Antiepileptic Drug Treatment Patterns in Women of Childbearing Age With Epilepsy.

Importance: Limited population-based data are available on antiepileptic drug (AED) treatment patterns in women of childbearing age with epilepsy; the current population risk is not clear. Objectives: To examine the AED treatment patterns and identify differences in use of valproate sodium and topiramate by comorbidities among women of childbearing age with epilepsy. Design, Setting, and Participants: A retrospective cohort study used a nationwide commercial database and supplemental Medicare as well as Medicaid insurance claims data to identify 46 767 women with epilepsy aged 15 to 44 years. The eligible study cohort was enrolled between January 1, 2009, and December 31, 2013. Data analysis was conducted from January 1, 2017, to February 22, 2018. Exposures: Cases required an International Classification of Diseases, Ninth Revision, Clinical Modification-coded epilepsy diagnosis with continuous medical and pharmacy enrollment. Incident cases required a baseline of 2 or more years without an epilepsy diagnosis or AED prescription before the index date. For both incident and prevalent cases, focal and generalized epilepsy cohorts were matched by age, payer type, and enrollment period and then compared. Main Outcomes and Measures: Antiepileptic drug treatment pattern according to seizure type and comorbidities. Results: Of the 46 767 patients identified, there were 8003 incident cases (mean [SD] age, 27.3 [9.4] years) and 38 764 prevalent cases (mean [SD] age, 29.7 [9.0] years). Among 3219 women in the incident epilepsy group who received AEDs for 90 days or more, 3173 (98.6%) received monotherapy as first-line treatment; among 28 239 treated prevalent cases, 18 987 (67.2%) received monotherapy. In 3544 (44.3%) incident cases and 9480 (24.5%) prevalent cases, AED treatment was not documented during 180 days or more of follow-up after diagnosis. Valproate (incident: 35 [5.81%]; prevalent: 514 [13.1%]) and phenytoin (incident: 33 [5.48%]; prevalent: 178 [4.53%]) were more commonly used for generalized epilepsy and oxcarbazepine (incident: 53 [8.03%]; prevalent: 386 [9.89%]) was more often used for focal epilepsy. Levetiracetam (incident: focal, 267 [40.5%]; generalized, 271 [45.0%]; prevalent: focal, 794 [20.3%]; generalized, 871 [22.2%]), lamotrigine (incident: focal, 123 [18.6%]; generalized, 106 [17.6%]; prevalent: focal, 968 [24.8%]; generalized, 871 [22.2%]), and topiramate (incident: focal, 102 [15.5%]; generalized, 64 [10.6%]; prevalent: focal, 499 [12.8%]; generalized, 470 [12.0%]) were leading AEDs prescribed for both focal and generalized epilepsy. Valproate was more commonly prescribed for women with comorbid headache or migraine (incident: 53 of 1251 [4.2%]; prevalent: 839 of 8046 [10.4%]), mood disorder (incident: 63 of 860 [7.3%]; prevalent: 1110 of 6995 [15.9%]), and anxiety and dissociative disorders (incident: 57 of 881 [6.5%]; prevalent: 798 of 5912 [13.5%]). Topiramate was more likely prescribed for those with comorbid headache or migraine (incident: 335 of 1251 [26.8%]; prevalent: 2322 of 8046 [28.9%]). Conclusions and Relevance: Many women appear to be treated with valproate and topiramate despite known teratogenicity risks. Comorbidities may affect selecting certain AEDs despite their teratogenicity risks.

Control of Inflammatory Responses: a New Paradigm for the Treatment of Chronic Neuronal Diseases.

The term 'inflammation' was first introduced by Celsus almost 2000 years ago. Biological and medical researchers have shown increasing interest in inflammation over the past few decades, in part due to the emerging burden of chronic and degenerative diseases resulting from the increased longevity that has arisen thanks to modern medicine. Inflammation is believed to play critical roles in the pathogenesis of degenerative brain diseases, including Alzheimer's disease and Parkinson's disease. Accordingly, researchers have sought to combat such diseases by controlling inflammatory responses. In this review, we describe the endogenous inflammatory stimulators and signaling pathways in the brain. In particular, our group has focused on the JAK-STAT pathway, identifying anti-inflammatory targets and testing the effects of various anti-inflammatory drugs. This work has shown that the JAK-STAT pathway and its downstream are negatively regulated by phosphatases (SHP2 and MKP-1), inhibitory proteins (SOCS1 and SOCS3) and a nuclear receptor (LXR). These negative regulators are controlled at various levels (e.g. transcriptional, post-transcriptional and post-translational). Future study of these proteins could facilitate the manipulation of the inflammatory response, which plays ubiquitous, diverse and ambivalent roles under physiological and pathological conditions.

Evaluation of toxicity to triclosan in rats following 28 days of exposure to aerosol inhalation.

The present study was conducted to investigate the potential subchronic toxicity of triclosan (TCS) in rats following 28 days of exposure by repeated inhalation. Four groups of six rats of each sex were exposed to TCS-containing aerosols by nose-only inhalation of 0, 0.04, 0.13, or 0.40 mg/L for 6 h/day, 5 days/week over a 28-day period. During the study period, clinical signs, mortality, body weight, food consumption, ophthalmoscopy, hematology, serum biochemistry, gross pathology, organ weights, and histopathology were examined. At 0.40 mg/L, rats of both sexes exhibited an increase in the incidence of postdosing salivation and a decrease in body weight. Histopathological alterations were found in the nasal septum and larynx. There were no treatment-related effects in rats of either sex at ⩽0.13 mg/L. Under the present experimental conditions, the target organs in rats were determined to be the nasal cavity and larynx. The no-observed-adverse-effect concentration in rats was determined to be 0.13 mg/L.

Cytotoxic effects of air freshener biocides in lung epithelial cells.

This study evaluated the cytotoxicity of mixtures of citral (CTR) and either benzisothiazolinone (BIT, Mix-CTR-BIT) or triclosan (TCS, Mix-CTR-TCS) in human A549 lung epithelial cells. We investigated the effects of various mix ratios of these common air freshener ingredients on cell viability, cell proliferation, reactive oxygen species (ROS) generation, and DNA damage. Mix-CTR-BIT and Mix-CTR-TCS significantly decreased the viability of lung epithelial cells and inhibited cell growth in a dose-dependent manner. In addition, both mixtures increased ROS generation, compared to that observed in control cells. In particular, cell viability, growth, and morphology were affected upon increase in the proportion of BIT or TCS in the mixture. However, comet analysis showed that treatment of cells with Mix-CTR-BIT or Mix-CTR-TCS did not increase DNA damage. Taken together, these data suggested that increasing the content of biocides in air fresheners might induce cytotoxicity, and that screening these compounds using lung epithelial cells may contribute to hazard assessment.

Effects of woohwangcheongsimwon suspension on the pharmacokinetics of bupropion and its active metabolite, 4-hydroxybupropion, in healthy subjects.

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT: Woohwangcheongsimwon suspension has traditionally been used for the treatment and prevention of stroke, hypertension, palpitations, convulsions and unconsciousness in various Asian countries. Woohwangcheongsimwon suspensions showed an inhibitory effect on CYP2B6 activity in vitro. Two terpenoids, borneol and isoborneol, are major constituents of woohwangcheongsimwon suspension, and show a competitive inhibition of CYP2B6 with K(i) values of 9.5 and 5.9 microM, respectively. Bupropion undergoes metabolic transformation to the active metabolite, 4-hydroxybupropion, primarily via CYP2B6 both in vivo and in vitro. It is often used as a CYP2B6 substrate for clinical drug-drug interaction studies. Drug interactions may occur between woohwangcheongsimwon suspension and bupropion. WHAT THIS STUDY ADDS: Co-administration with woohwangcheongsimwon suspension did not alter the pharmacokinetics of bupropion or its metabolite, 4-hydroxybupropion. Dosage adjustment of bupropion is unnecessary in patients concomitantly administered the highest recommended daily dose of woohwangcheongsimwon suspension. AIMS: To examine the effects of woohwangcheongsimwon suspension on the pharmacokinetics of bupropion and its active metabolite, 4-hydroxybupropion, formed via CYP2B6 in vivo. METHODS: A two-way crossover clinical trial with a 2 week washout period was conducted in 14 healthy volunteers. In phases I and II, subjects received 150 mg bupropion with or without woohwangcheongsimwon suspension four times (at -0.17, 3.5, 23.5 and 47.5 h, with the time of bupropion administration taken as 0 h) in a randomized balanced crossover order. Bupropion and 4-hydroxybupropion plasma concentrations were measured for up to 72 h by LC-MS/MS. Urine was collected up to 24 h to calculate the renal clearance. In addition, the CYP2B6*6 genotype was also analyzed. RESULTS: The geometric mean ratios and 90% confidence interval of bupropion with woohwangcheongsimwon suspension relative to bupropion alone were 0.976 (0.917, 1.04) for AUC(0,infinity) and 0.948 (0.830,1.08) for C(max), respectively. The corresponding values for 4-hydroxybupropion were 0.856 (0.802, 0.912) and 0.845 (0.782, 0.914), respectively. The t(max) values of bupropion and 4-hydroxybupropion were not significantly different between the two groups (P > 0.05). The pharmacokinetic parameters of bupropion and 4-hydroxybupropion were unaffected by woohwangcheongsimwon suspension. CONCLUSIONS: These results indicate that woohwangcheongsimwon suspension has a negligible effect on the disposition of a single dose of bupropion in vivo. As a result, temporary co-administration with woohwangcheongsimwon suspension does not seem to require a dosage adjustment of bupropion.

Identification and characterization of potent CYP2B6 inhibitors in Woohwangcheongsimwon suspension, an herbal preparation used in the treatment and prevention of apoplexy in Korea and China.

Woohwangcheongsimwon is a traditional medicine for treating hypertension, arteriosclerosis, coma, and stroke in China and Korea. To assess potential interactions of herb and drug metabolism, commercially available Woohwangcheongsimwon suspensions were examined for their potential to inhibit the activity of nine human cytochrome P450 enzymes. The Woohwangcheongsimwon suspensions showed strong inhibition of CYP2B6 activity. To identify individual constituents with inhibitory activity, the suspension was partitioned using hexane, ethyl acetate, and dichloromethane, and each fraction was tested for its inhibitory effect on CYP2B6-catalyzed bupropion hydroxylation. The hexane fraction possessed inhibitory activity, and gas chromatography/mass spectrometry analysis identified borneol and isoborneol as major constituents of the hexane fraction. These two terpenoids moderately inhibited CYP2B6-catalyzed bupropion hydroxylase activity in a competitive manner, with K(i) values of 9.5 and 5.9 microM, respectively, as well as efavirenz 8-hydroxylase activity, with K(i) values of 22 and 26 microM, respectively. Additionally, reconstituted mixtures of borneol and isoborneol, at the same concentrations as in the Woohwangcheongsimwon suspension, had comparable potency in inhibiting bupropion hydroxylation. These in vitro data indicate that Woohwangcheongsimwon preparations contain constituents that can potently inhibit the activity of CYP2B6 and suggest that these preparations should be examined for potential pharmacokinetic drug interactions in vivo.

Effect of a Growth Protein-Colostrum Fraction on bone development in juvenile rats.

Colostrum is a complex mixture of bioactives that promotes neonate growth. Studies show that it contains components capable of promoting bone formation and inhibiting bone resorption. Although many colostrum-based nutritional supplements have been developed as growth promotants, few studies have investigated their functional effects. A bovine colostrum 1-30 kDa fraction, Growth Protein-Colostrum (GP-C), was administered to juvenile rats as a dietary supplement to determine effects on growth and development. GP-C enhanced the growth and mineralization of the femur as evidenced by increased serum osteocalcin and bone mineral density. Increased levels of serum growth hormone and insulin-like growth factor-1 suggest that the mechanism of enhanced growth is partially controlled by endocrine factors. GP-C was also found to increase osteoblast proliferation in vitro, a finding that indicates a possible mechanism of action of GP-C, but further studies are required. Based on our findings, we hypothesize that a colostrum-based dietary supplement enhances bone growth and development in humans.

Characterization of benidipine and its enantiomers' metabolism by human liver cytochrome P450 enzymes.

Benidipine is a dihydropyridine calcium antagonist that has been used clinically as an antihypertensive and antianginal agent. It is used clinically as a racemate, containing the (-)-alpha and (+)-alpha isomers of benidipine. This study was performed to elucidate the metabolism of benidipine and its enantiomers in human liver microsomes (HLMs) and to characterize the cytochrome P450 (P450) enzymes that are involved in the metabolism of benidipine. Human liver microsomal incubation of benidipine in the presence of NADPH resulted in the formation of two metabolites, N-desbenzylbenidipine and dehydrobenidipine. The intrinsic clearance (CL(int)) of the formation of N-desbenzylbenidipine and dehydrobenidipine metabolites from (-)-alpha isomer was similar to those from the (+)-alpha isomer (1.9 +/- 0.1 versus 2.3 +/- 2.3 microl/min/pmol P450 and 0.5 +/- 0.2 versus 0.6 +/- 0.6 microl/min/pmol P450, respectively). Correlation analysis between the known P450 enzyme activities and the rate of the formation of benidipine metabolites in the 15 HLMs showed that benidipine metabolism is correlated with CYP3A activity. The P450 isoform-selective inhibition study in liver microsomes and the incubation study of cDNA-expressed enzymes also showed that theN-debenzylation and dehydrogenation of benidipine are mainly mediated by CYP3A4 and CYP3A5. The total CL(int) values of CYP3A4-mediated metabolite formation from (-)-alpha isomer were similar to those from (+)-alpha isomer (17.7 versus 14.4 microl/min/pmol P450, respectively). The total CL(int) values of CYP3A5-mediated metabolite formation from (-)-alpha isomer were also similar to those from (+)-alpha isomer (8.3 versus 11.0 microl/min/pmol P450, respectively). These findings suggest that CYP3A4 and CYP3A5 isoforms are major enzymes contributing to the disposition of benidipine, but stereoselective disposition of benidipine in vivo may be influenced not by stereoselective metabolism but by other factors.

Hypoglycemic effect of crude exopolysaccharides produced by a medicinal mushroom Phellinus baumii in streptozotocin-induced diabetic rats.

The antidiabetic effect of the crude exopolysaccharides (EPS) produced from submerged mycelial culture of Phellinus baumii in streptozotocin (STZ)-induced diabetic rats was investigated. The produced EPS consisted of two different heteropolysaccharides and two proteoglycans. The food intake of the diabetic control rats (STZ) was increased by 28.1%, whereas body weight gain was reduced by 44.1% as compared to the nondiabetic animals (NC). The plasma glucose level in the EPS-fed rats (EPS) was substantially reduced by 52.3% as compared to the diabetic rats (STZ), which is the highest hypoglycemic effect among mushroom-derived materials documented in literature. The activities of alanine aminotransferase (ALT) and asparate aminotransferase (AST) were significantly decreased by administration of P. baumii EPS, thereby exhibiting a remedial role in liver function. The significant increase in weights of liver, spleen, and kidney was observed in diabetic groups (both STZ and EPS) compared to NC. The results suggest that orally administrated P. baumii EPS exhibited considerable hypoglycemic effect in STZ-induced diabetic rats and that these EPS may be useful for the management of diabetes mellitus.