Modulation of Rat Hepatic CYP1A and 2C Activity by Honokiol and Magnolol: Differential Effects on Phenacetin and Diclofenac Pharmacokinetics In Vivo.

Honokiol (2-(4-hydroxy-3-prop-2-enyl-phenyl)-4-prop-2-enyl-phenol) and magnolol (4-Allyl-2-(5-allyl-2-hydroxy-phenyl)phenol) are the major active polyphenol constituents of Magnolia officinalis (Magnoliaceae) bark, which has been widely used in traditional Chinese medicine (Houpu Tang) for the treatment of various diseases, including anxiety, stress, gastrointestinal disorders, infection, and asthma. The aim of this study was to investigate the direct effects of honokiol and magnolol on hepatic CYP1A and 2C-mediated metabolism in vitro using rat liver microsomes and in vivo using the Sprague-Dawley rat model. Honokiol and magnolol inhibited in vitro CYP1A activity (probe substrate: phenacetin) more potently than CYP2C activity (probe substrate: diclofenac): The mean IC50 values of honokiol for the metabolism of phenacetin and diclofenac were 8.59 µM and 44.7 µM, while those of magnolol were 19.0 µM and 47.3 µM, respectively. Notably, the systemic exposure (AUC and Cmax) of phenacetin, but not of diclofenac, was markedly enhanced by the concurrent administration of intravenous honokiol or magnolol. The differential effects of the two phytochemicals on phenacetin and diclofenac in vivo pharmacokinetics could at least be partly attributed to their lower IC50 values for the inhibition of phenacetin metabolism than for diclofenac metabolism. In addition, the systemic exposure, CL, and Vss of honokiol and magnolol tended to be similar between the rat groups receiving phenacetin and diclofenac. These findings improve our understanding of CYP-mediated drug interactions with M. officinalis and its active constituents.

Association between use of synthetic metalworking fluid and risk of developing rhinitis-related symptoms in an automotive ring manufacturing plant.

The main objective of this study was to determine the association between synthetic metalworking fluid (MWF) and rhinitis-related symptoms. At a plant manufacturing piston rings for automobiles, we interviewed grinders (19) and manufacturing workers (142) in operations where synthetic or semisynthetic MWF is handled, and administrative office workers (44) regarding the principal symptoms of rhinitis (nasal stuffiness, runny nose, anosmia, nasal itchiness, rhinorrhea, headache, epistaxis, and post-nasal drip). In addition, we assessed the current exposure of workers handling MWF to MWF aerosols, fungi, and endotoxins. Logistic regression analysis was used to examine the association between MWF surrogates indicative of MWF exposure and each rhinitis-related nasal symptom. Odds ratios (ORs) and 95% confidence intervals were adjusted for sex, age, smoking habit, and duration of employment. Among grinders handling synthetic MWF, the frequency of complaints of the dominant symptoms was 66.7% for nasal stuffiness, 77.8% for anosmia, 77.8% for runny nose, and 50.0% for headache. These rates are quite high even allowing for the common occurrence of rhinitis in the general population. Twenty eight of 34 grinding and manufacturing workers (82.4%) sampled were exposed to MWF mist above the threshold limit of 0.2 mg/m(3) listed as a notice of intended change by the American Conference for Governmental Industrial Hygienists (ACGIH). The percentage of workers exposed to MWF mist >0.5 mg/m(3) was 17.6%. Most workers were exposed to fungi levels >103 CFU/m(3). All exposures to endotoxins were <50 EU/m(3). Logistic regression analysis found that use of synthetic MWF was significantly associated with excess risk of nasal stuffiness (OR 3.5), nasal itchiness (OR 2.0), and runny nose (OR 2.1). The use of semi-synthetic MWF had little or no impact on the risk of developing rhinitis-related nasal symptoms. Grinding workers handling synthetic MWF had an increased risk of nasal stuffiness (OR 7.9), anosmia (OR 23.2), nasal itchiness (OR 8.3), runny nose (OR 20.4), post nasal drip (OR 18.4), and headache (OR 7.4) compared to administrative workers. Synthetic MWF may play an important role in the development of the dominant symptoms of rhinitis. Further study is needed to establish the risk of rhinitis or rhinitis-related symptoms according to MWF type.

Avoidance therapy in reactive dye-induced occupational asthma: long-term follow-up.

BACKGROUND: Previous studies reported that early diagnosis and avoidance therapy are the most important factors for prevention of permanent lung impairment; however, few studies have evaluated the long-term prognosis of reactive dye-induced occupational asthma (RD-OA). OBJECTIVE: To evaluate the long-term outcomes of RD-OA. METHODS: Methacholine airway hyperresponsiveness (AHR) and lung functions were evaluated and compared in 26 patients with RD-OA at the time of diagnosis and after complete avoidance of the causative agents. Patients with continued (n = 13) or remitted (n = 6) AHR were further monitored for up to a mean +/- SD of 8.7 +/- 1.8 years. RESULTS: The AHR resolved in 10 (38%) of 26 patients a mean +/- SD of 2.2 +/- 1.3 years after complete avoidance of RDs; however, prebronchodilator forced expiratory volume in 1 second (FEV1) values were not different. Levels of IgE specific to the RD-human serum albumin complex were markedly decreased at first follow-up in 5 RD-atopic patients from whom paired serum samples were compared (P = .02). The AHR disappeared in an additional 5 patients and improved in 4 by the second follow-up. The FEV1 values also improved compared with diagnosis and first follow-up levels. Favorable prognosis was associated with early diagnosis of RD-OA and complete avoidance of the causative agent. No association was found with smoking history, latent periods, the presence of RD specific IgE, baseline provocation concentration that caused a decrease in FEV1 of 20%, or FEV1. CONCLUSIONS: Early diagnosis and avoidance therapy are the most important prognostic factors in RD-OA. The AHR and lung function of patients with RD-OA can sometimes be recovered steadily and slowly through avoidance measures.