Idiosyncratic Side Effects Research Articles

Data from regulatory studies: what do they tell? What don't they tell?

Phase III studies of antiepileptic drugs (AEDs) are specifically designed to satisfy strict regulatory criteria. As they are conducted in protocol-restricted patient populations over short treatment periods and employ fixed study designs and dosing schedules, they are not fully representative of 'real-life' clinical practice. Therefore, in order to provide an overall assessment of clinical performance, regulatory studies must be backed up by post-marketing clinical experience. Phase IV studies provide information on a drug's performance in a setting more closely representing real clinical practice, with broader patient populations and a more flexible approach to individual treatment. Prospective long-term studies allow the determination of efficacy and safety (and cost-effectiveness) over extended treatment periods; these studies and audit data provide a means of assessing idiosyncratic side effects, unusual interactions and the effects of an AED in rare patient groups. By complementing regulatory evidence with real-life clinical experience, a comprehensive assessment of the risks and benefits of an AED can be made.

VNS Therapy versus the latest antiepileptic drug

ABSTRACT Pro AED: The central issue in medical decision‐making is risk‐benefit assessment. Surgery of any type is still considered to be a major undertaking. To warrant these risks, the patient has a right to expect that they have a greater chance of a good outcome with an invasive therapy than with a non‐invasive one. The main question is when, if ever, this becomes the case when comparing implantation of a VNS Therapy System versus adding an antiepileptic drug (AED)? After the first drug? The second? After all AEDs have failed? To date, no randomized trial comparing the addition of an AED against vagus nerve stimulation (VNS Therapy) has been undertaken, although several are currently being contemplated. Without this information, it is more difficult to make a case for early implementation of VNS Therapy. Unfortunately, few data are available regarding the potential for patients to become seizure‐free after implantation of a VNS Therapy System. Another issue is side effects. It is important to remember that VNS Therapy also produces adverse events, albeit very different in character than those associated with AEDs, to which physicians have become accustomed. These include cough, dyspnea, pharyngitis, voice alteration and sleep apnea. A less frequently discussed, potentially negative consequence of VNS Therapy relates to the ability to obtain imaging of the patient. Patients who have undergone VNS Therapy System implantation are not candidates for imaging of the chest, breast, or abdomen. A second issue is that imaging of the brain can only be performed with MRI scanners that meet certain requirements, and as MRI technology develops, scanners meeting these requirements may become harder to find. However, to summarize, VNS Therapy is an excellent and useful treatment choice. Fortunately, the choice between AEDs and VNS Therapy is not an “either/or” decision. Each has a role in the treatment of patients with epilepsy, and the advantages and disadvantages of each should be kept in perspective. Pro VNS Therapy VNS Therapy is no longer a new treatment for patients with refractory epilepsy. The first implant was performed in l988, and since then more than 30,000 patients have received this therapy. It is no longer considered an unusual or dangerous procedure, but it is still used almost exclusively for refractory epilepsy patients and it has not been generally accepted for use as a first line or even second line therapy. However, compared to the new AEDs, VNS Therapy has similar efficacy results in clinical trials and in many epilepsy syndromes and the long‐term efficacy results are even more positive, with continued improvement in seizure reduction for up to two years. Two of the major reasons for not using VNS Therapy early are that it is a surgical procedure, and its safety during MRI procedures, especially with 3 Tesla, has not yet been elucidated. The safety profile of VNS Therapy is very favorable; the side effects being totally different from those seen with AEDs. The most important aspects are that there have been no pharmacological interactions, cognitive or sedative side effects reported, and it is safe for use in all age groups. Side effects are restricted to local irritation, hoarseness, coughing and, in a few cases, swallowing difficulties when the stimulator is on, but these tend to disappear with time. No idiosyncratic side effect has emerged during the 16 years of use. Compliance is guaranteed. The cost of the implantation of the VNS Therapy System, when spread out over 8 years (battery life), is actually less than the cost of using a new AED over an eight‐year period, and real savings as regards hospital costs due to seizures can be expected.

Dapsone (Disulone ®) en dermatologie

Dapsone is a sulfone discovered in 1908. Since the 1940s, it is the gold standard in the treatment of leprosy. Dapsone indications have been extended to inflammatory dermatoses and other infections. These indications are based on its antibiotic and immunomodulatory effects. Its bioavailability and half-life characteristics allow single daily dose. Dapsone is metabolised by two enzymatic paths: N-acetylation and N-hydroxylation. The latter may result in dose-related side effects: haemolytic anaemia and methemoglobinaemia. Dapsone is also associated with idiosyncratic side effects (agranulocytosis, hypersensitivity syndrome).

Cardiovascular safety of COX-2 inhibition: time to inform systems of postmarketing surveillance?

Since late summer 2004, regulatory and patient concerns over retrospective data on the overall safety of cyclooxygenase (COX)-2 inhibitors (coxibs), such as rofecoxib, valdecoxib and celecoxib, in patients with coronary disease have evolved in an ever-upward spiral of increasingly public rather than scientific debate. The episode was heralded to the wider world by the precautionary withdrawal of rofecoxib from the world market following discussions by the US Food and Drug Administration (FDA). A serious drop in the stock valuation of Merck Sharpe and Dohme Ltd (MSD) and a worldwide media frenzy followed. In particular, the US media reaction to this step was openly criticised by AJJ Wood (the Scottish clinical pharmacologist based at Vanderbilt who chaired the relevant FDA advisory panel on COX-2 inhibitors and is a potential new commissioner of the FDA). Regulatory concern over data on safety is not a new feature in the assessment of drugs following marketing. Paradoxically, adverse events involving a common disease such as coronary disease are harder to define than rare or idiosyncratic side effects. Unlike the latter, they tend to be below the limits of recognition of individual clinicians and most current systems of postmarketing surveillance. Specifically, recognition of an impact of concomitant drug treatment on coronary disease in patients with arthritides (where the background symptom burden is traditionally very high) is a good case study in the complexity of pharmacoepidemiology. These patients have a long-established excess incidence of coronary and vascular events recognized long before the era of COX-2 inhibitor use [1]. The safety and efficacy of any drug entity (new or old) is of course a product of the number and duration of patient exposures and the unpredictable impact of prescription to unselected patients (those not systematically studied during development). Clearly there were no data to suggest an adverse interaction with coronary disease or its treatment before marketing. In general, no drug therapy is anything other than relatively safe in this regard and, routinely, prescribers place a disproportionate amount of faith in the developmental and regulatory assessment process. What can be learnt from the regulatory process laid out in the postmarketing surveillance of COX-2 inhibition?

N-glucuronidation of carbamazepine in human tissues is mediated by UGT2B7.

Carbamazepine (CBZ) is one of the most widely prescribed anticonvulsants despite a high incidence of idiosyncratic side effects. Metabolism of CBZ is complex, and of the more than 30 metabolites identified, one of the most abundant is CBZ N-glucuronide. To date the uridine diphosphate glucuronosyltransferase (UGT) isoform responsible for the N-glucuronidation of CBZ has not been identified. We have developed a sensitive liquid chromatography/mass spectrometry assay to quantify CBZ glucuronidation, and we report that CBZ is specifically glucuronidated by human UGT2B7. Kinetics of CBZ glucuronidation in human liver, kidney, and intestine microsomes were consistent with those of recombinant UGT2B7, which displayed a Km value of 214 microM and Vmax value of 0.79 pmol/mg/min. In addition to revealing the isoform responsible for CBZ glucuronidation, this is the first example of primary amine glucuronidation by UGT2B7.

Colorectal adenomas: a prototype for the use of surrogate end points in the development of cancer prevention drugs.

Carcinogenesis is a multiyear, multistep, multipath disease of progressive genetic alterations and associated tissue damage. Chemoprevention is the use of drugs or other agents to inhibit, delay, or reverse this process. Despite the enormous population at risk of cancer who would benefit, drug

Aportaciones de la genética a las epilepsias

In recent years the progress made in genetics has revolutionised our knowledge of the physiopathological mechanisms governing epilepsy. Just 20 years ago, none of the genes involved in epilepsy were known. Since then 11 genes have been identified and this has enabled us to better understand the mechanisms that generate the seizures. This is not only of interest to academics but can also have a practical application by helping when it comes to making a rational choice of a drug in a particular epileptic syndrome, or by allowing new drugs to be developed as new therapeutic targets are identified.Genetics can help us to understand the mechanisms that cause resistance to drugs and to determine the risk of a patient's suffering from idiosyncratic side effects or not. It is therefore to be expected that over the next few years it will become a fundamental body of doctrine for the daily management of epileptic patients.

Review of new antiepileptic drugs as initial therapy.

The new onset of epilepsy usually leads to initiation of treatment with antiepileptic drugs (AEDs). Selection of the appropriate drug in this clinical situation is usually based on several factors, including efficacy for the suspected epilepsy type, tolerability, acute and long-term idiosyncratic side effects, pharmacokinetic interactions, possibility of rapid titration, formulation, and expense. Over the last several years, the choices for treatment in newly diagnosed epilepsy have increased because a number of new AEDs have been approved for use in monotherapy. This article reviews randomized, controlled studies that have evaluated the use of new AEDs in monotherapy.

Management of dermatitis herpetiformis

Dermatitis herpetiformis (DH) is a vesiculo-bullous disease with a characteristic clinical picture. The diagnostic hallmark is the demonstration by direct immunofluorescence of IgA deposits in the dermal papillae of uninvolved skin. The diagnosis should not be made without this finding. Patients with DH have an associated gluten sensitive enteropathy and overwhelming evidence has been presented over the last 30 years that gluten causes both the rash and the enteropathy of DH in genetically predisposed individuals. Nearly all patients with DH have the histocompatibility antigens HLA B8 DR3 and DQw2 and associated target specific autoimmune disease. The management of DH has to be directed at control of the rash, identification of the severity and treatment of the associated gluten sensitive enteropathy and identification and treatment of associated autoimmune disease. The rash of DH responds impressively to oral therapy with dapsone. Itching subsides within 24 h of starting treatment and new lesions stop appearing after 48 h. Cessation of therapy leads to recurrence of the rash. The use of dapsone is limited by its side-effects. It is a powerful oxidizing agent and in therapeutic dosages of about 100 mg daily causes a chemical haemolysis. Elderly atherosclerotic patients will not tolerate even moderate degrees of haemolysis. Dapsone also has idiosyncratic side-effects such as headache and lethargy. These unwanted effects lead to withdrawal of dapsone therapy in about 25% of patients in whom it is prescribed and substitution with a sulphonamide such as sulphapyridine or sulphamethoxypyridazine, usually brings about adequate control. Once the rash is controlled it is important to establish the minimum drug requirements as many of the toxic side-effects are dose dependent. The severity of the associated gluten sensitive enteropathy is variable ranging from symptomatic coeliac disease to a mild abnormality of permeability. Patients with DH should be placed on a strict gluten-free direct (GFD). After approximately 6 months the minimum drug requirements start to fall and patients are usually able to withdraw completely from drug therapy after about 2 years on the diet. The GFD controls the rash of DH regardless of the severity of associated enteropathy and has to be maintained indefinitely. The most common autoimmune associations of DH are thyroid disease and pernicious anaemia. Annual monitoring of serum autoantibodies is important to identify patients at risk.

The interface of preclinical evaluation with clinical testing of antiepileptic drugs: role of pharmacogenomics and pharmacogenetics

Despite the release of eight antiepileptic drugs (AEDs) during the last decade, the incidence of pharmacoresistant epilepsy has changed relatively little. Predicting efficacy and safety of AEDs in people with epilepsy from acute seizure models in rodents is difficult and risky. It is becoming increasingly clear that genetic polymorphisms play an integral role in variability in both antiepileptic drug pharmacokinetics and pharmacodynamics. The publication of the human genome and increasing sophisticated and powerful genetic tools offers new methods for screening drugs and predicting deadly idiosyncratic side effects. In this review the use of pharmacogenomic and pharmacokinetic techniques in the development and monitoring of antiepileptic drug therapy is reviewed. Genetic techniques have the potential of identifying novel drug targets, predicting drug response, and identifying individuals at risk for serious idosyncratic reactions.

Issues in the Treatment of Epilepsy

Issues in the Treatment of Epilepsy

Therapeutic safety monitoring: what to look for and when to look for it.

This review focuses on the safety problems associated with antiepileptic drugs (AEDs) as revealed by laboratory testing and clinical examination. There are two classes of side effects: (a) common and mild and (b) rare and severe. Allergic reactions to AEDs are common and usually mild. However, on rare occasions, they can progress to more severe cutaneous disorders, including Stevens-Johnson syndrome and toxic epidermal necrolysis. Severe allergic reactions to AEDs range from immune responses with fever to multiorgan dysfunction. Allergic rashes may be genetically or immunologically determined. Laboratory abnormalities produced by AEDs are common and mild, and include hepatic enzyme elevation associated with phenytoin and mild elevation in ammonia associated with valproate. Serious, although rare, idiosyncratic side effects, such as aplastic anemia, hepatotoxicity, and thrombocytopenia, have also occurred with AEDs. These reactions are largely confined to the "classic" AEDs. With the exception of felbamate, AEDs approved in the past decade have not been plagued by severe idiosyncratic reactions. Subtle endocrine abnormalities, including variations in thyroid function tests and bone metabolism, and the often subclinical effects on peripheral nerve conduction produced by phenytoin and carbamazepine, are also examined.

Carbamazepine‐induced combined phonic and motor tic in a boy with Down's syndrome

ABSTRACT We report the occurrence of a tic in a boy with Down's syndrome. The movement disorder was induced by carbamazepine (CBZ) and resolved completely after discontinuation of CBZ. The development of tics seems to be a rare, idiosyncratic side effect of CBZ in children.

Psychiatric Syndromes Related to Antiepileptic Drugs

All antiepileptic drugs may provoke positive or negative psychiatric reactions in individual patients. These psychotropic effects are not simply idiosyncratic but depend on the drug's anticonvulsive strength and the person's genetic and biographic psychiatric predisposition. Mechanisms related to psychiatric adverse events are polytherapy and folate deficiency, forced normalization, drug toxicity, and withdrawal. Our knowledge on dose independent, idiosyncratic psychotropic side effects is still limited. With respect to the older antiepileptic drugs there are almost no systematic data, and knowledge is largely empirical and based on anecdotal reports. With respect to the new generation of anticonvulsants there are data on psychiatric side effects from drug trials. However, these data are not always entirely transparent to the interested epileptologist. Moreover, drug trials are designed to test anticonvulsive efficacy and psychiatric adverse events are not systematically reported, thus severity psychopathologic nature of behavioral problems remain obscure. Differences in patients included in trials do not allow comparisons of psychiatric risks of specific drugs, particularly since following the vigabatrin experience, patients with a psychiatric history were often excluded from trials. In this chapter, methodological issues related to data on psychiatric adverse events of AED are discussed followed by an overview on the current knowledge on psychiatric side effect profiles of old and new antiepileptic drugs.

Isolated ataxia as an idiosyncratic side-effect under gabapentin

Gabapentin has been accepted worldwide as a novel antiepileptic drug with a favourable tolerability profile. However, movement disorders have been reported previously as rare side-effects in individual patients. We report on two patients who developed isolated severe ataxia under low-dose gabapentin which resolved abruptly after discontinuation of the drug. This side-effect probably resembled a rare idiosyncratic adverse reaction. We propose the gabapentin-specific neuronal binding site which has a high density in the cerebellum as a possible mechanism of action and suggest that the initiation of gabapentin requires caution if pre-existing cerebellar function impairment is evident.

Felbamate: Therapeutic range and other kinetic information

A retrospective study was performed to identify the therapeutic range and pharmacokinetic parameters of felbamate (FBM). Data from 104 patients visits were analyzed. FBM was the sole agent in 40%. Dose-related side effects were graded numerically, and seizure experience was coded qualitatively. For 76 visits, seizure control was better than that observed at the previous visit. The FBM therapeutic window was 50–110 mg/L. Doeses required to achieve these levels were 50–55 mg/kg/day. FBM clearance in monotherapy was 0.67 L/kg/day, with a corresponding half-life (+1/2) of 24 h. FBM clearance increased when carbamazepine (CBZ) was combined with FBM, as evidenced by a decrement in FBM +1/2 to 15 h (61% of the FBM +1/2 in monotherapy). No appreciable changes in FBM clearance were demonstrated for comedication with phenytoin (PHT) or lamotrigine (LTG). A slight decrease in clearance was apparent when FBM was combined with valprate (VPA). We identified an interaction between FBM and gabapentin (GBP) in which the elimination of FBM was strikingly reduced, corresponding to a prolonged +1/2 of 35 h (146% of baseline). No idiosyncratic side effects were noted. A new concept, “response/toxicity rario”, is introduced to improve clinicians' use of the therapeutic range.

Acute Cholestatic Hepatitis with Rash and Hypereosinophilia Associated with Ranitidine Treatment

We report a case of acute cholestatic hepatitis associated with rash and hypereosinophilia, in which the absence of transfusion, intercurrent viral infection, alcohol consumption or other hepatotoxic drugs are suggestive of ranitidine-induced hepatotoxicity. The pathogenesis of the disorder is unknown, but the lack of a dose-effect relationship, the rarity and unpredictability of the reaction, as well as the clinical signs suggest that hypersensitivity is involved. Physicians should be aware of this rare and idiosyncratic side-effect of ranitidine.

Idiosyncratic side effects of short half‐life benzodiazepine hypnotics: Fact or fancy?

Idiosyncratic side effects of short half‐life benzodiazepine hypnotics: Fact or fancy?

Phenacemide: A New clinical pharmacologic perspective

Phenacemide (Phenurone®) is an older antiepileptic agent about which little modern clinical pharmacologic information has been available. As assay was developed to measure serum phenacemide levels, and kinetic parameters were studied. In the course of therapy of maximally severe epilepsy in 21 patients, clinical and pharmacologic data were gathered. The therapeutic range for phenacemide is 50–100 μg/ml. Mean dose to reach these levels is 56 mg/kg/day. It is not strongly bound to serum proteins (76% unbound in serum). Phenacemide clearance was significantly lower in the presence of valproic acid but was not changed by any other antiepileptic drug. Elimination T/2 in one patient was 15 h. Seizures were consistently better in 10 of 21 patients (4 with complex partial seizures, 5 with atypical absences with minor motor phenomena, and 1 with generalized convulsions). No idiosyncratic side effects were seen to affect marrow, liver, skin, kidney, etc. Mood-altering side effects were seen in seven patients: five showed a withdrawn syndrome and two showed a restless syndrome. This drug is not frequently useful, but the availability of modern pharmacologic information will maximize the success when it is used.

Use of Ethosuximide and Valproate in the Treatment of Epilepsy

Ethosuximide is the drug of first choice in absence seizures. Idiosyncratic side effects are rare. Valproate is effective against absence, generalized tonic-colonic, and partial seizures. It is the drug of choice in photosensitive seizures. Valproate is, on the whole, free from unpleasant side effects, but fatal hepatotoxicity and hyperamnionemia have been reported very rarely.