The pharmacokinetics and interactions of new antiepileptic drugs: an overview

In the past decade 10 new antiepileptic drugs (AEDs)have been introduced: felbamate, gabapentin, lamotrigine, levetiracetem, oxcarbazepine, pregabalin, tiagabine, topiramate, vigabatrin,and zonisamide. The pharmacokinetics (PK) of these new AEDs as well as their potential for drug interactions are reviewed in this article.In general, new AEDs have better PK profiles and are less involved in drug interactions than the 4 established AEDs: phenobarbital,phenytoin, carbamazepine, and valproic acid. However, in spite of the large therapeutic arsenal of old and new AEDs, about 30% of epileptic patients are still not seizure-free, and thus, there is a substantial need to develop new AEDs.     

Pharmacokinetics of antiepileptic drugs in pregnancy

A substantial proportion of women with epilepsy experience seizure deterioration during pregnancy. This is most likely explained by a drop in plasma levels of antiepileptic drugs (AEDs) as a consequence of altered drug pharmacokinetics. It has been known for many years that gestation induces the elimination of standard AEDs (phenytoin, barbiturates, carbamazepine and valproate). In general, newer AEDs have more simple pharmacokinetic properties and it should, therefore, be expected that the pharmacokinetics of these drugs are influenced in a simpler manner by physiological changes, such as pregnancy. However, within the last few years it has been established that the elimination of several newer AEDs is significantly accelerated during pregnancy. This is particularly the case for glucuronidated AEDs (i.e., lamotrigine) and the pharmacological active metabolite of oxcarbazepine (metabolite 10-hydroxycarbazepine). Recent observations show it is probable that the elimination of levetiracetam is also increased during pregnancy. Pharmacokinetic alterations during pregnancy show wide interindividual variability and the effects on the plasma levels are mostly unpredictable. Regular routine drug monitoring during pregnancy is therefore recommended. The future perspective involves the development of pharmacogenetic charting, which may assist in providing an individualized treatment strategy and refine preconceptional therapeutic planning to ensure the best possible health for the mother and developing child.     

Safety of antiepileptic drugs during pregnancy

Women with epilepsy taking antiepileptic drugs during pregnancy have been shown to have an increased risk of having a child with a major malformation. There is some recent evidence to suggest that these drugs may also affect cognitive and behavioural development. Epilepsy is a common neurological condition and women with epilepsy constitute a significant number of pregnancies in the UK each year. Some of the drugs used to treat epilepsy are increasingly being used in the treatment of migraine and other pain syndromes and also in psychiatry principally for the control of bipolar affective disorder. This article looks at the evidence currently available in assessing the safety of the individual agents used in pregnancy.     

Safety of antiepileptic drugs during pregnancy

Women with epilepsy taking antiepileptic drugs during pregnancy have been shown to have an increased risk of having a child with a major malformation. There is some recent evidence to suggest that these drugs may also affect cognitive and behavioural development. Epilepsy is a common neurological condition and women with epilepsy constitute a significant number of pregnancies in the UK each year. Some of the drugs used to treat epilepsy are increasingly being used in the treatment of migraine and other pain syndromes and also in psychiatry principally for the control of bipolar affective disorder. This article looks at the evidence currently available in assessing the safety of the individual agents used in pregnancy.     

Effect of antiepileptic drugs on bodyweight: overview and clinical implications for the treatment of epilepsy

The potential of specific antiepileptic drugs (AEDs) to cause clinically significant changes in bodyweight is a key consideration in the management of epilepsy; changes in weight can pose health hazards, impair body image and self-esteem, and lead to noncompliance with therapy. This article reviews the data regarding the effects of conventional and newer AEDs on weight and discusses the clinical implications of these effects for the management of patients with epilepsy. The data demonstrate that AEDs can differ substantially in their effects on weight. Some, such as valproate and carbamazepine, increase weight; others, such as topiramate and felbamate, decrease it. Still others, such as lamotrigine, levetiracetam and phenytoin, are weight neutral. Because most data regarding the effects of AEDs on weight are circumstantial, the incidence, magnitude and determinants of weight changes with AEDs remain poorly elucidated. Furthermore, little is known about the mechanisms of AED-induced changes in weight. The importance of effects on weight in selecting an AED depends largely upon the individual patient's needs and the risks and benefits of therapy for that patient. The most appropriate therapeutic choice is a weight-neutral medication unless circumstances dictate otherwise.     

Behavioural effects of the newer antiepileptic drugs: an update

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.     

Risk factors for ovarian cancer: an overview with emphasis on hormonal factors

Ovarian cancer is the fifth most frequently occurring cancer among women and leading cause of gynecological cancer deaths in North America. Although the etiology of ovarian cancer is not clear, certain factors are implicated in the etiology of this disease, such as ovulation, gonadotropic and steroid hormones, germ cell depletion, oncogenes and tumor suppressor genes, growth factors, cytokines, and environmental agents. Family history of breast or ovarian cancer is a prominent risk factor for ovarian cancer, with 5-10% of ovarian cancers due to heritable risk. Reproductive factors such as age at menopause and infertility contribute to greater risk of ovarian cancer, whereas pregnancy, tubal ligation, and hysterectomy reduce risk. Oral contraceptive (OC) use has clearly been shown to be protective against ovarian cancer. In contrast, large epidemiologic studies found hormone replacement therapy (HRT) to be a greater risk factor for ovarian cancer. The marked influence of hormones and reproductive factors on ovarian cancer suggests that endocrine disrupters may impact risk; however, there is a notable lack of research in this area. Lifestyle factors such as cigarette smoking, obesity, and diet may affect ovarian cancer risk. Exposure to certain environmental agents such as talc, pesticides, and herbicides may increase risk of ovarian cancer; however, these studies are limited. Further research is needed to strengthen the database of information from which an assessment of environmental and toxicological risk factors for ovarian cancer can be made.     

The treatment of epilepsy in pregnancy: The neurodevelopmental risks associated with exposure to antiepileptic drugs

A number of antiepileptic drugs (AEDs) have been confirmed as teratogens due to their association with an increased malformation rate. The majority of research to date does not find an association between prenatal exposure to monotherapy carbamazepine, lamotrigine or phenytoin and neurodevelopmental outcome in comparison to control children and noted higher abilities in comparison to children exposed to valproate; but further work is needed before conclusions can be drawn. Data for levetiracetam was limited to one study, as was the evidence for topiramate. Sodium valproate exposure appeared to carry a dose dependent risk to the developing brain, with evidence of reduced levels of IQ, poorer verbal abilities and increased rate of autistic spectrum disorder both in comparison to control children and children exposed to other AEDs. The severity of the neurodevelopmental deficits associated with prenatal exposure to valproate highlight the critical need to consider neurodevelopmental outcomes as a central aspect of teratological research.     

新型抗癫痫药之间及其与传统抗癫痫药的相互作用和机制*

分别综述了几种新型抗癫痫药（托吡酯、非氨酯、奥卡西平、拉莫三嗪、唑尼沙胺、左乙拉西坦、噻加宾、加巴喷丁及氨己烯酸）与传统抗癫痫药联合应用时以及这些新型抗癫痫药之间的相互作用及其发生机制，阐明细胞色素P450酶和葡萄糖苷酸转移酶在新型抗癫痫药的相互作用中的意义及重要性。为临床合理联合应用提供理论依据，提高抗癫痫治疗的可靠性、安全性和有效性。     

Oral anticancer drugs in the elderly: an overview

The increasing number of elderly people in the world population has led to a parallel increase in the number of older cancer patients, with over 45% of all cancers in Europe occurring in patients >70 years of age. The increasing tendency to use oral chemotherapy is thus of interest in the elderly, given that both elderly patients and their physicians prefer to use less complex and toxic regimens when such treatments have equivalent efficacy to more complex regimens. However, data from studies designed to evaluate these therapies in the elderly are currently limited. Factors that must be considered before prescribing oral agents to this subset of patients include age-related physiological changes affecting clinical pharmacology, adherence, the patient's capability to self-administer medications, and safety issues concerning the older patient and his or her caregivers. The idea that elderly patients may benefit from the introduction of oral chemotherapy is very fashionable, but to date there is no proof that this approach is as effective as intravenous therapy in this age group, particularly since randomised trials are lacking. This review discusses these issues and reviews current information about the use of specific oral chemotherapeutic drugs for major neoplastic diseases in the elderly.     

Intelligent noncompliance with special emphasis on the elderly

Intelligently noncompliant patients alter their prescribed therapy on a rational basis that often represents advanced therapeutic principles. The literature contains many examples of patients who alter their medication but still have good treatment outcome. Doses are altered to avoid adverse effects or because the dose was excessive or inconvenient. When compliance studies are done in a large heterogeneous group, the rates for different age groups are almost always similar. Health professionals have devised compliance-ensuring strategies such as educational programs and modification of the regimen. Use of compliance-ensuring strategies, however, opposes the current trend which advocates a more direct, active patient participation in treatment decisions.     

Oxime-type acetylcholinesterase reactivators in pregnancy: an overview

Oxime-type acetylcholinesterase reactivators (oxime-AChER) are used as an adjunct in the treatment for organophosphorus anticholinesterase poisoning. Because of the widespread usage and exposure of organophosphorus compounds (OPCs), its poisoning and fatalities is obvious in pregnant women, embryos and fetuses. OPCs irreversibly inhibit acetylcholinesterase (AChE) at nerve synapses. Furthermore, the role of AChE other than neurotransmission termination has been defined in the literature. The growing evidences show that cholinergic mechanisms are involved during growth and development of other organ systems. In contrary to the fact, the data on the use of oxime-AChER in OPC poisoning in pregnancy are scanty. The present review aimed to comprehend the status of oximes in pregnancy in lieu of the published literature. A thorough literature search was performed in January 2013, using ten popular search engines including Medline/PubMed, Google scholar, etc., using nine standard keywords. The search period was set from 1966 to present. The search did not reveal substantial data. No considerable studies were retrieved which could really demonstrate either the beneficial, harmful or even null effect of oxime-AChER usage in pregnancy. Only eighteen relevant articles were obtained for a period of about 47 years. In the literature, there is no report available to demonstrate the risk of using oxime-AChER in pregnancy for the treatment of OPC poisoning. The study reveals that the use of oxime-AChER in pregnancy is largely un-addressed, inconclusive and based on speculation albeit the incidences of OPC poisoning are quite prevalent. Well-designed studies are warranted for a tangible conclusion.     

抗癫痫药的药物基因组学研究进展

抗癫痫药的疗效和副作用存在着显著的个体差异,现认为药物基因组学在个体差异中发挥了重要作用.本文通过整理、分析近几年的文献,阐述抗癫痫药基因多态性在药物代谢、转运和不良反应等方面的作用,从而为临床个体化用药提供参考.     

Bartscontrol: an external quality control scheme for antiepileptic drugs

Bartscontrol is described in short: the need for its development and its use as an external quality control programme for the assay of eight antiepileptic drugs. In Figures 1, 2 and 3 some results are presented.     

The influence of sodium bromide in man: a study in human volunteers with special emphasis on the endocrine and the central nervous system

Sodium bromide was administered orally in capsules to healthy volunteers in doses of 0, 4 or 9 mg Br-/kg/day using a double-blind design. Each treatment was given to seven males for 12 weeks and to seven non-pregnant females (not using oral contraceptives) over three full cycles. Special attention was paid to possible effects on the endocrine and central nervous systems. At the start and end of the study, a full medical history, the results of a physical examination, haematological studies and standard clinical chemistry and urine analyses were recorded for each subject. These showed no changes for individuals following treatment, except for some incidence of nausea associated with bromide-capsule ingestion. Mean plasma-bromide concentrations at the end of treatment were 0.08, 2.14 and 4.30 mmol/litre for males and 0.07, 3.05 and 4.93 mmol/litre for females of the 0-, 4- and 9-mg Br-/kg/day groups, respectively. Plasma half-life was about 10 days. In the females taking 9 mg Br-/kg/day (but in no other group) there was a significant (P less than 0.01) increase in serum thyroxine and triiodothyronine between the start and end of the study but all concentrations remained within normal limits. No changes were observed in serum concentrations of free thyroxine, thyroxine-binding globulin, cortisol, oestradiol, progesterone or testosterone, or of thyrotropin, prolactin, luteinizing hormone (LH) and follicle-stimulating hormone before or after the administration of thyrotropin-releasing hormone and LH-releasing hormone. Analysis of neurophysiological data (EEG and visual evoked response) showed a decrease in delta 1- and delta 2-activities and increases in beta-activities and in mean frequency (Mobility parameter) in the groups on 9 mg Br-/kg/day, but all the findings were within normal limits.     

Protein binding of antiepileptic drugs during pregnancy, labor, and puerperium

Twenty-four epileptic women were followed-up during late pregnancy, labor, and early puerperium in order to detect possible alterations in serum protein binding of antiepileptic drugs (AEDs). The total and free concentrations of carbamazepine (CBZ), phenytoin (PHT), and valproate (VPA) in maternal serum were measured. In addition, the concentrations of albumin, alpha 1-acid glycoprotein (AGP), and free fatty acids (FFA) were also measured. Total AED concentrations during labor were influenced by changes in drug dosages; total PHT increased during the first puerperal weeks. During labor the free fraction of CBZ remained stable, whereas PHT and particularly VPA free fractions increased. This phenomenon was parallel to the increase in FFA concentration; FFA concentrations decreased again during the first days postpartum. Albumin and AGP concentrations were low during pregnancy and labor, and increased after delivery. The total umbilical CBZ and PHT concentrations were not significantly different from maternal concentrations. The total VPA concentration in umbilical serum was significantly higher than that in maternal serum. The free fraction of CBZ was higher and that of PHT and VPA lower in umbilical than in maternal serum at delivery. Umbilical cord serum had a higher albumin but a lower AGP and FFA concentration than maternal serum. The changes in PHT and particularly VPA free fraction associated with changes in FFA concentration should be considered when assessing the total concentration of these drugs in maternal and umbilical serum.     

Ozone: an overview of its toxicity in man and animals

Ozone is one of the most toxic and ubiquitous air pollutants. This review focuses on the toxic effects of ozone in animals and on the similarities and disimilarities between the toxic effects in animals and humans. The molecular basis for the toxicity of ozone is discussed, based on the vigorous oxidizing properties of ozone. Despite the existence of anatomical differences between human, subhuman primate, and dog lungs versus common experimental rodent lungs, the anatomical lesion of ozone inhalation occurs at the functionally equivalent site of the junction between the conducting airway and the respiratory region. Ciliated cells of the upper airways and the type 1 cell of the centriacinar region are most affected. Type 2 cell proliferation is a hallmark of ozone toxicity. A wide variety of biochemical and physiological changes have been noted in several animal species and in humans. Considerable evidence for a free-radical-mediated or lipid peroxide-mediated toxicity is evident, especially in the induction of the glutathione peroxidase system and the protective effects of vitamins C and E. Ozone appears to be a weak mutagen and to produce chromosomal abnormalities. Defects in defense against airborne infection are present in animals, which are more susceptible to airborne infection after ozone exposure. Epidemiological studies, however, fail to detect increased respiratory infections in humans due to ozone. Despite the variety of toxic effects, few qualitative differences between species are apparent; rather, quantitative differences do occur. Ozone may thus be an ideal compound for quantitative extrapolation of toxicity from animals to humans.     

Nanocrystal technology in the delivery of poorly soluble drugs: an overview

Extensive attempts to overcome problems related to solubility of drugs for maximizing bioavailability at targeted sites in the body have been made. The issue of drug solubility appears to attract the continued interest of pharmaceutical manufacturers. In this context, nanocrystallization has emerged as an important tool. In the present review, the authors discuss the advantages of nanocrystallized drugs and examine the products available in the market as well as drugs in the pipeline using nanocrystal-based formulations, which are being developed by pharmaceutical companies for drug delivery.