The interplay of epilepsy with impaired mitophagy and autophagy linked dementia (MAD): A review of therapeutic approaches.

The duration and, age of dementia have been linked to a higher risk of seizures. The exact mechanism that drives epileptogenesis in impaired mitophagy and autophagy linked dementia (MAD) is fully defined after reviewing the Scopus, Publon, and Pubmed databases. The epileptogenesis in patients with Alzheimer's disease dementia (ADD) and Parkinson's disease dementia (PDD) is due to involvement of amyloid plaques (Aß), phosphorylated tau (pTau), Parkin, NF-kB and NLRP3 inflammasome. Microglia, the prime protective and inflammatory cells in the brain exert crosstalk between mitophagy and inflammation. Several researchers believed that the inflammatory brain cells microglia could be a therapeutic target for the treatment of a MAD associated epilepsy. There are conventional antiepileptic drugs such as gabapentin, lamotrigine, phenytoin sodium, carbamazepine, oxcarbazepine, felbamate, lamotrigine, valproate sodium, and topiramate are prescribed by a psychiatrist to suppress seizure frequency. Also, the conventional drugs generate serious adverse effects and synergises dementia characteristics. The adverse effect of carbamazepine is neurotoxic and also, damages haemopoietic system and respiratory tract. The phenytoin treatment causes cerebellar defect and anemia. Dementia and epilepsy have a complicated relationship, thus targeting mitophagy for cure of epileptic dementia makes sense. Complementary and alternative medicine (CAM) is one of the rising strategies by many patients of the world, not only to suppress seizure frequency but also to mitigate dementia characteristics of patients. Therefore our present review focus on the interplay between epilepsy and MAD and their treatment with CAM approaches.

Allergic contact dermatitis to Tinosorb S, Scutellaria baicalensis, and other emerging allergens in cosmetics.

Patch tests are highly recommended in eczema patients with eyelid involvement. Sunscreen constitutes a potential cause of eyelid or facial allergic contact dermatitis, and should be considered in patients with refractory eczema on these locations. We report a patient sensitized to several emerging allergens such as bis-ethylhexyloxyphenol methoxyphenyl triazine (Tinosorb S), Scutellaria baicalensis extract, and propylene glycol with an eyelid dermatitis. Patch tests to the combined ingredients propylene carbonate, cyclopentasiloxane, and disteardimonium hectorite; and talc, Cl 77 491, and dimethicone/methicone copolymer were also positive. We highlight the importance of systematically patch testing with the cosmetics brought in by our patients, as well as with the individual ingredients whenever positive. The identification of emerging allergies to new compounds in cosmetics mainly depends on this practice.

Environmental and Genetic Factors Influencing Kidney Toxicity.

The kidneys are a frequent target organ for toxicity from exposures to various environmental chemicals and agents. To understand the risk to human health from such exposures, it is important to consider both the underlying chemical and pathologic mechanisms and factors that may modify susceptibility to injury. Choices of exemplary environmental agents to review are based on those with selective effects on the kidneys and for which significant amounts of mechanistic and human data are available. These include the heavy metals cadmium and arsenic, fluoride, the organic solvents trichloroethylene and perchloroethylene, drinking water disinfection by-products haloacids, food and herbal drug contaminants aristolochic acid and melamine, and heat stress. Some common mechanistic features of all these diverse exposures are highlighted, and include oxidative stress and mitochondrial damage. Two major genetic factors that are discussed include genetic polymorphisms in plasma membrane transporters that catalyze uptake and accumulation or efflux and elimination of environmental chemicals, and genetic polymorphisms in bioactivation enzymes that generate toxic and reactive metabolites. Identification of methods to prevent environmental toxicant-associated kidney damage and understanding the genetic factors that influence kidney function and the kidney's response to exposures can be applied to refine risk assessments.

Fatal adverse events with molecular targeted agents in the treatment of advanced hepatocellular carcinoma: a meta-analysis of randomized controlled trials.

AIMS: Concerns have increased about the risk of fatal adverse events (FAEs) associated with molecular targeted agents (MTAs) in the treatment of advanced hepatocellular carcinoma (HCC). The purpose of this study is to investigate the overall incidence and risk of FAEs in advanced HCC with administration of MTAs by using a meta-analysis of available clinical trials. MATERIALS AND METHODS: Electronic databases were searched for relevant articles before March 2017. Eligible studies were selected according to the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) statement. Pooled incidence, Peto ORs and 95% CIs were calculated according to the heterogeneity of selected studies. RESULTS: A total of 4,716 HCC participants from 10 randomized controlled trials (RCTs) were finally considered for this meta-analysis. The pooled incidence of death due to MTAs was 2.1% (95% CI 1.6%-2.8%) with a Peto OR of 1.79 (95% CI 1.07-3.01; p=0.027) in comparison with controlled groups. Subgroup analysis according to biological agents showed that brivanib treatment in HCC patients significantly increased the risk of developing FAEs (Peto OR 3.97; 95% CI 1.17-13.51; p=0.028) but not for sorafenib (Peto OR 1.78; 95% CI 0.54-5.89; p=0.34) and other MTAs (Peto OR 1.43; 95% CI 0.75-2.76; p=0.28). Sensitive analysis showed that the pooled results were influenced by removing each single trial. The most common causes of FAEs were hepatic failure (22.2%) and hemorrhage (13.3%), respectively. CONCLUSION: Clinicians should be aware of the risks of FAEs during the administration of MTAs in advanced HCC patients, especially for patients with abnormal liver function. However, the use of sorafenib remains justified in its approved indications due to their potential survival benefits and limited toxicities.

Ameliorative effects of supplemental folinic acid on Lamotrigine-induced fetal malformations in the mouse.

Data from our previous work indicate that Lamotrigine (LTG) is teratogenic in the mouse. In the present study, we attempted to determine the possible protective effects of exogenous folate on LTG-induced fetal anomalies in TO mouse. Experiment I entailed administering 4 mg/kg of folinic acid (FA) and (25 mg/kg) of LTG intraperitoneally three times on gestation day (GD) 8 to a group of mice; other groups were a group that received similar volumes of saline, a group that received LTG and Saline, a group that received FA and saline. Experiment 2 involved administering groups of mice with daily 3 doses FA (or proportionate volume of saline) on GD 5 through 10 and either 3 doses of saline on GD8, or 3 doses of LTG on GD8. Maternal plasma concentrations of FA, vitamin B12 and homocysteine were determined an hour after the last injection from one-half of all animals. The other half were allowed to go to term (GD18) when they were euthanized and their fetuses were examined for visceral and skeletal malformations. A high incidence of resorption, abortion, embryolethality, congenital malformations, and intrauterine growth restriction (IUGR), was observed in the LTG-treated group. Folic acid and B12 levels were decreased and homocysteine concentration increased significantly in LTG groups. Mice receiving LTG with FA had normal levels of folate, Vitamin B12 and homocysteine levels, and the fetuses had fewer birth defects similar to the controls which were given saline only. Supplemental FA ameliorated to a great extent the LTG-induced embryonic resorption and malformations and restored the FA status.

Mood-Stabilizing Anticonvulsants, Spina Bifida, and Folate Supplementation: Commentary.

PURPOSE/BACKGROUND: High risks of neural tube defects and other teratogenic effects are associated with exposure in early pregnancy to some anticonvulsants, including in women with bipolar disorder. METHODS/PROCEDURES: Based on a semistructured review of recent literature, we summarized findings pertaining to this topic. FINDINGS/RESULTS: Valproate and carbamazepine are commonly used empirically (off-label) for putative long-term mood-stabilizing effects. Both anticonvulsants have high risks of teratogenic effects during pregnancy. Risks of neural tube defects (especially spina bifida) and other major malformations are especially great with valproate and can arise even before pregnancy is diagnosed. Standard supplementation of folic acid during pregnancy can reduce risk of spontaneous spina bifida, but not that associated with valproate or carbamazepine. In contrast, lamotrigine has regulatory approval for long-term use in bipolar disorder and appears not to have teratogenic effects in humans. IMPLICATIONS/CONCLUSIONS: Lack of protective effects against anticonvulsant-associated neural tube defects by folic acid supplements in anticipation of and during pregnancy is not widely recognized. This limitation and high risks of neural tube and other major teratogenic effects, especially of valproate, indicate the need for great caution in the use of valproate and carbamazepine to treat bipolar disorder in women of child-bearing age.

Margin of safety for two UV filters estimated by in vitro permeation studies mimicking consumer habits: Effects of skin shaving and sunscreen reapplication.

Sunscreens are intended to work on the skin. To be both efficient and safe, the lowest possible percutaneous permeation of UV filters should occur. The potential for systemic absorption of Benzophenone-3 (BP3, 10%) and Ethylhexyl Triazone (EHT, 5%) in a silicone-based water-in-oil emulsion was assessed in vitro using a full-thickness porcine-ear skin mimicking in-use conditions. The estimated Systemic Exposure Dose (SED) after the sunscreen application at 1.0 mg/cm2 for 6 h (i) on the face; (ii) on the whole-body skin, was (i) 136 and 30; (ii) 4200 and 933 µg/kg_bw/d for BP3 and EHT, respectively. Reapplication does not mean the double risk; the SED values were only 1.40-1.37-fold greater. Skin shaving increased BP3 and EHT bioavailability 1.38 and 1.80-fold, respectively. Margin of Safety values were estimated according to guidelines applicable for European Union. For three realistic exposure scenarios, MoS of 48, 34 and 34 for BP3 in the sunscreen applied on the whole-body indicate some concerns regarding the safety for consumers (MoS<100). Despite undeniable functional benefits in sunscreens, BP3 concentration allowed in EU cosmetics (max. 10%) should be reviewed, especially in products intended for whole-body applications. The development of new UV filters should be focused on their specific physico-chemical properties.

Drug reaction with eosinophilia and systemic symptoms syndrome probably induced by a lamotrigine-ginseng drug interaction.

The likelihood of a drug reaction with lamotrigine is increased by dose escalation that is too rapid or drug interactions that increase the concentration of lamotrigine. There is a well-documented interaction between valproic acid and lamotrigine in which lamotrigine levels are increased, subsequently increasing the risk of a drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome. This syndrome is characterized by fever, lymphadenopathy, diffuse maculopapular rash, multivisceral involvement, eosinophilia, and atypical lymphocytes and has a mortality rate of 10-40%. We describe the first case, to our knowledge, of DRESS syndrome that was probably induced by a drug interaction between lamotrigine and ginseng. A 44-year-old white man presented to the emergency department after experiencing a possible seizure. His medical history included two other lifetime events concerning for seizures at ages 14 and 29 years old. After referral to the neurology clinic, he was diagnosed with generalized tonic-clonic seizure disorder, and lamotrigine was started with up-titration according to the drug's package insert to a goal dosage of 150 mg twice/day. The patient had also been taking deer antler velvet and ginseng that he continued during his lamotrigine therapy. On day 43 of therapy, the patient presented to the emergency department with a pruritic rash that had started on his extremities and spread to his torso. He was thought to have experienced a drug reaction to lamotrigine, and the drug was discontinued. Thirteen days later, the patient was admitted from the acute care clinic for inpatient observation due to laboratory abnormalities in the setting of continued rash, headache, and myalgias. His admission laboratory results on that day were remarkable for leukocytosis, with a white blood cell count up to 17.6 × 10(3) /mm(3) , with a prominent eosinophilia of 3.04 × 10(3) /mm(3) ; his liver enzyme levels were also elevated, with an aspartate aminotransferase level of 191 U/L, alanine aminotransferase level 473 U/L, alkaline phosphatase level 465 U/L, and total bilirubin level 1.4 mg/dl. Use of the Drug Interaction Probability Scale indicated that a drug interaction between lamotrigine and ginseng was the probable cause (score of 5). The proposed mechanism of the interaction is ginseng inhibition of the uridine diphosphate glucuronosyltransferase 2B7 enzyme, similar to the mechanism of the interaction with valproic acid. Clinicians should be aware of this probable drug interaction and avoid coadministration of ginseng and lamotrigine or use a more conservative dose titration of lamotrigine for patients who are also taking ginseng.

Combination of retinyl palmitate and UV-filters: phototoxic risk assessment based on photostability and in vitro and in vivo phototoxicity assays.

This study aimed to assess the phototoxic potential of combined UV-filters and retinyl palmitate (RP) in the presence or not of bemotrizinol (BMTZ), employing photostability and in vitro and in vivo phototoxicity assays. The formulations tested contained octocrylene (OCT), octyl methoxycinnamate (OMC), benzophenone-3 (BZP-3) and RP (photostable) or octocrylene (OCT), octyl methoxycinnamate (OMC), avobenzone (AVO) and RP (less photostable). Both formulations were supplemented with bemotrizinol. Photostability was evaluated by exposing, or not, formulations spread on a glass plate to UVA/UVB irradiation. The resulting products were quantified by HPLC analysis. In vitro phototoxicity of UV-filters and combinations were evaluated using 3T3 viable monolayer fibroblast cultures submitted, or not, to irradiation according to OECD TG 432. In vivo photoallergy and photoxicity were assessed by clinical studies (photopatch test). Photostability assays showed that UV-filter bemotrizinol was a better photostabilizer for RP/benzophenone-3 than for RP/avobenzone. The in vitro phototoxicity of the combination RP/avobenzone was reduced by bemotrizinol. Clinical studies did not indicate phototoxic or photoallergenic potentials in all formulations tested. It is concluded that the 3T3 NRU phototoxicity test may be considered a supplementary assay in formulation developments, since it can detect chemically unstable and potentially phototoxic combinations. However, extrapolation of in vitro positive results to human photopatch tests may be performed only to a limited extent.

IQ at 6 years after in utero exposure to antiepileptic drugs: a controlled cohort study.

OBJECTIVE: To delineate the risk to child IQ associated with frequently prescribed antiepileptic drugs. METHODS: Children born to women with epilepsy (n = 243) and women without epilepsy (n = 287) were recruited during pregnancy and followed prospectively. Of these, 408 were blindly assessed at 6 years of age. Maternal and child demographics were collected and entered into statistical models. RESULTS: The adjusted mean IQ was 9.7 points lower (95% confidence interval [CI] -4.9 to -14.6; p < 0.001) for children exposed to high-dose (>800 mg daily) valproate, with a similar significant effect observed for the verbal, nonverbal, and spatial subscales. Children exposed to high-dose valproate had an 8-fold increased need of educational intervention relative to control children (adjusted relative risk, 95% CI 8.0, 2.5-19.7; p < 0.001). Valproate at doses <800 mg daily was not associated with reduced IQ, but was associated with impaired verbal abilities (-5.6, 95% CI -11.1 to -0.1; p = 0.04) and a 6-fold increase in educational intervention (95% CI 1.4-18.0; p = 0.01). In utero exposure to carbamazepine or lamotrigine did not have a significant effect on IQ, but carbamazepine was associated with reduced verbal abilities (-4.2, 95% CI -0.6 to -7.8; p = 0.02) and increased frequency of IQ <85. CONCLUSIONS: Consistent with data from younger cohorts, school-aged children exposed to valproate at maternal doses more than 800 mg daily continue to experience significantly poorer cognitive development than control children or children exposed to lamotrigine and carbamazepine.

Clinical features of and genetic predisposition to drug-induced Stevens-Johnson syndrome and toxic epidermal necrolysis in a single Korean tertiary institution patients-investigating the relation between the HLA -B*4403 allele and lamotrigine.

PURPOSE: Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are rare but fatal adverse mucocutaneous reactions to certain drugs. Recent studies suggest that ethnicity and genetic predisposition may play a crucial role in the manifestation of the reaction. In this study, we described the role of human leukocyte antigen (HLA)-B alleles in the development of clinical characteristics and treatment outcomes of SJS/TEN in a single Korean tertiary hospital. METHODS: We retrospectively reviewed the medical records (from March 1, 2010 to February 28, 2014) of 30 patients diagnosed with SJS and/or TEN. RESULTS: The main causative drugs were anticonvulsants (26.7 %) and allopurinol (26.7 %), followed by antibiotics (16.7 %), acetazolamide (10.0 %), acetaminophen (10.0 %), and herbal medication (6.7 %). The mean latencies of these drugs were variable. Liver damage was the most common symptom (observed in 63.3 % of the patients). Of the five patients with lamotrigine-induced SJS/TEN, three expressed the HLA-B*4403 allele (60.0 %). Of the seven patients with allopurinol-induced SJS/TEN, five expressed the HLA-B*5801 allele (71.4 %). CONCLUSIONS: The major SJS/TEN-inducing drugs were found to be allopurinol and anticonvulsants (such as lamotrigine). We speculated that Korean individuals expressing the HLA-B*4403 allele may be highly susceptible to lamotrigine-induced SJS/TEN.

Malformation risks of antiepileptic drug monotherapies in pregnancy: updated results from the UK and Ireland Epilepsy and Pregnancy Registers.

OBJECTIVES: Antiepileptic drug (AED) exposure during pregnancy increases the risk of major congenital malformations (MCMs). The magnitude of this risk varies by AED exposure. Here we provide updated results from the UK Epilepsy and Pregnancy Register of the risk of MCMs after monotherapy exposure to valproate, carbamazepine and lamotrigine. METHODS: Fifteen-year prospective observational study from 1996 until 2012. The main outcome measure is the MCM rate. RESULTS: Informative outcomes were available for 5206 cases. 1290 women were exposed to valproate monotherapy, 1718 to carbamazepine monotherapy and 2198 to lamotrigine monotherapy. The MCM risk with valproate monotherapy exposure in utero was 6.7% (95% CI 5.5% to 8.3%) compared with 2.6% with carbamazepine (95% CI 1.9% to 3.5%) and 2.3% with lamotrigine (95% CI 1.8% to 3.1%). A significant dose effect was seen with valproate (p=0.0006) and carbamazepine (p=0.03) exposed pregnancies. A non-significant trend towards higher MCM rate with increasing dose was found with lamotrigine. MCM rate for high-dose lamotrigine (>400 mg daily) was lower than the MCM rate for pregnancies exposed to <600 mg daily of valproate, but this was not significant (3.4% vs 5.0%, p=0.31). CONCLUSIONS: In utero exposure to valproate carries a significantly higher MCM risk than lamotrigine (p=0.0001) and carbamazepine (p=0.0001) monotherapy. In contrast to prior findings, high-dose lamotrigine was associated with fewer MCMs than all doses of valproate. While lamotrigine has a favourable profile compared with valproate for adverse pregnancy outcomes, the requirements for seizure control should not be overlooked.

Reproductive endocrine health in pubertal females with epilepsy on antiepileptic drugs: time to screen?

OBJECTIVES: Although previous studies suggest that valproate (VPA) may induce reproductive endocrine disorders, the effects of newer antiepileptic drugs (AEDs) on reproductive endocrine health have not been widely investigated and compared with those of older AEDs. Therefore, this multicenter cross-sectional study aimed to evaluate the prevalence of reproductive endocrine dysfunctions in pubertal females with epilepsy receiving VPA, lamotrigine (LTG), or levetiracetam (LEV) monotherapy. PATIENTS AND METHODS: Pubertal girls on VPA (n = 11), LTG (n = 8), or LEV (n = 13) monotherapy for at least 6 months were recruited. Healthy sex-matched and age-matched subjects were enrolled as controls (n = 32). Each participant underwent a comprehensive physical examination concerning signs of hyperandrogenism. The Ferriman-Gallwey score of hirsutism was assessed. In addition, all patients completed a standardized questionnaire regarding epilepsy, menstrual cycle, and hirsutism features. Adiposity indices were measured and weight gain was documented for each subject. RESULTS: Hirsutism score, occurrence of hyperandrogenism features, and adiposity indices were significantly higher in the VPA group when compared with LEV and control groups. VPA therapy was more frequently associated with weight gain when compared with LTG and controls, whereas no significant differences with regard to signs of hyperandrogenism were found between VPA and LTG groups. Furthermore, no differences in menstrual disorders were observed between groups. CONCLUSIONS: Pubertal girls with epilepsy receiving VPA monotherapy were more likely to develop signs of hyperandrogenism, that is, hirsutism and acanthosis, than those on LEV or controls. However, no differences in occurrence of menstrual disorders and other reproductive dysfunctions were found between VPA, LTG, LEV, and control groups. These findings do not allow us to clearly determine whether or not VPA, LEV, and LTG monotherapies considerably affect reproductive endocrine health in pubertal girls with epilepsy. Therefore, further prospective studies of larger sample sizes are needed to establish if screening tests should be recommended.

Methods: implementation of in vitro and ex vivo phagocytosis and respiratory burst function assessments in safety testing.

Functional innate immune assessments, including phagocytosis and respiratory burst, are at the forefront of immunotoxicology evaluation in pre-clinical animal species. Although in the clinic and in academic science, phagocytosis, and respiratory burst assessments have been reported for over two decades, the implementation of phagocytosis and respiratory burst analyses in toxicology safety programs is just recently gaining publicity. Discussed herein are general methods, both microtiter plate-based and flow cytometric-based, for assessing phagocytosis and respiratory burst in pre-clinical species including mouse, rat, dog, and monkey. This methods-centric discussion includes a review of technologies and descriptions of method applications, with examples of results from analyses testing reported inhibitors (rottlerin, wortmannin, and SB203580) of phagocytosis and respiratory burst. Justification of implementation, strategic experimental design planning, and feasibility aspects of evaluating test article effects on phagocytosis and respiratory burst function are described within the context of a case study. The case study involves investigation of the effects of a small molecule p38 kinase inhibitor, BMS-582949, on phagocytosis and respiratory burst functions in rat and monkey neutrophils and monocytes in vitro, as well as ex vivo in these innate immune cells from monkeys administered BMS-582949 during a 1-week repeat dose investigative study. The results of the in vitro and ex vivo assessments demonstrated that BMS-582949 inhibited phagocytosis and respiratory burst. These findings correlated with incidences of opportunistic infections observed in rat and monkey toxicity studies.

[Juvenile myoclonic epilepsy]. / Juvenil myoklonusepilepsi.

BACKGROUND: Juvenile myoclonic epilepsy (JME) is a generalised epilepsy with seizure onset in youth. The aim of this review is to present updated knowledge about the etiology, diagnosis and treatment of JME. MATERIAL AND METHOD: The review is based on a judicious selection of original English language articles, meta-analyses, and reviews found in PubMed, and the authors' own experience with the patient group. RESULTS: Seizure onset occurs in adolescence. All have myoclonias, about 90 % have generalized tonic-clonic seizures, and one third have absences. Myoclonic jerks are frequently the debut symptom, while tonic-clonic seizures appear later on. Patients are particularly susceptible to seizures shortly after waking. It is important to ask specifically about myoclonias as most patients do not report jerks spontaneously. The electroencephalograms of 44-81 % of the patients show discharges of 4-6 Hz polyspike waves. Focal EEG abnormalities may be seen in about 30 %. When patients are treated with valproate and seizure-precipitating factors are avoided, especially sleep deprivation, about 80 % become seizure-free. Lamotrigine and levetiracetam are alternative therapies for women of childbearing age. Attempts to taper off the medication after several years of seizure freedom entail a high risk of seizure relapse. INTERPRETATION: As there may be features of focal epilepsy in the seizure semiology and/or the EEGs, it may be difficult to diagnose JME. Thus, many patients are misdiagnosed as having a focal epilepsy and are given antiepileptic drugs that may aggravate the tendency to seizures.

Cross-reactivity of skin rashes with current antiepileptic drugs in Chinese population.

OBJECTIVE: Due to less experience with the cross-reactivity of antiepileptic drugs (AEDs) in Chinese population, we surveyed the rates of cross- reactivity of rash among commonly used AEDs in Chinese patients with epilepsy, particularly between the traditional and the new compounds. METHODS: We have retrospectively reviewed the medical records concerning all antiepileptic drug treatment in consecutive Chinese patients with epilepsy in our center. The incidence of AED-related rash was determined in 3793 outpatients, taking at least one of the AEDs-carbamazepine (CBZ), valproic acid (VPA), phenytoin (PHT), phenobarbital (PB), clonazepam (CZP), oxcarbazepine (OXC), lamotrigine (LTG), gabapentin (GBP), topiramate (TPM), levetiracetam (LEV) and traditional Chinese medicine (TCM). We have performed telephone interviews among all patients with AEDs-related rash. We described the clinical characteristics of the 18 patients with cross-reactivity involving the AEDs, and the cross- reactivity pattern for CBZ, PHT, OXC, and LTG. RESULTS: A total of 3.61% (137/3793) of patients experienced a skin rash to at least one AEDs, of these patients, 73 (53.28%) were female and 64 were males (46.72%). While 18 patients had a rash to two or more AEDs. Of patients who had a rash to CBZ and were also prescribed PHT (n = 17), 52.9% had a rash to PHT (abbreviated as CBZ → PHT: 52.9%); of patients who had a rash to PHT and were also prescribed CBZ (n = 13), rate of rash was 69.2% (i.e., PHT → CBZ: 69.2%). Other results: CBZ → LTG: 25% (n = 16); LTG → CBZ: 44.4% (n = 9); CBZ→ OXC: 40% (n = 10); OXC → CBZ: 66.7% (n = 6); LTG → PHT: 20% (n = 5); PHT → LTG: 16.7% (n = 6); OXC → LTG: 25% (n=4); LTG → OXC: 33.3% (n = 3); OXC → PHT: 25% (n = 4); PHT → OXC: 16.7% (n = 6). There was a highly significant mutual risk for cross- reactivity for CBZ and PHT, and OXC, and LTG (p<0.001), mutual risk reached statistical significance for LTG and CBZ (p = 0.01). CONCLUSION: Cross-reactivity rates between certain AEDs are high, especially when involving carbamazepine and phenytoin. There were also too few patients with rash to reach definitely conclusions about possible cross-reactivity. Larger numbers of patients would be needed to assess this and the mechanism. Caution should be exercised when prescribing certain AEDs (especially CBZ and PHT, but also OXC, and LTG).

The mechanism of renal stone formation and renal failure induced by administration of melamine and cyanuric acid.

Renal stone formation and renal failure among Chinese infants administered melamine-containing formula were increasingly reported in 2008. We investigated the mechanism by which melamine and cyanuric acid induce renal stone formation and renal failure. Ten-week-old rats were administered either melamine [2.4, 24, or 240 mg/kg/day], both melamine and cyanuric acid [each at 1.2, 12, or 120 mg/kg/day], or water (controls). Blood and 24-h urine samples and kidney sections were evaluated on days 3, 7, and 14. In rats administered melamine alone or the low-dose melamine/cyanuric acid combination [1.2 mg/kg/day], crystals were not detected. On day 3, crystal formation was observed in the renal distal tubular lumens and collecting ducts of rats administered the intermediate-dose melamine/cyanuric acid [12 mg/kg/day], and the number of crystals increased during the course of the experiment. In rats administered the high-dose melamine/cyanuric acid [120 mg/kg/day], crystals were found in the proximal tubular lumens of the renal cortex on day 3, but acute renal failure resulted in death by day 7. Polarized light optical microphotography and scanning electron microscopy revealed tubular lumens occluded by a layer of axle-shaped crystals. X-ray diffraction findings revealed a nitrogen component but no calcium. The upper regions of occluded tubes were expanded, and the epithelium was thin. Melamine and cyanuric acid in combination, but not by melamine alone induce crystal formation and affected renal functioning. Renal failure due to melamine cyanurate crystals appears to occur via tubular occlusion.

The long-term effectiveness of clozapine and lamotrigine in a patient with treatment-resistant rapid-cycling bipolar disorder.

The challenges in the management of treatment-resistant rapid-cycling bipolar disorder are multifaceted and represent a significant burden to the patient. There is a need for more exploration into the potential utility of various combination therapies in the setting of severe affective states. A 52-year-old woman with a history of severe treatment-resistant rapid-cycling bipolar affective disorder (BPAD) was hospitalized for the treatment of a severe mixed episode. The introduction of lamotrigine and clozapine in combination proved remarkably effective and well tolerated in both the acute management and in subsequent maintenance. The patient has remained asymptomatic during the 5-year follow-up without any further mood disturbance. Lamotrigine and clozapine are among the less-prescribed agents for BPAD and there is as yet little research into their use in combination. It is possible that these agents have complementary modes of action on various facets of the affective pathology, resulting in superior mood stabilization in this patient.

The clinical analysis of young children's urolithiasis due to melamine-tainted infant formula.

OBJECTIVE: To analyze etiology, clinical features, effective diagnostic methods and therapeutic efficacy of infant urolithiasis related to melamine. METHODS: A total of 2,235 children fed with milk products were screened at the Second Hospital of Shandong University between 1st September and 31st December 2008. Of the children screened, 1,242 were male and 993 female, with a median age of 15 months (range 4-72 months). Among them, 182 with detailed data were enrolled and divided into Group 1 (calculus group, n = 79) and Group 2 (noncalculus group, n = 103) according to their results of the screening. All cases were reviewed with regard to melamine exposure, presentation, laboratory data, B-ultrasound findings and treatment efficacy. RESULTS: Compared to 103 patients without stones, the 79 patients with stones confirmed by B-ultrasound had significant differences in: melamine daily intake (5.17 ± 4.53 vs. 2.38 ± 3.39 mg/kg per day, P < 0.001) and duration of problematic milk feeding (12.53 ± 8.47 vs. 8.65 ± 3.40 months, P < 0.001). Most of the patients in Group 1 (65.82%) were asymptomatic. In Group 1, all the patients with kidney stones less than 10 mm (n = 75) were successively treated conservatively, whereas the other four with kidney stones >10 mm required surgical treatment. CONCLUSIONS: Melamine overdose can cause an increased risk of developing kidney stones in children. B-ultrasound is the first choice for the diagnosis of urolithiasis related to melamine. For most patients, the conservative treatment is effective; however, the patients with kidney stones >10 mm, surgery may be needed.