provide meaningful information on the safety of new drugs?

The number of open-label extension studies being performed has increased enormously in recent years. Often it is difficult to differentiate between these extension studies and the double-blind, controlled studies that preceded them. If undertaken primarily to gather more patient-years of exposure to the new drug in order to understand and gain confidence in its safety profile, open-label extension studies can play a useful and legitimate role in drug development and therapeutics. However, this can only occur if the open-label extension study is designed, executed, analysed and reported competently. Most of the value accrued in open-label extension studies is gained from a refinement in the perception of the expected incidence of adverse effects that have most likely already been identified as part of the preclinical and clinical trial programme. We still have to rely heavily on post-marketing safety surveillance systems to alert us to type B (unpredictable) adverse reactions because open-label extension studies are unlikely to provide useful information about these types of often serious and relatively rare adverse reactions. Random allocation into test and control groups is needed to produce precise incidence data on pharmacologically expected, or type A, adverse effects. Some increased confidence about incidence rates might result from the open-label extension study; however, as these studies are essentially uncontrolled and biased, the data are not of great value. Other benefits have been proposed to be gained from open-label extension studies. These include ongoing access to an effective but otherwise unobtainable medicine by the volunteers who participated in the phase III pivotal trials. However, there are unappreciated ethical issues about the appropriateness of enrolling patients whose response to previous treatment is uncertain, largely because treatment allocation in the preceding randomised, double-blind, controlled trial has not been revealed at the time of entry into the open-label extension study. Negative aspects of open-label extension studies revolve around their use as a marketing tool, as they build a market for the drug and generate pressure for subsidised access to the drug from consumers and their physicians. Consumers, institutions where these studies are conducted and research ethics committees need to be convinced of the motives, as well as the quality, of the open-label extension study and its execution before supporting such studies. Open-label extension studies do have a legitimate but limited place in the clinical development of new medicines. The negative perceptions about these studies have arisen because of perversion of acceptable rationales for this type of study and a failure to recognise (or disclose) the limitations resulting from the inherent weaknesses in their design. Increased human exposure to a new medicine under reasonably controlled circumstances to increase confidence in the safety of the medicine is an acceptable rationale for an open-label extension study, and a useful activity to increase the knowledge of the safety profile of a new medicine. However, this goal is increasingly being achieved by means other than open-label extension studies.     

On the Commonly Used Design and Statistical Considerations in Double Blind,Potentially Unblind,and Open‐Label Clinical Trials

In clinical trials, parallel group designs, such as placebo‐controlled trials or active‐controlled trials, are commonly used. The study design in comparative clinical trials to address the intended objective is vital to the interpretation of the trial results. If inappropriate study design are employed, they not only cannot answer the intended clinical hypothesis, but they can also impose adverse effects on the collection of efficacy and safety data that may further be compounded by observable and unobservable baseline data. Documentation and interpretation of the outcomes need to be carefully considered. It is well known that various sources of biases can arise during the course of the trial, for instance, design bias, operational bias, analytical bias, methodological bias, interpretation bias, and documentation bias. As a result of such biases, the accuracy and precision of the treatment effect estimate may be severely compromised, depending on the design considered. In this article, commonly used study designs for comparative clinical trials are described. Statistical considerations with various designs, the concept of robustness of statistical findings, and statistical evidence will be discussed in light of the blinding, potential unblinding, and open‐label designs.     

Benefit-risk analysis : a brief review and proposed quantitative approaches.

Given the current status of benefit-risk analysis as a largely qualitative method, two techniques for a quantitative synthesis of a drug's benefit and risk are proposed to allow a more objective approach. The recommended methods, relative-value adjusted number-needed-to-treat (RV-NNT) and its extension, minimum clinical efficacy (MCE) analysis, rely upon efficacy or effectiveness data, adverse event data and utility data from patients, describing their preferences for an outcome given potential risks. These methods, using hypothetical data for rheumatoid arthritis drugs, demonstrate that quantitative distinctions can be made between drugs which would better inform clinicians, drug regulators and patients about a drug's benefit-risk profile. If the number of patients needed to treat is less than the relative-value adjusted number-needed-to-harm in an RV-NNT analysis, patients are willing to undergo treatment with the experimental drug to derive a certain benefit knowing that they may be at risk for any of a series of potential adverse events. Similarly, the results of an MCE analysis allow for determining the worth of a new treatment relative to an older one, given not only the potential risks of adverse events and benefits that may be gained, but also by taking into account the risk of disease without any treatment. Quantitative methods of benefit-risk analysis have a place in the evaluative armamentarium of pharmacovigilance, especially those that incorporate patients' perspectives.     

Statistical Methods to Analyze Adverse Events Data of Randomized Clinical Trials

The adverse events data of randomized clinical trials are often analyzed based on either crude incidence rates or exposure-adjusted incidence rates. These rates do not adequately account for an individual patient's profile of adverse events over the study period when an individual may remain in the trial after experiencing one or more events (i.e., occurrence of multiple events of the same kind or different kinds). Moreover, the required statistical assumptions (e.g., constant hazard rate over time) for valid estimates of incidence rates are not likely to be met in practice by adverse events data of clinical trials. A nonparametric approach called the mean cumulative function (MCF) provides a valid statistical inference on recurrent adverse event profiles of drugs in randomized clinical trials. The estimate involves no assumptions about the form of MCF. To demonstrate the applicability and utility of the MCF approach in clinical trial datasets, an adverse event dataset obtained from a clinical trial is analyzed in this article. As compared to the crude or exposure-adjusted incidence rates of adverse events, the MCF estimates facilitate more understanding of safety profiles of a drug in a randomized clinical trial.     

Pinacidil. A review of its pharmacodynamic and pharmacokinetic properties, and therapeutic potential in the treatment of hypertension

Pinacidil is an orally administered antihypertensive drug that acts via direct relaxation of vascular smooth muscle to produce peripheral vasodilatation and a reduction in blood pressure without significant direct effects on cardiac electrophysiology. Pinacidil is unrelated to other antihypertensive drugs in clinical use, either in structure or mechanism of action. It belongs to a new class of agents called 'potassium channel openers' which act via potassium efflux to hyperpolarize cell membranes, indirectly causing a net reduction in intracellular calcium that leads to relaxation of vascular smooth muscle. Pinacidil is indicated in the management of essential hypertension. In clinical trials of up to 1 year duration, pinacidil administered twice daily in a controlled release capsule formulation has been shown to achieve adequate blood pressure control both in previously untreated patients and in those with blood pressure inadequately controlled by beta-adrenoceptor blocking drugs or thiazide diuretics. In long term (up to 1 year) comparative studies pinacidil was at least as effective as hydralazine, prazosin or nifedipine in maintaining blood pressure control. Pinacidil may also have a potential use in the treatment of patients with secondary renal hypertension. Clinical trials to date have usually allowed the addition of a thiazide diuretic and/or beta-adrenoceptor blocking drug to enhance the efficacy of pinacidil and/or to reduce the incidence of adverse effects. The main adverse effects of pinacidil treatment, which result from its peripheral vasodilator activity, are headache, oedema, palpitations and tachycardia. Although the overall incidence of adverse effects is quite high, they are usually mild, transient in nature and respond to a reduction in dose. Nevertheless, these effects may occasionally be severe, necessitating withdrawal from therapy. Thus, pinacidil is an effective antihypertensive drug for the treatment of mild to moderate essential hypertension. Despite its novel mechanism of action pinacidil causes adverse effects typical of peripheral vasodilators; during long term use with twice daily administration of the controlled release capsule formulation, the addition of a diuretic is often necessary to attenuate peripheral oedema and maintain adequate control of blood pressure. Further long term controlled trials are needed to determine the precise role of pinacidil relative to that of the angiotensin converting enzyme (ACE) inhibitors and calcium channel blocking drugs.     

Memantine: new preparation. Poor evaluation and uncertain benefit in Alzheimer's disease

(1) The standard treatment for mild to moderately severe Alzheimer's disease is donepezil, an anticholinesterase with some beneficial effects (progression is slowed in about 10% of patients, by six months on average) and mainly gastrointestinal adverse effects. (2) Memantine, a drug first developed several decades ago, belongs to the family of NMDA glutamate receptor inhibitors. Marketing authorisation was recently granted for memantine in moderately severe and severe Alzheimer's disease. (3) The clinical evaluation dossier on memantine is poor. Marketing approval was obtained thanks to only one placebo-controlled trial. It included only 252 patients treated for 28 weeks. Patients with moderately severe Alzheimer's disease were not analyzed separately from those with severe forms, even though the response criteria are different for the two categories of patients. (4) According to the chosen endpoint, 5% to 19% of patients were clinically improved by memantine. It is not known whether this benefit persists beyond six months. (5) The report of a trial comparing memantine + donepezil with placebo + donepezil does not analyse the response rate. Use of this combination is not currently justified. (6) In clinical trials the main adverse effects of memantine were neurological (dizziness and headache). Fairly lengthy pharmacovigilance data from Germany are relatively reassuring. (7) In practice, donepezil remains the reference option for moderately severe Alzheimer's disease. Memantine is a second-line option, as its adverse effects differ from those of anticholinesterases. There is still no drug offering a clear benefit for patients with severe forms of the disease.     

Patient compliance with drug therapy in schizophrenia. Economic and clinical issues

The effectiveness of drug treatment in clinical practice is considerably lower than the efficacy shown in controlled studies. The lower effectiveness in practice presumably leads to lower cost effectiveness of drug treatment in real-life situations compared with that demonstrated by studies based on results from controlled trials. Improved cost effectiveness in routine clinical practice would be a significant advantage in the treatment of schizophrenia, one of the most costly diseases in society. The aetiology of schizophrenia is unknown, and there is no cure. The main aims of therapy with antipsychotic medication include the effective relief of symptoms without the introduction of adverse effects or serious adverse events, improved quality of life, cost effectiveness and a positive long term outcome. The older classical antipsychotic drugs do not always meet these requirements because of their well-known limitations, such as a lack of response in a subgroup of individuals with schizophrenia and intolerable adverse effects. There has long been a need for new antipsychotics that can ameliorate more symptoms and have no or few adverse effects. Some of the recently introduced antipsychotics have been shown to be more effective in certain clinical situations and to have a more favourable adverse effect profile than the classical antipsychotics. A major factor contributing to the lower effectiveness of drug treatment is noncompliance, which may be very high in schizophrenia. There are several factors influencing compliance, including drug type and formulation, patient, disease status, physician, health care system, community care and family. There have been very few studies of compliance improvement strategies in schizophrenia or, indeed, in medicine in general. Current methods are relatively complex and there are differing opinions on their effectiveness. There are several ways to increase compliance in schizophrenia--the evidence is strongest for psychoeducative methods, changing to a new drug or using a depot formulation. However, considerably more research is needed in the field of compliance strategies.     

Statistical Monitoring of Safety in Clinical Trials

Appropriate monitoring of safety data during the conduct of a clinical trial can ensure timely alteration or termination of the trial to protect patients from potentially harmful treatment. Quantitative evaluation in safety monitoring is important for the study team and the data monitoring committee to make timely recommendations. This article provides an overview of statistical methods for monitoring a prespecified adverse event of interest in a single-arm or controlled clinical trial, including those described in the literature and two proposed methods following a general Bayesian framework using conjugate families. The implementation of statistical methods on safety monitoring is illustrated through clinical trial examples. Practical challenges and considerations are also discussed via simulation studies.     

Choice of NSAID and management strategy in rheumatoid arthritis and osteoarthritis. The impact on costs and outcomes in the UK

OBJECTIVE: Although nonsteroidal anti-inflammatory drugs (NSAIDs) are an effective therapy for rheumatoid arthritis, they are associated with significant adverse effects, the management of which imposes additional costs on the healthcare system. Prescribing NSAIDs which have a lower risk of major adverse effects as the first-line NSAID for patients with rheumatoid arthritis and osteoarthritis may be expected to lead to an improvement in clinical outcomes and reduce overall treatment costs. This analysis examines data from a published randomised controlled trial of 5 NSAIDs to explore these hypotheses. DESIGN AND SETTING: Data from a clinical trial comparing 5 NSAIDs were combined with published cost data to construct 2 clinical decision models, reflecting alternative approaches to the management of major and minor adverse effects in the UK. INTERVENTIONS: The 5 NSAIDs evaluated in the analysis were nabumetone, diclofenac, ibuprofen, piroxicam and naproxen, although only the results for ibuprofen and nabumetone are reported. MAIN OUTCOME MEASURES AND RESULTS: The total cost of care per patient receiving nabumetone was estimated to be between 25 pounds sterling (Pound) and 41 Pounds more expensive than ibuprofen. In a hypothetical cohort of 100,000 patients, there were between 690 and 821 more major adverse effects using ibuprofen than nabumetone. The cost per life-year gained (LYG) from using nabumetone rather than ibuprofen ranged between 1880 Pounds and 2517 Pounds (1995 values), depending upon the management of adverse effects. CONCLUSIONS: These results indicate that: (i) prescribing the newer, currently more expensive, NSAIDs will not necessarily lead to cost savings; (ii) the management of adverse effects can have a significant impact on costs; and (iii) the additional cost may be justifiable in terms of the mortality and morbidity gains associated with the new lower-risk NSAIDs.     

Developing a strategy for the nonclinical assessment of proarrhythmic risk of pharmaceuticals due to prolonged ventricular repolarization

The aspects for developing a strategy for the preclinical testing of drug candidates for proarrhythmic potential are presented. The rationale for such a strategy reflects primarily the needs for efficient and scientifically based drug development and also attempts to anticipate the possible outcomes of the currently ongoing regulatory activity (ICH S7b and E14). Whereas a wealth of new data have emerged over the past few years, demonstrating the utility of test systems for detecting drug effects on myocardial repolarization, the current regulatory trend appears to not use such data for the clinical trial design or risk assessment. Nevertheless, certain types of preclinical tests are highly recommended for optimizing drug development, despite their still questionable regulatory acceptance. This includes (1) testing for blockade of I(Kr) or hERG-mediated potassium current in heterologous cell systems, (2) measurement of effects on the myocardial action potential in vitro; and (3) assessment of effects on the ECG in a well-conducted in vivo study. Due to their requirement for little compound, the first two in vitro tests lend themselves for early safety testing of drug candidates still in the lead optimization phase of drug discovery; together, they form a useful and predictive in vitro assessment. This strategy is not new but reflects what was initially suggested by the Committee for Proprietary Medicinal Products (CPMP) some years ago. However, the validation of such a strategy and its utility in drug development is now well established and recommended, independent from future regulatory requirements.     

Association between prescribing of antimuscarinic drugs and antimuscarinic adverse effects in older people

Many commonly prescribed medications have antimuscarinic side effects. These can be severe and disabling, but it is not always possible to predict which patients will suffer these effects. The development of practical tools that predict the likelihood of adverse drug reactions would aid rational prescribing, thereby improving patient safety and outcomes. Avoiding predictable adverse drug reactions would also make significant cost savings. This paper discusses the current knowledge on the association between the prescribing of antimuscarinic drugs and adverse outcomes, and proposes novel ways to improve trial design, and data collection and interpretation in order to better identify those patients at the highest risk of antimuscarinic side effects.     

Association between prescribing of antimuscarinic drugs and antimuscarinic adverse effects in older people

Many commonly prescribed medications have antimuscarinic side effects. These can be severe and disabling, but it is not always possible to predict which patients will suffer these effects. The development of practical tools that predict the likelihood of adverse drug reactions would aid rational prescribing, thereby improving patient safety and outcomes. Avoiding predictable adverse drug reactions would also make significant cost savings. This paper discusses the current knowledge on the association between the prescribing of antimuscarinic drugs and adverse outcomes, and proposes novel ways to improve trial design, and data collection and interpretation in order to better identify those patients at the highest risk of antimuscarinic side effects.     

Can drugs or micronutrients prevent cataract?

Cataract is the major cause of blindness and of visual impairment worldwide, so its prevention is of the greatest importance. At present no drug therapy is licensed for use in the UK or the US, so the only treatment for cataract is by surgery, which is expensive and has adverse effects. This article reviews research on prevention of cataract by a variety of agents, including micronutrients as well as drugs. Benefits have been claimed for many compounds or mixtures and this review concentrates on those most extensively studied. Information on possible benefits of putative anticataract agents comes from a variety of approaches, from laboratory experiments, both in vitro and in vivo, to epidemiological studies in patients. Sorbitol-lowering drugs were the first to be examined systematically and progressed to clinical trials which were disappointing, and now the entire rationale for their use in prevention of cataract is questionable. Micronutrients showed little promise in animals but came to clinical trial in patients with cataract without the publication of any major benefit. Pantethine showed more promise in animal studies but the only clinical trial was abandoned early. A variety of laboratory and epidemiological evidence supports the benefits of aspirin-like drugs but there has been no trial specifically in patients with cataract. Add-on studies to trials of aspirin for other indications have not been encouraging. Research into other compounds is interesting but less advanced.     

注射用硫酸头孢噻利与头孢他啶治疗急性细菌性感染随机治疗临床研究

目的研究注射用头孢噻利治疗急性细菌性呼吸道和泌尿道感染的有效性和安全性。方法用双盲随机平行对照试验方法,以头孢他啶作为对照药。头孢噻利(127例)和头孢他啶(125例)均为每日2.0~4.0g,分2次静滴,疗程为7~14天。结果治疗后,2组总有效率分别为94.49%,92.00%;细菌清除率分别为96.26%,96.23%。药物不良反应发生率分别为5.43%,3.88%。结论注射用头孢噻利治疗急性细菌性呼吸道和泌尿道感染有效、安全,优于头孢他啶。     

Potential adverse effects of bronchodilators in the treatment of airways obstruction in older people: recommendations for prescribing

Asthma and chronic obstructive pulmonary disease (COPD) are common disorders that are associated with increasing morbidity and mortality in older people. Bronchodilators are used widely in patients with these conditions, but even when used in inhaled form can have systemic as well as local effects. Older people experience more adverse drug effects because of pharmacodynamic and pharmacokinetic changes and particularly drug-drug and drug-disease interactions. Cardiovascular disease is common in older people and beta-adrenoceptor agonists (beta-agonists) have inotropic and chronotropic effects that can increase arrhythmias and cardiomyopathy. They can also worsen or induce myocardial ischaemia and cause electrolyte disturbances that contribute to arrhythmias. Tremor is a well known distressing adverse effect of beta-agonist administration. Long-term beta-agonist use can be associated with tolerance, poor disease control, sudden life-threatening exacerbations and asthma-related deaths. Functional beta2-adrenoceptors are present in osteoblasts, and chronic use of beta-agonists has been implicated in osteoporosis. Inhaled anticholinergics are usually well tolerated but may cause dry mouth, which can be troublesome in older people. Pupillary dilatation, blurred vision and acute glaucoma can occur from escape of droplets from loosely fitting nebulizer masks. Although ECG changes have not been seen in randomized controlled trials of long-acting inhaled anticholinergics, supraventricular tachycardias have been observed in a 5-year randomized controlled trial of ipratropium bromide. Paradoxical bronchoconstriction can occur with inhaled anticholinergics as well as with beta-agonists, but tolerance has not been reported with anticholinergics. Anticholinergic drugs also cause central effects, most notably impairment of cognitive function, and these effects have been noted with inhaled agents. Use of theophylline is limited by its adverse effects, which range from commonly occurring gastrointestinal symptoms to palpitations, arrhythmias and reports of myocardial infarction. Seizures have been reported, but are rare. Theophylline is metabolized primarily by the liver, and commonly interacts with other medications. Its concentration in plasma should be monitored closely, especially in older people. Although many clinical trials have been conducted on bronchodilators in obstructive airways disease, the results of these clinical trials need to be interpreted with caution as older people are often under-represented and subjects with co-morbidities actively excluded from these trials.     

Ezetimibe: new preparation. A cholesterol-lowering drug with no clinical advantage

(1) Simvastatin and pravastatin are the drugs of choice for secondary or primary prevention of cardiovascular events in patients with hypercholesterolaemia. Both these statins have proven clinical efficacy. If statin therapy is inadequate, the dose can be increased or a drug combination can be tried, while keeping a lookout for adverse effects. (2) Ezetimibe is a cholesterol-lowering drug that is said to inhibit intestinal absorption of cholesterol and related phytosterols, while not affecting the uptake of other nutrients (unlike resins). (3) The clinical evaluation dossier contains no data from trials with relevant morbidity or mortality endpoints. Primary and secondary prevention were not studied separately. (4) In patients with hypercholesterolaemia, two placebo-controlled trials show that ezetimibe reduces total cholesterol concentration (by about 13%), and LDL-cholesterol (by about 18%). Its effects on HDL-cholesterol and triglyceride levels are at best moderate. It is not known whether these effects reduce mortality or prevent cardiovascular events. (5) Four trials tested initial combination therapy with a statin plus ezetimibe, in comparison with statin alone and ezetimibe alone. They showed an additive effect of the two drugs on LDL-cholesterol levels. Ezetimibe alone was no better than statin monotherapy. (6) A trial in patients who did not respond adequately to statin monotherapy showed that adding ezetimibe increased the number of patients whose LDL cholesterol level fell to a predetermined cutoff point. But the clinical relevance of this result is unknown. Two other trials have shown that, in this setting, adding ezetimibe to simvastatin or to atorvastatin increased the number of patients who reached the LDL-cholesterol cutoff relative to continued statin monotherapy at a higher dose. (7) In homozygous familial hypercholesterolaemia, high-dose statin and ezetimibe combination therapy reduced the LDL-cholesterol more effectively than high-dose statin alone. It is not known whether adding ezetimibe is more effective than LDL apheresis alone. (8) In homozygous familial sitosterolaemia, a very rare disorder due to increased absorption of dietary cholesterol and phytosterols, a placebo-controlled trial showed that ezetimibe had no significant impact on the absolute sitosterol value. (9) Comparative trials reported no major adverse effects associated with ezetimibe, but their duration (maximum three months) is too short to rule out long-term adverse effects. Initial pharmacovigilance reports cases of muscular and hepatic adverse effects. (10) In practice, ezetimibe has discernible effects in the laboratory. But the absence of data based on clinical endpoints and trials versus other cholesterol-lowering drugs with proven clinical benefits, together with the lack of information on possible long-term adverse effects, means ezetimibe must be evaluated more thoroughly before it can be recommended for routine use.     

麦考酚吗乙酯治疗肾病的临床疗效评价

目的：通过对麦考酚吗乙酯（MMF）治疗肾病的临床疗效进行评价，为临床合理应用提供依据。方法：通过目前可获得的临床观察结果（系统评价、Meta分析和随机对照试验）进行检索、收集、利用和评价，明确MMF应用于肾脏疾病的临床疗效。结果：各种系统评价、Meta分析和随机对照试验的结果虽不尽相同，但肯定有效，而且其不良反应均低于对照组。结论：MMF对治疗肾脏疾病（IgA肾病、狼疮肾炎、原发性肾病综合征）具有一定疗效，且不良反应少。但需要大规模多中心随机对照试验以及长期随访，才能进一步评价MMF在肾脏疾病应用的安全性和有效性。