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ABSTRACTIntroductionAntiseizure medications (ASMs) and antipsychotic drugs are frequently coadministered with the potential for drug-drug interactions. Interactions may either be pharmacokinetic or pharmacodynamic, resulting in a decrease or increase in efficacy and/or an increase or decrease in adverse effects.Areas coveredThe clinical evidence for pharmacokinetic and pharmacodynamic interactions between ASMs and antipsychotics is reviewed based on the results of a literature search in MEDLINE conducted in April 2023.Expert opinionThere is now extensive published evidence for the clinical importance of interactions between ASMs and antipsychotics. Enzyme-inducing ASMs can decrease blood concentrations of many of the antipsychotics. There is also evidence that enzyme-inhibiting ASMs can increase antipsychotic blood concentrations. Similarly, there is limited evidence showing that antipsychotic drugs may affect the blood concentrations of ASMs through pharmacokinetic interactions. There is less available evidence for pharmacodynamic interactions, but these can also be important, as can displacement from protein binding. The lack of published evidence for an interaction should not be interpreted as meaning that the given interaction does not occur; the evidence is building continually. There is no substitute for careful patient monitoring and sound clinical judgment.

ABSTRACTIntroductionLennox-Gastaut syndrome (LGS) is a severe childhood-onset epileptic encephalopathy, characterized by multiple seizure types, generalized slow spike-and-wave complexes in the EEG, and cognitive impairment. Seizures in LGS are typically resistant to treatment with antiseizure medications (ASMs). Tonic/atonic (‘drop’) seizures are of particular concern, due to their liability to cause physical injury.Areas coveredWe summarize evidence for current and emerging ASMs for the treatment of seizures in LGS. The review focuses on findings from randomized, double-blind, placebo-controlled trials (RDBCTs). For ASMs for which no double-blind trials were identified, lower quality evidence was considered. Novel pharmacological agents currently undergoing investigation for the treatment of LGS are also briefly discussed.Expert opinionEvidence from RDBCTs supports the use of cannabidiol, clobazam, felbamate, fenfluramine, lamotrigine, rufinamide, and topiramate as adjunct treatments for drop seizures. Percentage decreases in drop seizure frequency ranged from 68.3% with high-dose clobazam to 14.8% with topiramate. Valproate continues to be considered the first-line treatment, despite the absence of RDBCTs specifically in LGS. Most individuals with LGS will require treatment with multiple ASMs. Treatment decisions should be individualized and take into account adverse effects, comorbidities, general quality of life, and drug interactions, as well as individual efficacy.

ABSTRACTIntroductionExogenous melatonin is regulated as a drug in the UK and EU but is available as an over-the-counter dietary supplement in the US and Canada. In the last 15 years, melatonin use has increased rapidly in many countries, in particular, in children and adolescents who frequently have many years of continuous exposure. Despite this, the potential risks associated with extended use continue to be unclear, and there remains a lack of systematically assessed safety data from long-term prospective trials.Areas coveredThis review focuses on adverse event data reported in long-term (≥6 months) prospective trials of melatonin.MethodsThe Embase and Medline electronic databases were searched from inception to 12 September 2022 for long-term studies of melatonin, in which adverse events were systematically monitored and reported.Expert opinionAlthough the reported frequency of possible adverse events associated with long-term melatonin use is low and few clinically significant adverse events have been reported, the scarcity of data from double-blind randomized placebo-controlled trials should caution against complacency. Ideally, analysis of data from large well-established research databases should be conducted to provide good quality evidence on which to base a more rigorous evaluation of the safety profile.

Epilepsy and autism frequently co-occur. Epilepsy confers an increased risk of autism and autism confers an increased risk of epilepsy. Specific epilepsy syndromes, intellectual disability, and female gender present a particular risk of autism in individuals with epilepsy. Epilepsy and autism are likely to share common etiologies, which predispose individuals to either or both conditions. Genetic factors, metabolic disorders, mitochondrial disorders, and immune dysfunction all can be implicated.

Epilepsy and autism frequently co-occur. Epilepsy confers an increased risk of autism and autism confers an increased risk of epilepsy. Specific epilepsy syndromes, intellectual disability, and female gender present a particular risk of autism in individuals with epilepsy. Epilepsy and autism are likely to share common etiologies, which predispose individuals to either or both conditions. Genetic factors, metabolic disorders, mitochondrial disorders, and immune dysfunction all can be implicated.

Individuals with attention-deficit hyperactivity disorder (ADHD) are at increased risk of seizures. Stimulant medications such as methylphenidate are the most commonly prescribed treatment for ADHD, but the association between their therapeutic use and the risk of seizures is unclear. We aimed to investigate the association between methylphenidate treatment and the risk of seizure.

ABSTRACTIntroduction: Lennox-Gastaut syndrome (LGS) is a chronic, epileptic encephalopathy, characterized by multiple seizure types, distinctive slow spike-wave patterns in the electroencephalogram (EEG), and severe cognitive and behavioral comorbidities. Seizures are typically refractory and long-term prognosis is poor. No antiseizure drug (ASD) is fully effective as a monotherapy. Clobazam (CLB) was licensed in the United States in 2011 as an adjunctive therapy for seizures in LGS. In 2018, a new formulation, CLB oral soluble film (COSF) (AQST-120), was approved by the Federal Drug Administration (FDA) for the same indication.Areas covered: The authors summarize current pharmacological options and guidelines for the management of seizures in LGS and efficacy and safety findings from phase II and III randomized controlled trials of adjunctive CLB in patients with LGS. An open-label extension trial is also considered. A pharmacokinetic comparison of COSF and CLB tablets is also undertaken.Expert opinion: CLB is partly effective as an add-on therapy in treating seizures in LGS. Adverse effects, pharmacokinetic interactions and the potential for tolerance with long-term treatment should be weighed against the clinical benefit when considering the introduction of CLB in this population. COSF has a similar pharmacokinetic profile to CLB tablets and may help to improve adherence to treatment.

Data on baseline (antipsychotics-naïve) age, weight, and height, and change in these at 3 subsequent follow-up time points up to 313.6 days (95% CI 303.5–323.7) were collected from 181 risperidone-treated children and adolescents (mean age 12.58 years, SD 4.99, range 2.17–17.7) attending a pediatric neurology clinic in Saudi Arabia. Owing to differences in genotypic distributions in the subsamples, results are reported for the white Arab population (n= 144). Age- and gender-normed body mass index (BMI)-standardized zscores (BMI z) were calculated (LMSgrowth program). Linear regression was performed for baseline weight and BMI z, while change in BMI zwas assessed using random effects ordered logistic regression. The following single nucleotide polymorphisms (SNPs) were analyzed: rs7799039 in the LEPpromoter, rs1805094 (previously rs8179183), rs1137100 and rs1137101 in the LEPR, and rs1414334 in HTR2C. We found a nominally significant association between rs7799309 and baseline weight, adjusting for height, age, gender, and diagnosis (A/G, p= 0.035, β= –3.62 vs. G/G). The rs1137101 (G/G, p= 0.018, odds ratio [OR] = 4.13 vs. A/A) and rs1805094 C allele carriers (p= 0.019, OR = 0.51) showed nominally significant associations with change in BMI zcategories. Our data support and replicate previous relevant associations for these variants (including with weight gain when on risperidone), whilst being the first report of such associations in patients of Arab ethnicity.

Purpose: To determine whether lamotrigine affects serum concentrations of valproic acid. Methods: Pre-morning-dose serum valproic acid concentrations were measured in 76 subjects with epilepsy (48 M, 28 F, age range 6-20 years, mean age 14 years) in whom lamotrigine was added while the dose of valproate and other medication remained unchanged. In a comparison group, either acetazolamide or gabapentin was added to sodium valproate. Results: Far more subjects (26/7634) had an increase of >25 in valproic acid concentration with lamotrigine than those who had a decrease of >25 (4/765.3). The mean valproic acid concentration before starting lamotrigine was 61.0 mg/L and on lamotrigine was 67.1 mg/L; the difference in means was 6.1 mg/L (standard error 2.1, 95 confidence limits 2.0, 10.2, p0.004, highly significant, paired sample t-test, two-tailed), a rise of 10. The change in valproic acid concentration appeared to depend on the initial valproic acid concentration (Pearson r-0.405, p<0.001). In 14.5 of the subjects the increase in valproate concentration was >50, which could lead to toxicity, although the increase tended to occur with lower or intermediate initial valproic acid concentrations whereas a small overall decrease in valproic acid concentrations with lamotrigine was found with the higher initial valproic acid concentrations. One subject had abnormal bruising with the increased valproate level after lamotrigine was added, which resolved on decreasing the valproate dose. The changes in valproic acid concentrations in the comparison group were small (mean increase 2.6) and were not statistically significant. Conclusions: Although there is a wide variation in the changes of valproic acid concentrations when lamotrigine is added, the concentrations tend to increase rather than decrease, especially with low or intermediate initial valproic acid concentrations. In some cases valproate toxicity, manifested by abnormal bruising, may result, although at higher initial valproic acid concentrations the valproic acid concentration usually tends to fall slightly with the addition of lamotrigine.

Antiepileptic drugs (AEDs) have many benefits but also many side effects, including aggression, agitation, and irritability, in some patients with epilepsy. This article offers a comprehensive summary of current understanding of aggressive behaviors in patients with epilepsy, including an evidence-based review of aggression during AED treatment. Aggression is seen in a minority of people with epilepsy. It is rarely seizure related but is interictal, sometimes occurring as part of complex psychiatric and behavioral comorbidities, and it is sometimes associated with AED treatment. We review the common neurotransmitter systems and brain regions implicated in both epilepsy and aggression, including the GABA, glutamate, serotonin, dopamine, and noradrenaline systems and the hippocampus, amygdala, prefrontal cortex, anterior cingulate cortex, and temporal lobes. Few controlled clinical studies have used behavioral measures to specifically examine aggression with AEDs, and most evidence comes from adverse event reporting from clinical and observational studies. A systematic approach was used to identify relevant publications, and we present a comprehensive, evidence-based summary of available data surrounding aggression-related behaviors with each of the currently available AEDs in both adults and in children/adolescents with epilepsy. A psychiatric history and history of a propensity toward aggression/anger should routinely be sought from patients, family members, and carers; its presence does not preclude the use of any specific AEDs, but those most likely to be implicated in these behaviors should be used with caution in such cases.

Introduction:Lennox––Gastaut syndrome (LGS) is a severe treatment-resistant childhood-onset epilepsy. This review examines the role of the new drug rufinamide for the treatment of LGS.Areas covered:MEDLINE and Google Scholar searches were undertaken. The pharmaceutical company was contacted for the latest information. LGS is characterized by the triad of diffuse slow spike––wave discharges in the electroencephalogram (EEG), learning disability (mental retardation) and frequent generalized seizures of multiple types, usually including tonic, atonic and atypical absence seizures. Felbamate, lamotrigine and topiramate have resulted in significant reductions in some seizure types, but no treatment has achieved acceptable seizure control in most patients. In a pivotal randomized, double-blind, placebo-controlled trial, the new drug rufinamide achieved significant improvements in seizure control in previously resistant subjects when added to up to three concomitant antiepileptic drugs. Open studies including patients with LGS have also demonstrated efficacy. These trials and a large open trial in adults and adolescents with partial seizures have revealed no serious adverse effects so far. The most common adverse events were fatigue/somnolence and vomiting. Rufinamide is of value in decreasing seizure frequency in LGS, but seizure freedom is seldom achieved. Although no serious adverse effects have been identified, the limited data available at present allow no firm conclusions to be drawn with regard to safety.Expert opinion:The data support a role for rufinamide in treating LGS. However, more efforts are required to provide antiepileptic drugs for this treatment-resistant epilepsy syndrome. Rufinamide might also be of value in treating other forms of epilepsy.

At first sight the question: "Is current drug safety an issue?" might appear to be unnecessary. On one hand, it might be argued that drug safety is straightforward: all the physician has to do is to consult his formulary and he will have all the information he requires to use drugs safely. On the other hand, the major clinical, medicolegal and financial aspects of drug safety, together with the ever-increasing store of knowledge and the burgeoning of scientific methods applied to the subject, might be taken to imply that there is no question about the fact that drug safety remains an enormous issue...

INTRODUCTION At first sight the question: “Is current drug safety an issue?” might appear to be unnecessary. On one hand, it might be argued that drug safety is straightforward: all the physician has to do is to consult his formulary and he will have all the information he requires to use drugs safely. On the other hand, the major clinical, medicolegal and financial aspects of drug safety, together with the ever-increasing store of knowledge and the burgeoning of scientific methods applied to the subject, might be taken to imply that there is no question about the fact that drug safety remains an enormous issue. Lazarou et al. [1] estimated that 2,216,000 hospitalised patients had serious adverse drug reactions (ADRs) and 106,000 died in a single year in the USA. This implied that ADRs were a major cause of fatality, ranking between four and six in the list of most common causes of death. In a prospective UK study, Pirmohamed et al. [2] found that ADRs accounted for around 6.5 of hospital admissions, and 4 of the hospital bed capacity. They concluded that most ADRs were predictable from the known pharmacology of the drugs and many represented known interactions that were probably preventable. The overall mortality was 0.15. The projected annual cost to the National Health Service was £466 million or 847 million. These papers lead to some unavoidable conclusions. The cost in human terms is immeasurable. The cost in financial terms is very high. Many would consider that the situation is unacceptable. The need to take measures to reduce the distress, morbidity, mortality and cost of ADRs is compelling. What are the issues in the field of drug safety and how do they differ in the 21st century from those that were prevalent from the earliest times that medicinal preparations were used to treat an illness? Some of the issues are similar but others are very different. In particular, advances in genetics and other scientific methods hold great promise for avoiding, or at least reducing, ADRs. Some sceptics within the field of medicine, when speaking of genetics generally, would say that the geneticists claim to have all the answers, but not quite yet. There is, however, no denying that there have been extraordinary developments in this field as far as drug safety is concerned. A whole new vocabulary has developed, including terms such as: pharmacogenomics, theragenomics, toxicogenomics, chemogenomics, metabonomics, chemometrics, transcriptome analysis and many others. It is interesting and perhaps ironic to note that, despite all these advances, disasters in the testing of new drugs can still occur. A recent dramatic episode illustrated this all too well [3]. Eight healthy volunteers took part in the first human phase I trial of a monoclonal T cell agonist, TGN1412, intended to treat autoimmune and immunodeficiency disease. The trial took place in a unit at Northwick Park Hospital, London. The six men who received the active component rapidly developed very serious multisystem failure. There was grave concern that some of the men might not survive. The safety aspects of this trial will certainly have far-reaching consequences. A number of specific areas are worthy of attention when considering the area of drug safety. The following selection is not intended to be comprehensive but might give some indication of why drug safety remains such a major field of interest. Population and Individual Characteristics Some of the more obvious factors that need to be taken into account when prescribing medication include age, gender, race and comorbid medical conditions such as renal impairment. Lifestyle issues such as smoking, alcohol intake and diet can also affect drug metabolism to a great degree. There has been an increasing recognition of the importance of individual variation in factors such as the activity of certain isoenzymes, not only including the cytochrome P-450 family but also the UGT (uridine diphosphate glucuronosyltransferase) group. Some individuals appear to be remarkably resistant to medication and this has led to an interest in multidrug resistance (MDR) and the role of specific proteins such as P-glycoprotein (PGP) or MDR-1......

In April 2004, a group of physicians with an interest in nonconvulsive status epilepticus representing a spectrum of opinion met in Oxford, sponsored by the Epilepsy Research Foundation (a charitable organization), to discuss and debate the definition, diagnosis and treatment of nonconvulsive status epilepticus. We felt that such a meeting would be useful, as nonconvulsive status epilepticus is a subject that provokes strong reactions, perhaps largely due to the relative lack of evidence and the surfeit of opinion. The meeting was arranged such that there were formal talks followed by a discussion led by one of the attendees. We present here the extended abstracts of the main talks with the points raised by the discussants. Despite disagreements on certain issues there was much in the way of consensus. First, it was agreed that nonconvulsive status epilepticus is a term that covers a range of disparate conditions with varying prognoses and treatments. The agreed definition was thus suitably vague, «Nonconvulsive status epilepticus is a term used to denote a range of conditions in which electrographic seizure activity is prolonged and results in nonconvulsive clinical symptoms». Secondly, it was agreed that even within a specific condition (e.g.complex partial status epilepticus), the prognosis and treatment depends upon the context in which the condition occurs (e.g.in the critically ill, in coma, in the «walking wounded» and in people with prior epilepsy). Perhaps, most importantly it was agreed that we lacked good clinical data, and the challenge was to design good studies for a condition that is underrecognised and often difficult to diagnose.

The negative and positive effects of the nine newer antiepileptic drugs that have received a product licence in the UK or in the US are reviewed. The importance of avoiding misinterpretation of the data because of confounding factors such as alternative psychosis, the release phenomenon or drug interactions is emphasised. Vigabatrin has been associated with both psychosis and depression. Due to the concentric visual field defects that may occur with vigabatrin, its use is now limited, although it remains the drug of choice for infantile spasms. Lamotrigine seems to be largely associated with improvement rather than deterioration of mood and behaviour. It may have a role in treating affective disorder. Gabapentin probably has relatively little effect on behaviour but may exacerbate behavioural problems in some children with pre-existing difficulties. Topiramate may precipitate both psychosis and depression, but these are less likely to occur if the currently recommended lower starting doses, escalation rates and target doses are used. The data for tiagabine are limited, but there is no clear evidence for psychosis or depression being caused by this drug. Oxcarbazepine may be of value in treating mood disorder, but the information is very limited. There are few reports of behavioural disturbances with levetiracetam, but the data suggest that there is no significant increase in psychosis or depression. There are some reports of psychosis and other behavioural disturbances with felbamate, but the use of this drug is limited by the serious adverse effects of hepatotoxicity and aplastic anaemia. There is some evidence for psychosis with zonisamide, but there is also a suggestion that this drug may be of benefit in treating psychiatric disorders. Careful individual assessment of each patient should enable the clinician to determine whether the medication or some other factor is responsible for any behavioural disturbance.

The authors investigated whether methsuximide affects serum levels of valproic acid. Pre–morning-dose serum valproic acid levels were measured in 17 patients (12 male, 5 female; age range, 8–19; mean, 14.5 years) who either started or stopped taking methsuximide but whose dose of valproate and other medication remained unchanged. Four of these patients both started and stopped taking methsuximide. For the whole group the mean valproic acid level (± standard error) while not taking methsuximide was 81.9 ± 5.3 mg/L and while taking methsuximide was 55.7 ± 4.3 mg/L. The difference between the means was highly significant (paired ttest, p < 0.001). The mean valproic acid serum level before taking methsuximide was 85.4 ± 4.5 mg/L (14 patients), which decreased to 58.2 ± 4.8 mg/L while taking methsuximide (difference highly significant, p < 0.001). In the eight patients who stopped taking methsuximide the mean serum level increased from 49.8 ± 7.5 mg/L to 71.7 ± 8.5 mg/L (difference significant p 0.025). Because methsuximide reduces valproic acid serum levels, it may be necessary to increase the valproate dose when methsuximide is added or reduce the valproate dose when methsuximide therapy stops, to avoid loss of seizure control or valproate toxicity respectively.

A recently introduced optometric technique, colorimetry, enables the perceptual effects of ophthalmic tints to be evaluated subjectively, optimized, and then prescribed in tinted spectacles. The new technique is beneficial in reducing visual stress in patients with dyslexia and migraine. We describe an open trial designed to ascertain: (1) whether the colorimetry assessment, as it is now given, is safe for the investigation of photosensitive patients in optometry clinics where colorimetry equipment is most readily available, but where EEG control is not practical; (2) what proportion of patients with photosensitive epilepsy is likely to benefit to the extent already described in individual cases ; (3) whether a tint selected by colorimetry could be shown to reduce the incidence of paroxysmal epileptiform EEG activity in response to flicker and patterns, thereby validating the subjective methods and corroborating the reported seizure reduction. Twenty-four females and nine males (aged 12–43 years) took part. All the patients had suffered visually-provoked seizures, had exhibited a photoparoxysmal response on at least one previous EEG recording, and had received a diagnosis of photosensitive epilepsy. Twenty-two were currently experiencing seizures. A further EEG was recorded in all except seven cases: a routine resting record, followed by hyperventilation. Colorimetry was performed after hyperventilation and before photic stimulation. Twenty-three (70%) reported beneficial effects during colorimetry and were prescribed glasses. There was a preponderance of lenses with a rose or purple colour, in contrast to patients with dyslexia. Seventeen of the 23 patients were available at follow-up, an average of 2.4 years later. Thirteen (57%) reported benefits, and said they were still using the lenses. In six of the 13 the benefits were pronounced, including a reduction of dizziness from fluorescent lighting, elimination of aura when using computer screens etc. Only in three cases was there a reduction in seizures that could reasonably be attributed to the use of lenses; in two of these cases no medications were prescribed, and in the third the medications remained unchanged for four years, two before and two after the introduction of the glasses. In an additional four cases a reduction in seizures was observed but medication had been changed. There was a modest reduction in EEG photosensitivity with the coloured lenses but also to an equivalent or lesser extent with grey in all of the eight patients examined in this way. One patient had seizures during colorimetry, but the seizures were not accompanied by scalp EEG changes.

The opportunities for treating epilepsy have improved greatly over recent years because of advances in presurgical investigation and the availability of a number of new antiepileptic drugs. There is a growing awareness of the way in which medication can be used to maximum advantage, minimizing adverse effects, particularly in special groups such as those with learning disability. Genetics is beginning to show promise for the future in relation to the causes of epilepsy, the underlying mechanisms of the condition and the scientific basis for its treatment.

We describe modifications made to the Rivermead Behavioural Memory Test (RBMT) to make it appropriate for use with children. Results of a sample of 335 children aged 5 to 10 years, attending mainstream schools, are reported. Each child was given two of the four versions of the modified test for children together with a number of tests of memory and achievement from the Wechsler Intelligence Test for Children (Revised WISC-R), and the British Ability Scales (BAS). The children's version of the behavioural memory test (RBMTC) has good interrater and parallel form reliability. The validity of the RBMTC was established in two ways. First, with other tests of memory from the WISC and BAS. Second, a small (n = 36) group of children with severe epilepsy and memory difficulties, attending a residential school, were tested. The houseparents of these children were asked to complete rating scales on everyday memory performance. There was significant agreement between houseparents' observations and scores on the RBMTC (Spearman rank correlation = .71, p > 001), indicating that the test is indeed assessing everyday memory.

Chi square significance tests often overemphasize the strengths of relationships.

Convulsive status epilepticus is the most common neurological medical emergency and has high morbidity and mortality. Early treatment before admission to hospital is best with an effective medication that can be administered safely. We aimed to find out whether there are differences in efficacy and adverse events between buccal administration of liquid midazolam and rectal administration of liquid diazepam in the acute treatment of seizures.

Background: Bipolar disorder (BD) is a cyclic mood disorder characterised by alternating episodes of mania/hypomania and depression interspersed with euthymic periods. Lamotrigine (LTG) demonstrated some mood improvement in patients treated for epilepsy, leading to clinical studies in patients with BD and its eventual introduction as maintenance therapy for the prevention of depressive relapse in euthymic patients. Most current clinical guidelines include LTG as a recommended treatment option for the maintenance phase in adult BD, consistent with its global licencing status.Aims: To review the evidence for the efficacy and safety of LTG in the treatment of all phases of BD.Methods: PubMed was searched for double-blind, randomised, placebo-controlled trials using the keywords: LTG, Lamictal, ‘bipolar disorder’, ‘bipolar affective disorder’, ‘bipolar I’, ‘bipolar II’, cyclothymia, mania, manic, depression, depressive, ‘randomised controlled trial’, ‘randomised trial’, RCT and ‘placebo-controlled’ and corresponding MeSH terms. Eligible articles published in English were reviewed.Results: Thirteen studies were identified. The strongest evidence supports utility in the prevention of recurrence and relapse, particularly depressive relapse, in stabilised patients. Some evidence suggests efficacy in acute bipolar depression, but findings are inconsistent. There is little or no strong evidence in support of efficacy in acute mania, unipolar depression, or rapid-cycling BD. Few controlled trials have evaluated LTG in bipolar II or in paediatric patients. Indications for safety, tolerability and patient acceptability are relatively favourable, provided there is slow dose escalation to reduce the probability of skin rash.Conclusion: On the balance of efficacy and tolerability, LTG might be considered a first-line drug for BD, except for acute manic episodes or where rapid symptom control is required. In terms of efficacy alone, however, the evidence favours other medications.

Is drug safety dangerous? At first sight, this question might appear ludicrous. Some might even say that it is a contradiction in terms. However, there is a strong case for giving the question very serious consideration. Of course “drug safety” is not dangerous in itself. In general, however, the term is often taken to mean “information on drug safety”. It is used in this sense in at least three journals that include the words “drug safety” in their titles. It might be argued that there is a strong analogy between “drug safety” and the drugs themselves, in this context. In both cases, wise use can be beneficial and unwise use can be harmful. Examples of how the same drug could be used in a beneficial or harmful way were given in a previous editorial [1]. Two examples should suffice to illustrate this point. The misuse of heroin (diamorphine) could be viewed as one of the major scourges of our society. Diamorphine is, however, one of the most useful drugs that doctors have at their disposal; it has improved the quality of life of countless patients with terminal cancer, not to mention those who would otherwise be in agony from the pain of myocardial infarction. One of the most toxic substances known to man is botulinum toxin. There are many beneficial effects of this drug; of course it is best known for use in the cosmetic field but it is also of major benefit in relieving spasticity, treating drooling in patients with uncontrolled salivation and in treating embarrassing/incapacitating conditions such as blepharospasm. These examples illustrate that a drug that could be viewed as being dangerous or even evil if used unwisely can be of major benefit if it is used with properly and well. Can an analogous argument be put forward for information on drug safety? The beneficial effects of good-quality information on drug safety would not be disputed. Are there the adverse or harmful effects? A number of examples follow. Many years ago, a temporal association between the pertussis (whooping cough) immunisation and West syndrome (infantile spasms), a serious syndrome of childhood epilepsy, was reported [2]. The seizures occurred soon after the immunisation. There appeared to be a clear relationship between the immunisation and the seizures. Many professionals would have considered the causal link to be unquestionable. This led to a reluctance to having babies immunised against pertussis. Whooping cough can be a devastating condition in young children. It can be very distressing. It can even be life-threatening. There would need to be a very strong argument for reluctance to immunising against it. On the face of it, that strong argument existed with the apparent association described. A careful assessment showed that there was, indeed, an increase in the number of babies with infantile spasms soon after the immunisation but, in those who were immunised, there was a below-expected incidence in the next time period [3]. The rise in cases soon after the immunisation was exactly equal to the fall in cases in the next time period, confirming that the immunisation did not actually cause infantile spasms, it simply brought them forward in time. However, as a result of the “scare” many young children were exposed to a very distressing and, in some cases, dangerous infection. The drug safety information had a major harmful effect. A more recent and infamous example is the reported association between the MMR immunisation and autism [4]........

Should patients with epilepsy be monitored during sleep to prevent sudden unexpected death in epilepsy (SUDEP)? The study by van der Lende et al.1provides additional evidence that the answer is probably yes in certain populations. These investigators compared the incidence of SUDEP at 2 residential centers for adults with severe epilepsy (>90% had convulsive seizures, and ∼50% were on ≥3 antiepileptic drugs). The center with less intensive nocturnal monitoring had a nearly 3-fold higher SUDEP incidence that was not explained by other factors (e.g., seizure severity). Sadly, despite monitoring, supervision, and expert care at both centers, the SUDEP rate remained 2- to 5-fold greater than population-based studies of patients with epilepsy. Unlike some other case-control studies, the incidence of SUDEP was higher among individuals with higher IQ and less benzodiazepine use.

It could be argued that the primary aim of drug safety investigations is to determine factors related to the frequency and severity of adverse effects so as to minimise them. Second only to efficacy, adverse effects of the drug are of major importance. Both patients and clinicians are keen to know about adverse effects before deciding whether the benefits of taking any drug outweigh the potential risks. However, adverse effects are not always easy to determine. In this context it is very important to distinguish between adverse effects, adverse events and side-effects. Some working in the field of drug safety might consider it quite unnecessary to discuss the difference between these terms but regrettably, many papers offered to scientific journals do not use the terminology in a scientifically correct way. How are these terms defined? Wikipedia [1] provides the following definitions. “‘Side effect’ can mean: a ‘therapeutic effect’, an unintended but desirable consequence of medical treatment or an ‘adverse effect’, an unintended and undesirable consequence of medical treatment or an adverse drug reaction, such an effect caused by a drug.” In relation to adverse effects of drugs, the term “adverse drug reaction” is equivalent to “adverse effect”. The broader term “adverse event” is sometimes restricted to clinical trials but there is no reason why this should be the case. How are adverse effects to be distinguished from adverse events? Consider the following hypothetical situation. After a baseline evaluation period of one month, a new drug is prescribed to a group of patients for a further month. In this trial patients act as their own controls. The drug is, accordingly, withdrawn for one month to determine whether any adverse events during the treatment period were genuinely associated with the drug or simply occurred by chance. The entire group has an adverse event that potentially affects quality of life in a major way and which was not present in the baseline period nor in the subsequent period after the drug had been stopped. Some might argue that there is no doubt whatever that this major adverse event was an adverse effect, since the patients were acting as their own controls and the adverse event was not experienced before or after the drug was taken. However, if the major adverse event was that none of them was able to fly in an aeroplane during the drug treatment, they all resided in the UK and the period during which they were treated happened to coincide with the volcanic eruption in Iceland that grounded all aircraft, it is immediately clear that the major adverse event was certainly not an adverse effect of the drug. This simple hypothetical example is intended to illustrate that adverse events are not necessarily adverse effects, even if there appears to be quite strong evidence suggesting that they might be. Drug trials can provide good data on adverse events but seldom provide good data on adverse effects. The determination of whether an adverse event is an adverse effect depends on a number of factors. If an adverse event occurs with a statistically significantly higher frequency in the treatment group than in the placebo group in well-designed, randomised, double-blind, placebo-controlled trial on well-matched groups of patients there is a stronger basis for judging it to be an adverse effect rather than a chance association or the result of some confounding issue. However, other factors will also influence the assessment of whether an adverse event is an adverse effect. The time relation to the prescription of the drug may be important, although it should be noted that some adverse effects may not appear until the drug has been taken for several weeks or, indeed, for years [2]. If an adverse event otherwise occurs rarely but is consistently associated with a particular drug, then it becomes much more plausible to consider that it might be an adverse effect of the drug. This introduces the concept of “plausibility” but it would be unwise to over-emphasise the role of plausibility without a strong basis for doing so. For example, if a drug is found to be associated with a higher rate of road traffic accidents in drivers this might not immediately appear to be a plausible association but the possibility that the medication concerned might be affecting judgement or impulsivity would have to be considered. On the other hand, if a particular drug were associated with an increased risk of being killed by lightning, the plausibility of a causal association would be very low and, in that case, the adverse event would be unlikely to be an adverse effect. Pharmacovigilance provides a very important means of collecting drug safety data, particularly with regard to rarer adverse events. However, it is again important to distinguish between adverse events, which may be associated with taking a drug, from adverse effects that are the result of taking that drug. Patients treated for depression with selective serotonin reuptake inhibitors (SSRIs) are at increased risk of having seizures. If a group of people in the general population, matched for age, sex, educational status and other factors is compared with a group of people taking SSRIs, the second group would have more seizures. This clearly demonstrates that SSRIs are associated with seizures. However, it does not demonstrate that SSRIs cause seizures. One of the commonest indications for SSRIs is depression, which is a major risk factor for seizures. The wrong choice of comparison groups has been made; if a group of depressed people treated with placebo is compared with a group of depressed people treated with SSRIs, the latter group has less not more seizures, suggesting that, far from precipitating seizures, SSRIs may protect against them [3]. Again, very careful evaluation needs to be made before drawing any conclusions with regard to causality. The term “side effect” can refer to any effect, either beneficial or harmful, of the drug other than on the condition or symptom that is the target indication for that drug. One of the prime examples of a drug that had a notable side effect which was not considered to be an adverse effect is sildenafil citrate (Viagra) [4]. This was initially prescribed to treat angina but was found to have a side effect that some of the patients considered to be beneficial. It has subsequently attracted a major market for what was originally considered to a side effect. Other side-effects are used intentionally by prescribers in certain situations. For example, weight loss, which can occur with the antiepileptic drug topiramate [5], may be considered to be either an adverse effect or a beneficial effect, depending on the patient. The patient who is overweight might choose this drug in preference to sodium valproate [6], which can be associated with weight gain. Some antiepileptic drugs can also have beneficial or adverse effects on mental state. For example, carbamazepine and valproate are viewed as mood-levelling drugs [7] and, in addition to their use in psychiatric patients who do not have epilepsy, they might be chosen to improve seizure control in a patient with epilepsy who also had a mood disorder, in preference to the drug such as topiramate, which is associated with depression. Should these beneficial effects still be considered as “side effects” or should they be viewed as a secondary indication for prescribing the chosen medication? .......

As is the case for most drugs, vigabatrin (VGB) has major advantages and also has significant adverse effects. However, the situation for VGB is somewhat unusual. The drug was prescribed for many years before Eke et al. [1] reported peripheral visual field defects (VFDs) in three adult patients. Other adverse effects [2], including psychiatric changes and transient MRI abnormalities have been reported but will not be discussed here. VFDs appear to be common, having been found in 25 to 50 of adult patients taking VGB [2]. Although the VFDs are asymptomatic in most patients [3, 4], this must be viewed as a serious adverse effect. For example, those with horizontal visual fields less than 120° are not permitted to hold a driving licence. Visual acuity is not usually affected and, although those with VFDs retain an average lateral visual field of 65° [5] (i.e., 130° horizontal), sometimes the visual field constriction may be severe [3]. There is debate about whether the VFDs are reversible [6, 7] but a number of reports have suggested that they are not [8, 9]. Does the emergence of this frequent, serious, and possibly irreversible adverse effect imply that VGB should no longer be prescribed or should be withdrawn from the market? The recent FDA approval would suggest that this is certainly not the case. What is the justification for the availability of this drug? VGB is almost unique in having an apparently single, intended mode of action, namely inhibition of GABA-transaminase, the enzyme that breaks down the inhibitory neurotransmitter GABA, with result that GABA concentrations in the brain are increased. It can be of benefit in treating partial-onset seizures in some patients for whom no other drug has been effective. VGB also has a major role to play in the treatment of infantile spasms, a very severe form of epilepsy with a high risk of poor outcome, both in terms of ongoing seizures and in terms of significant cognitive impairment [10]. If the infantile spasms are secondary to tuberous sclerosis, VGB appears to be particularly effective; in the initial studies 100 of the babies became spasm free [11]. In subsequent studies the response rate has been less but has remained very high. The other effective treatment for infantile spasms is ACTH or steroids, which can be also associated with serious adverse effects [10]. How is the clinician to weigh the risk of the serious adverse effect of VFDs against the possible advantage of good seizure control? In the case of partial-onset seizures, the decision-making process might be easier because the advantages and disadvantages can usually be discussed directly with the patient, who can then make an informed decision. However, this is not always the case. One of my patients was a wheelchair-bound teenager with severe learning disability (mental retardation) and severe epilepsy, in whom good seizure control had been achieved with VGB. Another clinician stopped the VGB because of concerns about the possibility of VFDs. If this patient had developed visual field constriction, it would almost certainly not affected his quality of life, which was much more severely impaired by his other problems and which was certainly very severely decreased when the uncontrolled seizures returned. After consultation with his carers, the VGB was re-instituted, with a good response. The remainder of the discussion will concentrate on infantile spasms because the situation with this severe form of epilepsy is very different. Because the onset is typically around 4 to 9 months of age, it is up to the parents or carers to decide on treatment, in discussion with the clinician. Concerns about possible VFDs may weigh heavily with parents. They might also have difficulty in appreciating what the implications of this possible adverse effect could be for their child. What guidance can be given? To answer this question, further information is required. Perhaps the best way of considering this situation is to ask a series of additional questions. Several of these issues are discussed in the excellent review by Willmore et al. [2]. Have visual field defects been described in children who took VGB for infantile spasms as infants? What is the minimum period or minimum dose of VGB that has resulted in apparently permanent visual field defects? If the VGB is stopped at the first sign of VFDs, will this adverse effect be less than it would have been if the VGB had been continued? Is there any evidence that treating infantile spasms promptly and effectively changes prognosis, particularly with regard to cognitive outcome? Which is superior in treating infantile spasms, VGB or ACTH/steroids; should different treatments be favoured in different circumstances?

Thalidomide is the most notorious example of a drug with serious adverse effects [1] that was initially declared to be safe [2]. This disastrous episode had a major influence on the stringency of pharmaceutical regulation and had a similarly great effect on what could be advertised legally. However, the same stringency does not seem to apply to scientific journals reporting on the safety of drugs. Investigators are allowed to state, in reputable peer-reviewed journals, that a drug is “safe” when they do not have the justification for doing so. Some examples follow. These are from the field of antiepileptic medication but similar examples could be drawn from a number of other therapeutic areas. It must be emphasised that the examples given are from publications in very reputable journals by highly-respected colleagues; the quality of the work is not being criticised but we are advocating a change in terminology and attitude. Felbamate is a broad-spectrum antiepileptic drug that was granted marketing approval in the USA in 1993. The initial publications stated, in good faith, that the drug was safe [3]. The problem is that the statement on safety was based on a trial of only 56 patients treated over a few weeks. Subsequently the potentially life-threatening adverse effects of liver toxicity and aplastic anaemia emerged [4, 5], with the result that the drug is now infrequently prescribed. Vigabatrin was said to be “a safe drug for the treatment of partial seizures” [6]. In 1997, the same year that the first report of serious visual field defects with vigabatrin was published [7], another report stated: “vigabatrin has been shown through several studies to be safe and effective” [8]. Prescribing fell sharply after this adverse effect was reported [9]. Buccal midazolam is now the standard emergency treatment for seizures in paediatric practice in the UK. A very valuable and informative study published in the Lancet, one of the most reputable international medical journals, showed that buccal midazolam was statistically significantly superior to rectal diazepam in the emergency room treatment of status epilepticus in children [10]. This was a landmark paper but why did the authors also conclude, on the basis of only 109 children, that this treatment was safe? It must be emphasised that there is no evidence to contradict this statement but there is also inadequate evidence to support it. If a drug is safe in about 100 patients the mortality rate might still prove to be unacceptably high when information from larger numbers of patients becomes available. It is reassuring to know that no such data of concern have emerged with regard to buccal midazolam but it could be argued that the original statement claiming safety for this treatment was, nevertheless, unjustified. Physicians and patients need to know how safe a drug is but the evidence seems to indicate that we might never be able to declare that a drug is truly “safe”. Infrequent serious adverse effects, including mortality, might not become evident until the drug has been used for several years. We strongly advocate a change in both terminology and attitude. Arguably, to refer to a drug as “safe” is the reassuring terminology of marketing, not of science. Scientific method requires observation and “a safe drug” is not a variable that can be observed. We have many important pre-clinical experiments that look for specific toxicities. In clinical studies we can compare reported adverse events in drug-treated and placebo-treated participants. However, we have no scientific experiment that can prove that a drug is safe. With post-marketing pharmacovigilance, generalisations are made about the tolerability and adverse-event profile of a drug based on a large number of exposures. Conclusions can be proposed about the likelihood of adverse events. However, these conclusions remain probabilities, which may be very unlikely for some drugs, but are never certainties. Journals should refuse to publish papers that claim to have established the safety of a drug on the basis of treatment of a few hundred patients or less. Instead they should insist that authors make more accurate statements. The term “safe” may not be appropriate to describe a drug in scientific writing.“Well tolerated” is more appropriate terminology as it refers to an observation rather than suggesting an inherent characteristic of the drug. For example, instead of “This drug appeared to be safe in the treatment of epilepsy in the 550 patients included in clinical trials” authors should write “This drug was well tolerated in the treatment of epilepsy in the 550 patients included in clinical trials”. If the number of patient years of treatment is large, typically over 100,000, and if this experience is spread over several years, it might be justifiable to state that extensive experience has revealed no serious adverse effects, implying that these are very unlikely to occur. Pharmaceutical companies should also state clearly what the percentage risks of serious adverse effects are, so that the relative safety can be assessed. For example, if an anti-cancer drug increases short-term mortality from 5% to 10% but decreases longterm mortality from 80% to 30%, the patient and physician might still want to give this drug serious consideration. Clinicians prescribing medication have a duty to their patients to provide accurate information so that informed decisions can be made with regard to be risk and benefit. However, they cannot provide this information if they do not have it. The most reliable source of information is generally considered to be reputable peer-reviewed journals. We recommend that journals should not accept unqualified statements about the safety of a drug but should insist that the limitations of the data, particularly with regard to the number of patients treated and the duration of the treatment, should always be specified.

Thalidomide is the most notorious example of a drug with serious adverse effects [1] that was initially declared to be safe [2]. This disastrous episode had a major influence on the stringency of pharmaceutical regulation and had a similarly great effect on what could be advertised legally. However, the same stringency does not seem to apply to scientific journals reporting on the safety of drugs. Investigators are allowed to state, in reputable peer-reviewed journals, that a drug is “safe” when they do not have the justification for doing so. Some examples follow. These are from the field of antiepileptic medication but similar examples could be drawn from a number of other therapeutic areas. It must be emphasised that the examples given are from publications in very reputable journals by highly-respected colleagues; the quality of the work is not being criticised but we are advocating a change in terminology and attitude. Felbamate is a broad-spectrum antiepileptic drug that was granted marketing approval in the USA in 1993. The initial publications stated, in good faith, that the drug was safe [3]. The problem is that the statement on safety was based on a trial of only 56 patients treated over a few weeks. Subsequently the potentially life-threatening adverse effects of liver toxicity and aplastic anaemia emerged [4, 5], with the result that the drug is now infrequently prescribed. Vigabatrin was said to be “a safe drug for the treatment of partial seizures” [6]. In 1997, the same year that the first report of serious visual field defects with vigabatrin was published [7], another report stated: “vigabatrin has been shown through several studies to be safe and effective” [8]. Prescribing fell sharply after this adverse effect was reported [9]. Buccal midazolam is now the standard emergency treatment for seizures in paediatric practice in the UK. A very valuable and informative study published in the Lancet, one of the most reputable international medical journals, showed that buccal midazolam was statistically significantly superior to rectal diazepam in the emergency room treatment of status epilepticus in children [10]. This was a landmark paper but why did the authors also conclude, on the basis of only 109 children, that this treatment was safe? It must be emphasised that there is no evidence to contradict this statement but there is also inadequate evidence to support it. If a drug is safe in about 100 patients the mortality rate might still prove to be unacceptably high when information from larger numbers of patients becomes available. It is reassuring to know that no such data of concern have emerged with regard to buccal midazolam but it could be argued that the original statement claiming safety for this treatment was, nevertheless, unjustified. Physicians and patients need to know how safe a drug is but the evidence seems to indicate that we might never be able to declare that a drug is truly “safe”. Infrequent serious adverse effects, including mortality, might not become evident until the drug has been used for several years. We strongly advocate a change in both terminology and attitude. Arguably, to refer to a drug as “safe” is the reassuring terminology of marketing, not of science. Scientific method requires observation and “a safe drug” is not a variable that can be observed. We have many important pre-clinical experiments that look for specific toxicities. In clinical studies we can compare reported adverse events in drug-treated and placebo-treated participants. However, we have no scientific experiment that can prove that a drug is safe. With post-marketing pharmacovigilance, generalisations are made about the tolerability and adverse-event profile of a drug based on a large number of exposures. Conclusions can be proposed about the likelihood of adverse events. However, these conclusions remain probabilities, which may be very unlikely for some drugs, but are never certainties. Journals should refuse to publish papers that claim to have established the safety of a drug on the basis of treatment of a few hundred patients or less. Instead they should insist that authors make more accurate statements. The term “safe” may not be appropriate to describe a drug in scientific writing.“Well tolerated” is more appropriate terminology as it refers to an observation rather than suggesting an inherent characteristic of the drug. For example, instead of “This drug appeared to be safe in the treatment of epilepsy in the 550 patients included in clinical trials” authors should write “This drug was well tolerated in the treatment of epilepsy in the 550 patients included in clinical trials”. If the number of patient years of treatment is large, typically over 100,000, and if this experience is spread over several years, it might be justifiable to state that extensive experience has revealed no serious adverse effects, implying that these are very unlikely to occur. Pharmaceutical companies should also state clearly what the percentage risks of serious adverse effects are, so that the relative safety can be assessed. For example, if an anti-cancer drug increases short-term mortality from 5 to 10 but decreases longterm mortality from 80 to 30, the patient and physician might still want to give this drug serious consideration. Clinicians prescribing medication have a duty to their patients to provide accurate information so that informed decisions can be made with regard to be risk and benefit. However, they cannot provide this information if they do not have it. The most reliable source of information is generally considered to be reputable peer-reviewed journals. We recommend that journals should not accept unqualified statements about the safety of a drug but should insist that the limitations of the data, particularly with regard to the number of patients treated and the duration of the treatment, should always be specified.

In this issue of Current Drug Safety, there is a single case report of topiramate-induced epistaxis in a 36 year old woman who was being treated for migraine [1]. The dose was increased gradually to 100 mg over one month. 35 days after starting the topiramate and five days after having been on the dose of 100 mg she had repeated prolonged epistaxis. The epistaxis resolved within 12 hours of discontinuing the topiramate. Page et al. [2] previously reported a 61 year old woman treated with topiramate 25 mg daily for lower limb neuropathy. Seven days after starting treatment she had severe epistaxis lasting 8 days, requiring emergency treatment. The epistaxis resolved one week after the topiramate was stopped. Three months later the topiramate was recommenced and she again developed intractable epistaxis. She was treated with two units of packed red cells. One week after stopping the topiramate, for a second time, the epistaxis stopped. She had no subsequent recurrence. No other cases could be located in the literature, although Page et al. have pointed out that epistaxis was reported on 1-4% of patients receiving topiramate in clinical trials. It has been suggested that topiramate might affect platelet function through modulation of L type calcium ion channels.

If the man in the street were to be asked this question, his response might well be as follows. “Of course it must be serious. Is your question a serious one?” It seems self-evident that suicidality must be taken seriously. However, like many things that appear to be self-evident, the seriousness of the concept of suicidality should be questioned. The first step in trying to answer the question posed in the title of this editorial must be to define the concept of “suicidality”. The “Wiktionary” (web-based dictionary) defines suicidality as “the tendency of a person to commit suicide” or “a fatality that is an instance of suicide”. The Oxford English dictionary defines suicidality as “the quality or condition of being suicidal”. Do these terms accurately reflect the meaning of the word “suicidality” as used in the medical literature? It would appear that the answer is, emphatically, no. A commonly used definition in the medical literature is “suicidal acts or ideation”. Silverman et al. use the operational definition “considered suicide, attempted suicide” [1]. In a review of the reported link between suicidality and the use of SSRIs, we defined the term as “suicidal ideation, self-harm and suicide attempt” [2]. In other papers, suicidality is not defined but, by implication, it appears to be defined as “suicidal ideation, intent or attempt”. Are these definitions simply too broad to be of practical use? Suicidal ideation might include anything from a transient thought that life is not worth living to a persistent determination to end life with a clear plan, using a means that is very likely to be effective, such as jumping off a high building. Similarly, suicide attempt might cover anything from being seen in an accident and emergency department for having taken more than the recommended dose of aspirin through to shooting oneself in the head with non-fatal consequences. Most people who make apparent suicidal gestures do not seriously wish to end their lives but instead want to draw attention to their difficult predicament. Should this situation be classified as “suicide attempt” or should another term, such as “deliberate self-harm” be preferred? The problem with the term “deliberate self-harm” is that it would normally include a much wider variety of behaviours, for example, self-cutting, that are carried out with no intention of suicide.

Assuming no experience with computing, this book teaches the BASIC language with an emphasis on programming educational applications. Part of the two-volume Computer Literacy for Teachersset, the major advantage of this book is that each topic is presented in the context of practical applications. The clear, concise, unintimidating approach allows users to begin programming early and effectively. Overall, the book is a good place for the beginning user to begin to acquire skills in BASIC. (Reviewed by Manuel Frau-Ramos, University of Puerto Rico, Rio Piedras.)

Most researchers and academics in drug safety focus their work on the toxicity and side-effect profiles of pharmacologically active agents. As a professional group, we have become experts at screening drug candidates for potential to cause harm to biological systems or potential to interact adversely with other therapeutic agents. We are vigilant in documenting adverse events through all phases of clinical trials and post-marketing. We constantly refine our screening techniques, making use of the latest available technologies. Consequently, in many fields of medicine the newer drugs have significantly more benign adverse-effect profiles than their predecessors. The public expects safer drugs and new research is delivering them. Nevertheless, maintaining drug safety continues to be a difficult challenge. Discussions about drug safety with our colleagues in the regulatory authorities suggest that most of their time is spent not dealing with issues of drug toxicity but is instead spent dealing with issues of negligence and error. These are issues that we, as researchers and clinicians, rarely consider. From reports to US health authorities in January 2008, one of the most serious recent challenges for drug safety was recognised when some patients undergoing dialysis were found to have acute hypersensitivity reactions, subsequently associated with the contamination of heparin-containing products with oversulfated chondroitin sulphate (OSCS), an impurity that is structurally similar to heparin [1]. Clusters of patients had been having such reactions from November 2007. The symptoms included, lowered blood pressure, facial swelling, tachycardia, urticaria and nausea. By April 2008, 81 deaths associated with contaminated heparin had been reported. Adverse effects of OSCS-contaminated heparin have been demonstrated in rodent and swine models, confirming a reduction in diastolic pressure with administration and that the effect is dependant both on dose and route of administration [2]. Contaminated heparin products have been found in Australia, Canada, China, Denmark, France, Germany, Italy, Japan, The Netherlands, New Zealand and the United States. The source of the contamination was traced to a manufacturing facility in Changzhou, China, which was inspected by investigators from the US Food and Drug Administration in February 2008. Many inadequacies were reported with the facility itself, as well with suppliers of crude materials to the facility [3]. It is still unclear whether the contamination was accidental or due to replacing the correct raw materials with a cheaper substitute. The impact of the contaminated heparin problem continued throughout 2008. As late as May, new recall notices were being issued for products, including heparin-coated thoracic drainage catheters and some devices used in cardiac surgery. The example of heparin contamination highlights numerous problems for drug safety. The increasingly global nature of the pharmaceutical industry means that errors can be on a larger scale, more difficult to regulate and harder to track to their source. Industry purchases from networks of manufacturers, each of which has a further network of corporations and suppliers. Each supplier and manufacturer has to comply with its own local laws and regulations as well those of the country where its products are used. Then there are language and cultural differences to overcome. This can be a difficult challenge, even for people with the best of intentions. Industries do not exist for altruistic reasons of helping the sick. They are there to make a profit and that brings strong pressures to minimise costs. However, most pharmaceutical companies recognise that it is in their own best interests to comply with safety standards. If they breach standards, not only do they risk expensive legal process but they also lose credibility, which means that they lose business. The manufacturers of contaminated heparin clearly breached regulations. While traditional toxicology and safety monitoring will continue to be core research activities for those interested in drug safety, we should always be prepared to look beyond our traditional horizons. A potential for error and negligence exists which can compromise drug safety throughout the manufacturing, distribution and storage process. Increasing globalisation has heightened the challenge of providing safe drugs. Let us hope that contaminated heparin is no more than a consequence of a world adjusting to new trading relationships and not a sign of things to come.

Bone fractures are a source of considerable morbidity that is likely to increase as the age of the general population rises. Physicians should avoid additional fracture risk that might result from choosing inappropriate drugs or failing to attend to other important factors such as vitamin D or nutritional status. This collection of papers on the bone changes and fracture risk associated with prescribed medication is both fascinating and informative. The conclusions of some of the contributions are contrary to traditional views, implying that a re-examination of practice may be warranted. Other reviews in the collection make it clear that a drug that can reduce one public health problem may increase fracture risk, leading to a different public health concern. Some of the salient points from the review papers in this series follow. Oral corticosteroids are associated with an increased fracture risk from effects on sex steroids, vitamin D, calcium balance, bone cells and the bone matrix. However, the increase in fracture risk with oral administration seems to be more linked to daily than to cumulative dose. Inhaled and topical steroids are generally not associated with an increased fracture risk unless higher than recommended doses are used. Proton pump inhibitors may increase fracture risk, implying that the lowest doses together with maintenance of good vitamin D and calcium status are advisable. Some drugs used to treat cardiovascular conditions might actually increase bone mineral density (BMD) but loop diuretics and amiodarone appear to decrease it and to increase fracture risk. There is not sufficient evidence for many of the cardiovascular drugs to allow firm conclusions to be drawn. Bone problems and fracture risk have long been associated with antiepileptic drugs but it appears that the risk attributable to the medication may have been overestimated. Good control of seizures and attention to vitamin D/nutritional status may be much more important factors. Benzodiazepines are associated with a small increase in fracture risk, possibly because of increased falls. Tricyclic antidepressants and SSRIs are associated with an increased fracture risk; it is of particular interest to note that the SSRIs might be worse in this regard, probably both through effects on BMD and on balance. Neuroleptics appear to be associated with a small increase in fracture risk but lithium, in contrast, appears to decrease fracture risk. Antineoplastic drugs that decrease sex steroid effects increase fracture risk but tamoxifen, which is a partial oestrogen agonist, increases BMD and may reduce the risk. Diabetes appears to increase fracture risk through a number of mechanisms and glitazones may increase the risk further but metformin and the sulphonylureas decrease fracture risk. With regard to analgesic medication, paracetamol (acetaminophen) increases fracture risk but aspirin (acetylsalicylic acid) does not. Some non-steroidal anti-inflammatory drugs (NSAIDs) appear to increase BMD but this potentially beneficial effect on fracture risk might be lost because of an increase in adverse effects leading to falls; fracture risk is increased with some but not all NSAIDs. Opiates have been shown to decrease BMD but effects on falls might be of greater importance. There are many factors affecting fracture risk, implying that research in this field needs to be meticulous in analysing the importance of each of these factors if misleading conclusions are to be avoided. This is the first in the Current Drug Safety “Hot Topics” series. It is unusual, in that most of the papers come from one centre, a practice that, as Editor-in-Chief, I should not generally encourage. However, the centre concerned specialises in the area and the quality of the reviews from experienced workers in the field speaks for itself. I hope that other readers of these papers will find them as interesting as I have.

Bone fractures are a source of considerable morbidity that is likely to increase as the age of the general population rises. Physicians should avoid additional fracture risk that might result from choosing inappropriate drugs or failing to attend to other important factors such as vitamin D or nutritional status. This collection of papers on the bone changes and fracture risk associated with prescribed medication is both fascinating and informative. The conclusions of some of the contributions are contrary to traditional views, implying that a re-examination of practice may be warranted. Other reviews in the collection make it clear that a drug that can reduce one public health problem may increase fracture risk, leading to a different public health concern. Some of the salient points from the review papers in this series follow. Oral corticosteroids are associated with an increased fracture risk from effects on sex steroids, vitamin D, calcium balance, bone cells and the bone matrix. However, the increase in fracture risk with oral administration seems to be more linked to daily than to cumulative dose. Inhaled and topical steroids are generally not associated with an increased fracture risk unless higher than recommended doses are used. Proton pump inhibitors may increase fracture risk, implying that the lowest doses together with maintenance of good vitamin D and calcium status are advisable. Some drugs used to treat cardiovascular conditions might actually increase bone mineral density (BMD) but loop diuretics and amiodarone appear to decrease it and to increase fracture risk. There is not sufficient evidence for many of the cardiovascular drugs to allow firm conclusions to be drawn. Bone problems and fracture risk have long been associated with antiepileptic drugs but it appears that the risk attributable to the medication may have been overestimated. Good control of seizures and attention to vitamin D/nutritional status may be much more important factors. Benzodiazepines are associated with a small increase in fracture risk, possibly because of increased falls. Tricyclic antidepressants and SSRIs are associated with an increased fracture risk; it is of particular interest to note that the SSRIs might be worse in this regard, probably both through effects on BMD and on balance. Neuroleptics appear to be associated with a small increase in fracture risk but lithium, in contrast, appears to decrease fracture risk. Antineoplastic drugs that decrease sex steroid effects increase fracture risk but tamoxifen, which is a partial oestrogen agonist, increases BMD and may reduce the risk. Diabetes appears to increase fracture risk through a number of mechanisms and glitazones may increase the risk further but metformin and the sulphonylureas decrease fracture risk. With regard to analgesic medication, paracetamol (acetaminophen) increases fracture risk but aspirin (acetylsalicylic acid) does not. Some non-steroidal anti-inflammatory drugs (NSAIDs) appear to increase BMD but this potentially beneficial effect on fracture risk might be lost because of an increase in adverse effects leading to falls; fracture risk is increased with some but not all NSAIDs. Opiates have been shown to decrease BMD but effects on falls might be of greater importance. There are many factors affecting fracture risk, implying that research in this field needs to be meticulous in analysing the importance of each of these factors if misleading conclusions are to be avoided. This is the first in the Current Drug Safety “Hot Topics” series. It is unusual, in that most of the papers come from one centre, a practice that, as Editor-in-Chief, I should not generally encourage. However, the centre concerned specialises in the area and the quality of the reviews from experienced workers in the field speaks for itself. I hope that other readers of these papers will find them as interesting as I have.