In vitro evidence of possible influence of scutellarein towards bile acids' metabolism

Background

The glucuronidation process has been regarded as the key elimination process for toxic bile acids. UDP-glucuronosyltransferase (UGT) 1A3 is one important metabolizing enzyme involved in this process.

Objective

To evaluate the inhibition of UGT1A3 by scutellarein which is an important herbal ingredient using in vitro method, trying to indicate the possibility of toxicity due to the accumulation of toxic bile acids.

Methods

Due to the difficulty to gain the standards of biles acids'' glucuronides, the recombinant UGT1A3-catalyzed 4-methylumbelliferone (4-MU) glucuronidation reaction was employed to profile the activity of UGT1A3.

Results

The results showed that scutellarein inhibited UGT1A3 in a concentration-dependent behaviour. Competitive inhibition was demonstrated using both Dixon plot and Lineweaver-Burk plot, and the inhibition kinetic parameter (K_i) was calculated to be 5.8uM.

Conclusion

All these data reminded the necessary monitoring of the levels of bile acids in plasma when utilizing scutellarein and the herbs containing this compound.     

In vitro evidence for bakuchiol's influence towards drug metabolism through inhibition of UDP-glucuronosyltransferase (UGT) 2B7

Background

Inhibition of drug-metabolizing enzymes (DMEs) has been regarded as one of the most important reason for clinical drug-drug interaction.

Aim

The aim of the present study is to evaluate the inhibition of bakuchiol towards UDP-glucuronosyltransferase (UGT) 2B isoforms.

Methods

In vitro recombinant UGT2B-catalyzed 4-methylumbelliferone glucuronidation was used as the probe reaction. Dixon plot and Lineweaver-Burk plot were employed to determine the inhibition kinetic type, and nonlinear regression of data was utilized to calculate the inhibition kinetic parameter (Ki). In vitro-in vivo extrapolation (IVIVE) was carried out to predict in vivo inhibition magnitude.

Results

Among the tested UGT2B isoforms, UGT2B7 was inhibited by the strongest intensity. The noncompetitive inhibition was demonstrated by the results obtained from Dixon plot and Lineweaver-Burk plot. The K_i value was calculated to be 10.7 µM. In combination with the reported concentration after an intravenous administration of bakuchiol (15 mg/kg) in rats, the high risk of in vivo inhibition of bakuchiol towards UGT2B7-catalyzed metabolism of drugs was indicated.

Conclusion

All these results provide an important information for the risk evaluation of the clinical utilization of bakuchiol.     

In vitro evidence for endocrine-disrupting chemical (EDC)'s inhibition of drug metabolism

Background

Humans can be frequently exposed to Bisphenol A (BPA) via multiple sources, and babies are considered to be the most sensitive group to exposure of BPA.

Aims

To investigate the inhibition potential of BPA towards human liver microsomes (HLMs)-catalyzed zidovudine (AZT) glucuronidation.

Materials and Methods

In vitro HLMs incubation system was used to investigate the inhibition potential of BPA towards AZT glucuronidation. Both Dixon and Lineweaver-Burk plots were employed to determine the inhibition kinetic type, and nonlinear repression was utilized to calculate the inhibition kinetic parameters (Ki).

Results

Concentration-dependent inhibition of BPA towards AZT glucuronidation was observed. Both Dixon and Lineweaver-Burk plots showed that BPA exerted competitive inhibition towards the glucuronidation of AZT, and nonlinear repression with competitive equation was used to calculate the Ki value to be 3.2 µM.

Conclusion

Potential BPA-AZT interaction might occur when the patients administered with AZT is also exposed to BPA.     

In vitro evidence of baicalein's inhibition of the metabolism of zidovudine (AZT)

Background

Herb-drug interaction (HDI) has been regarded as a key factor limiting the clinical application of herbs and drugs.

Aims

Potential baicalein-zidovudine (AZT) interaction was predicted in the present study.

Methods

In vitro evaluation of baicalein''s inhibition towards human liver microsomes (HLMs)-catalyzed metabolism of zidovudine (AZT) was performed. Dixon and Lineweaver-Burk plots were used to determine the inhibition kinetic type, and second plot with the slopes from Lineweaver-Burk plot versus the concentrations of baicalein was employed to calculate the inhibition parameter (Ki). In combination with the in vivo concentration of baicalein, in vitro-in vivo extrapolation (IVIVE) was carried out to predict in vivo baicalein-AZT interaction.

Results

Competitive inhibition of baicalein towards AZT metabolism was demonstrated, and the K_i value was calculated to be 101.2 µM. The value of AUCi/AUC was calculated to be 2.

Conclusion

Potential baicalein-AZT interaction was indicated in the present study, indicating the need for monitoring when AZT is co-administrated with baicalein or baicalein-containing herbs.     

Bile acids cycle disruption in patients with nasopharyngeal carcinoma promotes the elevation of interleukin-10 secretion

Background

Unclear pathogenesis existed for nasopharyngeal carcinoma.

Aims

to analyze the role of bile acids in the pathogenesis of nasopharyngeal carcinoma.

Methods

20 healthy volunteers and 20 patients with nasopharyngeal carcinoma were enrolled between January 1^st, 2013 and December 31^st, 2014. ESI-QTOF-MS analysis of serum was performed to find altered bile acids components. The biological function of changed bile acids was investigated using in vitro experiment.

Results

Compared with healthy volunteers, the level of DCA and GDCA exhibited higher abundance in patients with nasopharyngeal carcinoma (p<0.01). Furthermore, the biological function was investigated for the inhibition of DCA and GDCA towards the secretion of IL-10 by CD4+CD25− T cells. Both DCA and GDCA significantly inhibited the secretion of IL-10 by CD4+CD25− T cells. Furthermore, DCA+GDCA can show stronger inhibition towards the secretion of IL-10 than DCA and GDCA.

Conclusion

The inhibition of IL-10 secretion by elevated DCA and GDCA components in nasopharyngeal carcinoma patients is the inducer for nasopharyngeal carcinoma.     

Bioactivity-Guided Isolation of Anticancer Agents from Bauhinia Kockiana Korth

Background

Flowers of Bauhinia kockiana were investigated for their anticancer properties.

Methods

Gallic acid (1), and methyl gallate (2), were isolated via bioassay-directed isolation, and they exhibited anticancer properties towards several cancer cell lines, examined using MTT cell viability assay. Pyrogallol (3) was examined against the same cancer cell lines to deduce the bioactive functional group of the phenolic compounds.

Results

The results showed that the phenolic compounds could exhibit moderate to weak cytotoxicity towards certain cell lines (GI₅₀ 30 – 86 µM), but were inactive towards DU145 prostate cancer cell (GI₅₀ > 100 µM).

Conclusion

It was observed that pyrogallol moiety was one of the essential functional structures of the phenolic compounds in exhibiting anticancer activity. Also, the carboxyl group of compound 1 was also important in anticancer activity. Examination of the PC-3 cells treated with compound 1 using fluorescence microscopy showed that PC-3 cells were killed by apoptosis.     

Pharmacodynamic Estimate of Propofol-Induced Sedation and Airway Obstruction Effects in Obstructive Sleep Apnea-Hypopnea Syndrome

Purpose

Sedatives must be carefully titrated for patients with obstructive sleep apnea-hypopnea syndrome (OSAHS) as oversedation may lead to disastrous respiratory outcomes. This study aimed to investigate the relations between the effect-site concentration (Ce) of propofol and sedation and airway obstruction levels in patients with OSAHS.

Materials and Methods

In 25 patients with OSAHS, sedation was induced by 2% propofol using target-controlled infusion. Sedation and airway obstruction levels were assessed using the Observer''s Assessment of Alertness/Sedation Scale and a four-category scale, respectively. The relationships between propofol Ce and sedation and airway obstruction were evaluated using a sigmoid Emax model. Pharmacodynamic modeling incorporating covariates was performed using the Nonlinear Mixed Effects Modeling VII software.

Results

Increased propofol Ce correlated with the depth of sedation and the severity of airway obstruction. Predicted Ce_50(m) (Ce associated with 50% probability of an effect≥m) for sedation scores (m≥2, 3, 4, and 5) and airway-obstruction scores (m≥2, 3, and 4) were 1.61, 1.78, 1.91, and 2.17 µg/mL and 1.53, 1.64, and 2.09 µg/mL, respectively. Including the apnea-hypopnea index (AHI) as a covariate in the analysis of Ce₅₀₍₄₎ for airway obstruction significantly improved the performance of the basic model (p<0.05).

Conclusion

The probability of each sedation and airway obstruction score was properly described using a sigmoid Emax model with a narrow therapeutic range of propofol Ce in OSAHS patients. Patients with high AHI values need close monitoring to ensure that airway patency is maintained during propofol sedation.     

Remifentanil-based total intravenous anesthesia for pediatric rigid bronchoscopy: comparison of adjuvant propofol and ketamine

OBJECTIVE:

Laryngoscopy and stimuli inside the trachea cause an intense sympatho-adrenal response. Remifentanil seems to be the optimal opioid for rigid bronchoscopy due to its potent and short-acting properties. The purpose of this study was to compare bolus propofol and ketamine as an adjuvant to remifentanil-based total intravenous anesthesia for pediatric rigid bronchoscopy.

MATERIALS AND METHODS:

Forty children under 12 years of age who had been scheduled for a rigid bronchoscopy were included in this study. After midazolam premedication, a 1 µg/kg/min remifentanil infusion was started, and patients were randomly allocated to receive either propofol (Group P) or ketamine (Group K) as well as mivacurium for muscle relaxation. Anesthesia was maintained with a 1 µg/kg/min remifentanil infusion and bolus doses of propofol or ketamine. After the rigid bronchoscopy, 0.05 µg/kg/min of remifentanil was maintained until extubation. Hemodynamic parameters, emergence characteristics, and adverse events were evaluated.

RESULTS:

The demographic variables were comparable between the two groups. The decrease in mean arterial pressure from baseline values to the lowest values during rigid bronchoscopy was greater in Group P (p = 0.049), while the reduction in the other parameters and the incidence of adverse events were comparable between the two groups. The need for assisted or controlled mask ventilation after extubation was higher in Group K.

CONCLUSION:

Remifentanil-based total intravenous anesthesia with propofol or ketamine as an adjuvant drug along with controlled ventilation is a viable technique for pediatric rigid bronchoscopy. Ketamine does not provide a definite advantage over propofol with respect to hemodynamic stability during rigid bronchoscopy, while propofol seems more suitable during the recovery period.     

Reliability and Validity of a Novel Muscle Contusion Device

Context:

Many models have been employed to replicate skeletal muscle injury associated with trauma; however, most are restricted to 1 level of severity.

Objective:

To create and validate an injury-producing device that could generate multiple levels of injury severity.

Design:

Validation study.

Patients or Other Participants:

Twenty-six male Wistar rats, 3 to 4 months old.

Intervention(s):

A contusion device was developed and its ability to deliver consistent impacts was validated alone and in the presence of an experimental animal. A free-falling mass (267 g) was adjusted to the desired height (40, 50, 60, or 70 cm) and then dropped.

Main Outcome Measure(s):

Peak load, peak displacement, impulse, energy, and velocity peak were measured. Injury severity was determined using magnetic resonance imaging.

Results:

Outcome measures observed from the device alone were different by height (F_18,136  =  21.807, P < .001, 1−β  =  1.0). Outcomes using the experimental animals were also dependent on height (F_14,102  =  68.679, P < .001, 1−β  =  1.0). Linear regression analyses indicated that height accounted for 17% to 89% of the variance.

Conclusions:

Mild to moderate and moderate to severe injuries can be replicated with this device, which will be useful in evaluating clinical treatments on acute muscle injury.     

Sex Differences in Head Acceleration During Heading While Wearing Soccer Headgear

Context:

Researchers have indicated that female soccer players may be at greater risk of concussion compared with their male counterparts. Soccer headgear is marketed for reducing head acceleration and risk of concussion.

Objective:

To determine the effect of sex and soccer headgear on head impact kinematics and dynamic stabilization during soccer heading.

Design:

Cross-sectional design.

Setting:

Research laboratory.

Patients or Other Participants:

Forty-four college-aged soccer players (29 women, 15 men).

Intervention(s):

Using a head impact model, participants performed 4 soccer headers under 3 headgear conditions (control, Head Blast Soccer Band, and Full90 Select Performance Headguard).

Main Outcome Measure(s):

Dependent variables assessed before soccer heading were head-neck anthropometrics and isometric neck muscle strength, and those assessed during soccer headers were resultant linear head acceleration, Head Injury Criteria (HIC₃₆), and superficial neck muscle electromyography. Statistical analyses included multivariate and univariate analyses of variance with repeated measures, independent-samples t tests, appropriate follow-up analyses of variance and post hoc t tests, and Pearson product moment correlations (α  =  .05).

Results:

Head acceleration in women was 32% and 44% greater than in men when wearing the Head Blast (21.5 g versus 16.3 g) and Full90 Select (21.8 g versus 15.2 g), respectively (P < .05). Compared with men, women exhibited 10% greater head accelerations (20.2 g versus 18.2 g) during the control condition (P  =  .164).

Conclusions:

Female soccer players exhibited greater head accelerations than their male counterparts when wearing headgear. Our results are important clinically because they indicate that soccer headgear may not be an appropriate head injury prevention tool for all athletes.     

Insomnia with Objective Short Sleep Duration is Associated with Deficits in Neuropsychological Performance: A General Population Study

Study Objectives:

To examine the joint effect of insomnia and objective short sleep duration on neuropsychological performance.

Design:

Representative cross-sectional study.

Setting:

Sleep laboratory.

Participants:

1,741 men and women randomly selected from central Pennsylvania.

Interventions:

None.

Measurements:

Insomnia (n = 116) was defined by a complaint of insomnia with a duration ≥ 1 year and the absence of sleep disordered breathing (SDB), while normal sleep (n = 562) was defined as the absence of insomnia, excessive daytime sleepiness, and SDB. Both groups were split according to polysomnographic sleep duration into 2 categories: ≥ 6 h of sleep (“normal sleep duration”) and < 6 h of sleep (“short sleep duration”). We compared the groups'' performance on a comprehensive neuropsychological battery that measured processing speed, attention, visual memory, and verbal fluency, while controlling for age, race, gender, education, body mass index, and physical and mental health.

Results:

No significant differences were detected between insomniacs and controls. However, the insomnia with short sleep duration group compared to the control with normal or short sleep duration groups showed poorer neuropsychological performance in variables such as processing speed, set-switching attention, and number of visual memory errors and omissions. In contrast, the insomnia with normal sleep duration group showed no significant deficits.

Conclusions:

Insomnia with objective short sleep duration is associated with deficits in set-switching attentional abilities, a key component of the “executive control of attention.” These findings suggest that objective sleep duration may predict the severity of chronic insomnia, including its effect on neurocognitive function.

Citation:

Fernandez-Mendoza J; Calhoun S; Bixler EO; Pejovic S; Karataraki M; Liao D; Vela-Bueno A; Ramos-Platon MJ; Sauder KA; Vgontzas AN. Insomnia with objective short sleep duration is associated with deficits in neuropsychological performance: a general population study. SLEEP 2010;33(4):459-465.     

Alterations in Knee Kinematics and Dynamic Stability Associated With Chronic Ankle Instability

Context:

Chronic ankle instability (CAI) has been previously and separately associated with deficits in dynamic stability and proximal joint neuromuscular alterations, but how the 2 factors relate is unclear.

Objective:

To examine the contributions of lower extremity kinematics during an assessment of dynamic stability in participants with CAI.

Design:

Repeated-measures case-control design.

Setting:

Research laboratory.

Patients or Other Participants:

Thirty-eight volunteers were categorized into groups of those with unilateral CAI (10 men, 9 women; age  =  20.3 ± 2.9 years, height  =  1.77 ± 0.1 m, mass  =  76.19 ± 13.19 kg) and those without (10 men, 9 women; age  =  23.1 ± 3.9 years, height  =  1.72 ± 0.1 m, mass  =  72.67 ± 16.0 kg).

Intervention(s):

Participants performed 10 jump landings on each limb with a rest period between test limbs.

Main Outcome Measure(s):

Ankle plantar flexion, knee flexion, and hip flexion were captured with an electromagnetic tracking device at the point of ground impact. Ground reaction force data were used to calculate time to stabilization in the anteroposterior and mediolateral planes.

Results:

For the anteroposterior plane, we found a group-by-side interaction (P  =  .003), with the injured side of the CAI group demonstrating reduced dynamic stability. For knee flexion, a group main effect (P  =  .008) showed that the CAI group landed with less knee flexion than the control group.

Conclusions:

Diminished dynamic stability and decreased knee flexion angle at initial contact were apparent in the CAI group and may play a role in contributing to CAI. This altered kinematic pattern may influence preventive and therapeutic interventions for those with CAI.     

Bispectral Index Monitoring during Anesthesiologist-Directed Propofol and Remifentanil Sedation for Endoscopic Submucosal Dissection: A Prospective Randomized Controlled Trial

Purpose

Endoscopic submucosal dissection (ESD) is a technically difficult and lengthy procedure requiring optimal depth of sedation. The bispectral index (BIS) monitor is a non-invasive tool that objectively evaluates the depth of sedation. The purpose of this prospective randomized controlled trial was to evaluate whether BIS guided sedation with propofol and remifentanil could reduce the number of patients requiring rescue propofol, and thus reduce the incidence of sedation- and/or procedure-related complications.

Materials and Methods

A total of 180 patients who underwent the ESD procedure for gastric adenoma or early gastric cancer were randomized to two groups. The control group (n=90) was monitored by the Modified Observer''s Assessment of Alertness and Sedation scale and the BIS group (n=90) was monitored using BIS. The total doses of propofol and remifentanil, the need for rescue propofol, and the rates of complications were recorded.

Results

The number of patients who needed rescue propofol during the procedure was significantly higher in the control group than the BIS group (47.8% vs. 30.0%, p=0.014). There were no significant differences in the incidence of sedation- and/or procedure-related complications.

Conclusion

BIS-guided propofol infusion combined with remifentanil reduced the number of patients requiring rescue propofol in ESD procedures. However, this finding did not lead to clinical benefits and thus BIS monitoring is of limited use during anesthesiologist-directed sedation.     

Persistent motor system abnormalities in formerly concussed athletes

Context:

The known detrimental effects of sport concussions on motor system function include balance problems, slowed motor execution, and abnormal motor cortex excitability.

Objective:

To assess whether these concussion-related alterations of motor system function are still evident in collegiate football players who sustained concussions but returned to competition more than 9 months before testing.

Design:

Case-control study.

Setting:

University laboratory.

Patients or Other Participants:

A group of 21 active, university-level football players who had experienced concussions was compared with 15 university football players who had not sustained concussions.

Intervention(s):

A force platform was used to assess center-of-pressure (COP) displacement and COP oscillation regularity (approximate entropy) as measures of postural stability in the upright position. A rapid alternating-movement task was also used to assess motor execution speed. Transcranial magnetic stimulation over the motor cortex was used to measure long-interval intracortical inhibition and the cortical silent period, presumably reflecting γ-aminobutyric acid subtype B receptor-mediated intracortical inhibition.

Main Outcome Measure(s):

COP displacement and oscillation regularity, motor execution speed, long-interval intracortical inhibition, cortical silent period.

Results:

Relative to controls, previously concussed athletes showed persistently lower COP oscillation randomness, normal performance on a rapid alternating-movement task, and more M1 intracortical inhibition that was related to the number of previous concussions.

Conclusions:

Sport concussions were associated with pervasive changes in postural control and more M1 intracortical inhibition, providing neurophysiologic and behavioral evidence of lasting, subclinical changes in motor system integrity in concussed athletes.     

Insomnia with Short Sleep Duration and Mortality: The Penn State Cohort

Study Objectives:

Because insomnia with objective short sleep duration is associated with increased morbidity, we examined the effects of this insomnia subtype on all-cause mortality.

Design:

Longitudinal.

Setting:

Sleep laboratory.

Participants:

1,741 men and women randomly selected from Central Pennsylvania.

Measurements:

Participants were studied in the sleep laboratory and were followed-up for 14 years (men) and 10 years (women). “Insomnia” was defined by a complaint of insomnia with duration ≥ 1 year. “Normal sleeping” was defined as absence of insomnia. Polysomnographic sleep duration was classified into two categories: the “normal sleep duration group” subjects who slept ≥ 6 h and the “short sleep duration group” subjects who slept < 6 h. We adjusted for age, race, education, body mass index, smoking, alcohol, depression, sleep disordered breathing, and sampling weight.

Results:

The mortality rate was 21% for men and 5% for women. In men, mortality risk was significantly increased in insomniacs who slept less than 6 hours compared to the “normal sleep duration, no insomnia” group, (OR = 4.00, CI 1.14-13.99) after adjusting for diabetes, hypertension, and other confounders. Furthermore, there was a marginally significant trend (P = 0.15) towards higher mortality risk from insomnia and short sleep in patients with diabetes or hypertension (OR = 7.17, 95% CI 1.41-36.62) than in those without these comorbid conditions (OR = 1.45, 95% CI 0.13-16.14). In women, mortality was not associated with insomnia and short sleep duration.

Conclusions:

Insomnia with objective short sleep duration in men is associated with increased mortality, a risk that has been underestimated.

Citation:

Vgontzas AN; Liao D; Pejovic S; Calhoun S; Karataraki M; Basta M; Fernández-Mendoza J; Bixler EO. Insomnia with short sleep duration and mortality: the Penn State Cohort. SLEEP 2010;33(9):1159-1164.     

Upper Airway Sensory Function in Children with Obstructive Sleep Apnea Syndrome

Study Objectives:

Children with the obstructive sleep apnea syndrome (OSAS) have impaired responses to hypercapnia, subatmospheric pressure, and inspiratory resistive loading during sleep. This may be due, in part, to an impairment in the afferent limb of the upper airway sensory pathway. Therefore, we hypothesized that children with OSAS had diminished upper airway sensation compared to controls.

Design:

Case-control

Setting:

Academic hospital

Participants:

Subjects with OSAS aged 6–16 years, and age- and BMI-matched controls.

Interventions:

Two-point discrimination (TPD) was measured during wakefulness with modified calipers in the anterior tongue, right interior cheek, and hard palate.

Results:

Thirteen children with OSAS and 9 controls were tested. The age (mean ± SD) for OSAS and controls was 11 ± 4 vs. 13 ± 2 years (NS); OSAS BMI Z score 2.4 ± 0.5, controls 2.2 ± 0.5 (NS); OSAS apnea hypopnea index 31 ± 48, controls 0.4 ± 0.5 events/hour (P < 0.001). Children with OSAS had impaired TPD in the anterior tongue (median [range]) = 9 [3–14] mm, controls 3 [1–7], P = 0.002) and hard palate (OSAS 6 [3–9] mm, controls 3 [1–4], P < 0.001). TPD in the cheek was similar between the groups (P = 0.12).

Conclusion:

TPD in the anterior tongue and hard palate was impaired in children with OSAS during wakefulness. We speculate that this impairment might be due to a primary sensory function abnormality or secondary to nerve damage and/or hypoxemia caused by OSAS. Further studies after treatment of OSAS are needed.

Citation:

Tapia IE; Bandla P; Traylor J; Karamessinis L; Huang J; Marcus CL. Upper airway sensory function in children with obstructive sleep apnea syndrome. SLEEP 2010;33(7):968–972.     

Knowledge,attitudes & barriers to condom use among female sex workers and truck drivers in Uganda: a mixed-methods study

Background

There is limited documentation on knowledge, attitudes and barriers to condom use among female sex workers (FSWs) and truck drivers (truckers).

Objective

To explore knowledge, attitudes and barriers to condom use among FSWs and truckers operating along major transport corridors in Uganda

Methods

Structured questionnaires were administered to explore FSWs'' and truckers'' knowledge of and attitudes towards condom use among 259 FSWs and 261 truckers. Qualitative data were collected on barriers to condom use using focus group discussions. Quantitative data were analyzed using SPSS while qualitative data were audio-recorded, transcribed and thematically analyzed.

Results

Condom knowledge was high with 97% of FSWs and 95% of truckers agreeing with the statement, “using condoms properly and consistently reduces risk of HIV infection”. Attitudes towards condom use were generally favorable with 91% of FSWs and 82% of truckers agreeing with the statement, “condom use is the best method of HIV prevention”. Qualitative findings show that poverty, refusal to use condoms by male partners, alcohol use before sex and beliefs that condoms ‘kill the mood for sex’ remain key barriers to consistent condom use.

Conclusions

Consistent condom use among FSWs and truckers is still hampered by economic and relationship factors.     

Elevated Anti-Streptococcal Antibodies in Patients with Recent Narcolepsy Onset

Study Objectives:

Narcolepsy-cataplexy has long been thought to have an autoimmune origin. Although susceptibility to narcolepsy, like many autoimmune conditions, is largely genetically determined, environmental factors are involved based on the high discordance rate (∼75%) of monozygotic twins. This study evaluated whether Streptococcus pyogenes and Helicobacter pylori infections are triggers for narcolepsy.

Design:

Retrospective, case-control.

Setting:

Sleep centers of general hospitals.

Participants:

200 patients with narcolepsy/hypocretin deficiency, with a primary focus on recent onset cases and 200 age-matched healthy controls. All patients were DQB1*0602 positive with low CSF hypocretin-1 or had clear-cut cataplexy.

Measurements and Results:

Participants were tested for markers of immune response to β hemolytic streptococcus (anti-streptolysin O [ASO]; anti DNAse B [ADB]) and Helicobacter pylori [Anti Hp IgG], two bacterial infections known to trigger autoimmunity. A general inflammatory marker, C-reactive protein (CRP), was also studied. When compared to controls, ASO and ADB titers were highest close to narcolepsy onset, and decreased with disease duration. For example, ASO ≥ 200 IU (ADB ≥ 480 IU) were found in 51% (45%) of 67 patients within 3 years of onset, compared to 19% (17%) of 67 age matched controls (OR = 4.3 [OR = 4.1], P < 0.0005) or 20% (15%) of 69 patients with long-standing disease (OR = 4.0 [OR = 4.8], P < 0.0005]. CRP (mean values) and Anti Hp IgG (% positive) did not differ from controls.

Conclusions:

Streptococcal infections are probably a significant environmental trigger for narcolepsy.

Citation:

Aran A; Nevsimalova S; Plazzi G; Hong SC; Weiner K; Zeitser J; Mignot E. Elevated anti-streptococcal antibodies in patients with recent narcolepsy onset. SLEEP 2009;32(8):979-983.     

Effect of an ethanol extract of <Emphasis Type="Italic">Descurainia sophia</Emphasis> seeds on Phase I and II drug metabolizing enzymes and P-glycoprotein activity <Emphasis Type="Italic">in vitro</Emphasis>

Background

Descurainia sophia seeds have a variety of pharmacological functions and been widely used in traditional folk medicine. However, their effects on human drug metabolizing enzyme (DME) activities have not been elucidated. The present study investigated the inhibitory effects of an ethanol extract of D. sophia seeds (EEDS) on human Phase I/II (DMEs) and P-glycoprotein (p-gp) in vitro.

Methods

The enzyme activities of human Phase I (cytochrome P450s, CYPs), Phase II (uridine diphosphate glucuronosyltransferases, UGTs) DMEs, and the drug transporter P-gp were determined in the presence of various concentrations of EEDS using commercially available luminogenic assay systems. The mode of enzyme inhibition and the inhibitory constant (K_i) value of EEDS were graphically determined with Lineweaver-Burk double reciprocal plots and secondary plots, respectively.

Results

The enzyme activity assays showed that EEDS moderately inhibited the CYP1A2, CYP2C9, and CYP2C19 isoforms with half maximal inhibitory concentrations (IC₅₀) of 47.3, 25.8, and 38.7 μg/mL, respectively. Graphical analyses with Lineweaver-Burk double reciprocal plots and secondary plots indicated that EEDS competitively inhibited CYP2C9 with a K_i value of 19.8 μg/mL; however, it inhibited CYP2C9 and CYP2C19 in a mixed mode with K_i values of 5.2, and 11.9 μg/mL, respectively. Other Phase I (CYP2C8, CYP2D6, and CYP3A4) and Phase II (UGT1A1 and UGT2B7) enzymes as well as P-gp were weakly or negligibly affected by EEDS with concentrations up to 500 μg/mL.

Conclusions

EEDS is a selective inhibitor of CYP1A2, CYP2C9, and CYP2C19 with moderate enzymatic inhibition. Clinically, full consideration should be given to a potential toxic adverse effect from a herb-drug interaction when drugs that are particularly susceptible to CYP1A2, CYP2C9, or CYP2C19-mediated metabolism are taken together with EEDS. Characterization of metabolic profiles of specific herbal drugs could help consumers and medical specialists to use them safely as a complementary and alternative medicine.