Publications by authors named "Takuro Endo"

47 Publications

Sacral plexus disorder caused by a wooden toothpick in the rectum.

BMJ Case Rep 2021 Jan 5;14(1). Epub 2021 Jan 5.

Department of Spinal Surgery, Akita Cerebrospinal and Cardiovascular Center, Akita, Japan.

A 67-year-old man presented with a 2-month history of pain in his right buttock and lower limb. MRI depicted right L5/S1 lateral recess stenosis requiring surgical treatment; however, preoperative CT showed an approximately 7 cm long, thin, rod-shaped structure in the rectum, which was ultimately determined to be an accidentally ingested toothpick. It was removed surgically 6 days after diagnosis, because right leg pain worsened rapidly. The pain disappeared thereafter, and the symptoms have not recurred since. The pain might have been localised to the right buttock and posterior thigh in the early stages because the fine tip of the toothpick was positioned to the right of the anterior ramus of the S2 spinal nerve. Although sacral plexus disorder caused by a rectal foreign body is extremely rare, physicians should be mindful to avoid misdiagnosis.
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http://dx.doi.org/10.1136/bcr-2020-238690DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7786803PMC
January 2021

Cervical myelopathy due to neurovascular compression syndrome caused by persistent first intersegmental artery: a case report.

BMC Neurol 2020 Nov 3;20(1):402. Epub 2020 Nov 3.

Department of Spinal Surgery, Akita Cerebrospinal and Cardiovascular Center, 6-10 Senshu Kubotamachi, Akita-shi, Akita-ken, 010-0874, Japan.

Background: Persistent first intersegmental artery (PFIA) is a rare anatomical variation of vertebral arteries and is an asymptomatic finding in most cases. Here we report a rare case of cervical myelopathy caused by spinal cord compression by the PFIA.

Case Presentation: The patient was a 52-year-old man who complained of numbness and burning sensation around the neck and left shoulder area, partial weakness in the left deltoid muscle, right side thermal hypoalgesia, and disturbance of deep sensation since the past 1 year, and the symptoms had gradually worsened. Magnetic resonance imaging (MRI) and computed tomography (CT) showed spinal cord compression by the left PFIA at the C1/C2 level. Because conservative treatment was ineffective, microvascular decompression (MVD) of the PFIA was performed. The left PFIA was laterally transposed using polytetrafluoroethylene (PTFE) bands and anchored to the dura mater using three PTFE bands. To achieve adequate transposition, the small blood vessels bridging the spinal cord and PFIA and the dorsal root nerve had to be sacrificed. Postoperative T2-weighted MRI showed a small hyperintense region in the lateral funiculus of the spinal cord, but no new neurological deficits were identified. In the early postoperative stage, the patient's deep sensory impairment and motor dysfunction were improved. His numbness and burning sensation almost disappeared, but slight thermal hypoalgesia remained in the lower limb.

Conclusion: MVD is an effective treatment for spinal cord compression caused by the PFIA, but further studies are necessary to help address technical difficulties and avoid complications.
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http://dx.doi.org/10.1186/s12883-020-01976-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7607829PMC
November 2020

Cyclosporine Improves Sleep Quality in Patients with Atopic Dermatitis.

Dermatol Ther (Heidelb) 2020 Dec 25;10(6):1359-1369. Epub 2020 Sep 25.

Department of Dermatology, The Jikei University School of Medicine, Tokyo, Japan.

Introduction: Atopic dermatitis (AD) is a chronic, relapsing, inflammatory skin disease characterized by eczema and pruritus, and frequently impairs sleep quality. Although cyclosporine improves symptoms of AD, objective evaluation of sleep in patients with AD treated with cyclosporine has not been reported. This study was conducted to elucidate the effects of cyclosporine on sleep quality for patients with AD.

Methods: Twelve patients with moderate-to-severe AD were recruited. Nocturnal sleep quality was evaluated for 7 days using a sleep analyzer, which patients wore at the waist before and after cyclosporine was administered at 2.0-4.0 mg/kg per day. Seven parameters of sleep quality were measured before and after cyclosporine administration for a period of 7 days for each patient.

Results: The administration of cyclosporine significantly improved total sleep time in four cases, sleep latency in two cases, wake after sleep onset in six cases, number of awakenings in two cases, sleep efficiency in seven cases, number of awakenings for more than 8 min in three cases, and number of position changes recorded every 2 min in three cases. The mean values of sleep latency significantly decreased after cyclosporine administration (P = 0.023). The mean value of sleep efficiency significantly increased after the administration (P = 0.002).

Conclusion: Cyclosporine improves sleep quality in patients with moderate-to-severe AD.
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http://dx.doi.org/10.1007/s13555-020-00451-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7649172PMC
December 2020

Efficacy of prehospital National Early Warning Score to predict outpatient disposition at an emergency department of a Japanese tertiary hospital: a retrospective study.

BMJ Open 2020 06 15;10(6):e034602. Epub 2020 Jun 15.

Department of Emergency and Critical Care Medicine, St Marianna University School of Medicine, Kawasaki, Kanagawa, Japan

Objectives: The National Early Warning Score (NEWS) was originally developed to assess hospitalised patients in the UK. We examined whether the NEWS could be applied to patients transported by ambulance in Japan.

Design: This retrospective study assessed patients and calculated the NEWS from paramedic records. Emergency department (ED) disposition data were categorised into the following groups: discharged from the ED, admitted to the ward, admitted to the intensive care unit (ICU) or died in the ED. The predictive performance of NEWS for patient disposition was assessed using receiver operating characteristic curve analysis. Patient dispositions were compared among NEWS-based categories after adjusting for age, sex and presence of traumatic injury.

Setting: A tertiary hospital in Japan.

Participants: Overall, 2847 patients transported by ambulance between April 2017 and March 2018 were included.

Results: The mean (±SD) NEWS differed significantly among patients discharged from the ED (n=1330, 3.7±2.9), admitted to the ward (n=1263, 60.3±3.8), admitted to the ICU (n=232, 9.4±4.0) and died in the ED (n=22, 110.7±2.9) (p<0.001). The prehospital NEWS C-statistics (95% CI) for admission to the ward, admission to the ICU or death in the ED; admission to the ICU or death in the ED; and death in the ED were 0.73 (0.72-0.75), 0.81 (0.78-0.83) and 0.90 (0.87-0.93), respectively. After adjusting for age, sex and trauma, the OR (95% CI) of admission to the ICU or death in the ED for the high-risk (NEWS ≥7) and medium-risk (NEWS 5-6) categories was 13.8 (8.9-21.6) and 4.2 (2.5-7.1), respectively.

Conclusion: The findings from this Japanese tertiary hospital setting showed that prehospital NEWS could be used to identify patients at a risk of adverse outcomes. NEWS stratification was strongly correlated with patient disposition.
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http://dx.doi.org/10.1136/bmjopen-2019-034602DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7299041PMC
June 2020

Pharmacokinetic Drug Interactions of an Orally Available TRH Analog (Rovatirelin) With a CYP3A4/5 and P-Glycoprotein Inhibitor (Itraconazole).

J Clin Pharmacol 2020 10 27;60(10):1314-1323. Epub 2020 May 27.

Central Research Laboratories, Kissei Pharmaceutical Co, Ltd., Azumino, Nagano, Japan.

The effects of itraconazole on the pharmacokinetics of rovatirelin were investigated in an open-label, single-sequence drug-drug interaction study in 16 healthy subjects. Subjects were administered a single oral dose of rovatirelin (1.6 mg) on day 1 and day 15. From day 8 through 16, subjects received daily oral doses of itraconazole (200 mg/day). Concentrations of rovatirelin and (thiazolylalanyl)methylpyrrolidine (TAMP), the major metabolite of rovatirelin formed by cytochrome P450 (CYP) 3A4/5, were determined in plasma and urine. Pharmacokinetic parameters were used to evaluate the drug-drug interaction potential of rovatirelin as a victim. With coadministration, maximum concentration (C ) and area under the concentration-time curve extrapolated to infinity (AUC ) of rovatirelin increased 3.05-fold and 2.82-fold, respectively, and the 90% confidence intervals of the ratios for C (2.64-3.52) and AUC (2.47-3.23) did not fall within the 0.8-1.25 boundaries. Urinary excretion of rovatirelin increased at almost the same ratio as the AUC ratio with coadministration; however, renal clearance did not change. C , AUC , and urinary excretion of TAMP were decreased by coadministration. Itraconazole has the potential to inhibit drug transport via intestinal P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP); therefore, substrate assessments of rovatirelin for the 2 transporters were evaluated using Caco-2 cell monolayers. In vitro studies showed that rovatirelin is a substrate for P-gp but not for BCRP. The current study shows that itraconazole's effect on rovatirelin pharmacokinetics is mediated through inhibition of CYP3A4/5 and intestinal P-gp.
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http://dx.doi.org/10.1002/jcph.1628DOI Listing
October 2020

Compartment syndrome due to infection: a case report.

Acute Med Surg 2020 Jan-Dec;7(1):e474. Epub 2020 Jan 1.

Department of Emergency and Critical Care Medicine St. Marianna University Hospital Kanagawa Japan.

Background: Purpura fulminans secondary to () infection without a wound is rare and often misdiagnosed initially. We report a patient who died due to bacteremia with purpura fulminans and acute compartment syndrome of all extremities.

Care Presentation: A 38-year-old Japanese man with a history of alcoholism presented with a 2-day history of gastroenteritis. The chief complaints were abdominal pain and diarrhea, and he had abdominal tenderness. Laboratory findings showed multiple organ failure. On day 2, pain in the lower extremities associated with motor and sensory dysfunction developed. On day 3, purpura on the whole body spread to all extremities. All four extremities became rigid, and acute compartment syndrome developed. The patient died due to uncontrolled hyperkalemia and lactic acidosis.

Conclusions: transmission can occur through licking or even close contact with animals when a risk factor of infection, such as alcoholism, is present.
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http://dx.doi.org/10.1002/ams2.474DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6971439PMC
January 2020

Evaluation of lumbar intervertebral disc degeneration using dual energy CT virtual non-calcium imaging.

Eur J Radiol 2020 Mar 8;124:108817. Epub 2020 Jan 8.

Department of Radiology and Nuclear Medicine, Research Institute for Brain and Blood Vessels-Akita, 6-10 Senshu-kubota-machi, Akita, 010-0874, Japan. Electronic address:

Purpose: To clarify the utility of dual energy CT (DECT) virtual non-calcium (VNCa) imaging for investigating lumbar intervertebral disc degeneration.

Method: Fifty-three patients who underwent both DECT and MR imaging were retrospectively reviewed. Midsagittal T2-weighted imaging findings of all discs were classified based on modified Pfirrmann grade (mPG). Quantitative evaluation of VNCa maps was achieved by setting volumes of interest on each disc. We compared VNCa CT values with mPG using Spearman's rank correlation and one-way ANOVA. VNCa imaging findings of each disc were classified by two neuroradiologists into one of three categories based on the attenuation of nucleus pulposus (NP) compared to that of annulus fibrosus (AF) or muscle. The relationship between the visual categories for each rater and mPGs was analyzed by chi-square test. Statistical significance was established at P < 0.05.

Results: Among the included 171 lumbar discs, significant positive correlation was found between VNCa CT values for NP and mPGs (R = 0.574, P < 0.05), whereas no significant correlation was found between those for AF and mPGs (R= -0.015, P = 0.846). Mean VNCa CT values for NP were significantly different among each mPG (P < 0.05 for each), except between grades 3 and 4 (P = 0.111). Mean VNCa CT values for AF were not significantly different among each mPG (P = 0.160-1.000). Statistically significant difference was observed among the visual categories for VNCa maps and mPGs in each rater (P < 0.05 for both).

Conclusions: VNCa imaging acquired by a single DECT scan and post-processing has potential as an imaging biomarker of lumbar intervertebral disc degeneration.
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http://dx.doi.org/10.1016/j.ejrad.2020.108817DOI Listing
March 2020

Quantitative Evaluation of Reactivity and Toxicity of Acyl Glucuronides by [S]Cysteine Trapping.

Chem Res Toxicol 2019 10 20;32(10):1955-1964. Epub 2019 Sep 20.

Central Research Laboratories , Kissei Pharmaceutical Co., Ltd. , 4365-1, Hotaka-Kashiwabara , Azumino , Nagano 399-8304 , Japan.

Acyl glucuronides (AGs) are reactive metabolites of carboxylic acid-containing drugs, which are associated with idiosyncratic toxicity (IDT) such as anaphylaxis, drug-induced liver injury, and so on. In this study, we developed a new approach for the quantitative assessment of the reactivity of AGs and their toxicity risk. Thirteen test drugs were incubated with human liver microsomes and uridine 5'-diphospho-glucuronic acid in the presence of cysteine (Cys) as a trapping agent. Both acylation and glycation Cys adducts formed from the AGs of the test drugs and were analyzed by ultraperformance liquid chromatography-quadrupole time-of-flight mass spectrometry. Acylation Cys adduct formation can closely reflect the reactivity of AGs to predict their IDT risk. Subsequently, we performed a quantitative trapping assay using radiometric analysis, with [S]-labeled Cys ([S]Cys) as the trapping agent, and the results showed that the test drugs associated with IDT resulted in a high product formation of [S]Cys adducts. In conclusion, this approach can be used for the easy and quantitative evaluation of the reactivity of AGs without the need for authentic AG standards and to screen the potential IDT of new chemical entities during the early drug discovery phase.
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http://dx.doi.org/10.1021/acs.chemrestox.9b00111DOI Listing
October 2019

Hydroxyapatite powder cake filtration reduces false positives associated with halophilic bacteria when evaluating Escherichia coli in seawater using Colilert-18.

J Microbiol Methods 2019 04 22;159:69-74. Epub 2019 Feb 22.

Faculty of Life and Environmental Sciences, Prefectural University of Hiroshima, Hiroshima, Japan. Electronic address:

Escherichia coli is an important fecal indicator bacterium that is used to evaluate the microbiological quality of water. The Colilert-18 (Quanti-Tray/2000) is a widely used, rapid, and simple quantitative method for detecting E. coli in drinking water, bathing water, and wastewater. However, Colilert-18 method is less reliable for seawater; false positives are often caused by halophilic bacteria such as Vibrio. While false positives can be avoided by diluting the sample by 10 times or more, the resulting decrease in detection limit makes it difficult to quantify E. coli in seawater. In this study, we combined cake filtration, using hydroxyapatite powder, with the Colilert-18 method to remove salinity without diluting the water sample. When quantifying E. coli in river water, the E. coli concentration obtained from the cake filtration/Colilert-18 method showed a high quantitative value of 90% or more, on average, compared to the concentration obtained with the original Colilert-18 method. The E. coli concentrations in seawater determined using the developed method were similar to those determined using the modified m-TEC method, with no false positives. Highly reliable quantitative values can be obtained using the proposed method because it is possible to measure 100 times as much sample compared to the dilution method. Thus, the developed method is expected to be a powerful tool that can eliminate the problem of false positives.
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http://dx.doi.org/10.1016/j.mimet.2019.02.012DOI Listing
April 2019

Human mass balance, pharmacokinetics and metabolism of rovatirelin and identification of its metabolic enzymes .

Xenobiotica 2019 Dec 5;49(12):1434-1446. Epub 2019 Mar 5.

Central Research Laboratories, Kissei Pharmaceutical Co., Ltd , Azumino , Nagano , Japan.

The mass balance, pharmacokinetics and metabolism of rovatirelin were characterised in healthy male subjects after a single oral dose of [C]rovatirelin. [C]Rovatirelin was steadily absorbed, and the peak concentrations of radioactivity and rovatirelin were observed in plasma at 5-6 h after administration. The of radioactivity was 4.9-fold greater than that of rovatirelin. Rovatirelin and its metabolite (thiazoylalanyl)methylpyrrolidine (TAMP) circulated in plasma as the major components. The total radioactivity recovered in urine and faeces was 89.0% of the administered dose. The principal route of elimination was excretion into faeces (50.1% of the dose), and urinary excretion was the secondary route (36.8%). Rovatirelin was extensively metabolised to 20 metabolites, and TAMP was identified as the major metabolite in plasma and excreta among its metabolites. To identify the metabolic enzymes responsible for TAMP formation, the activity was determined in human liver microsomes. The enzymatic activity depended on NADPH, and it was inhibited by ketoconazole. Furthermore, recombinant human cytochrome P450 (CYP) 3A4 and CYP3A5 displayed enzymatic activity in the assay. Therefore, CYP3A4/5 are the most important enzymes responsible for TAMP formation.
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http://dx.doi.org/10.1080/00498254.2019.1580796DOI Listing
December 2019

Prospective Multicenter Study of a Multistep Screw Insertion Technique Using Patient-Specific Screw Guide Templates for the Cervical and Thoracic Spine.

Spine (Phila Pa 1976) 2018 12;43(23):1685-1694

Department of Orthopedic Surgery, Kobe Rosai Hospital, Kobe, Japan.

Study Design: A prospective clinical study of a multistep screw insertion method using a patient-specific screw guide template system (SGTS) for the cervical and thoracic spine.

Objective: To evaluate the efficacy of SGTS for inserting screws into the cervical and thoracic spine.

Summary Of Background Data: Posterior screw fixation is a standard procedure for spinal instrumentation; however, screw insertion carries the risk of injury to neuronal and vascular structures.

Methods: Preoperative bone images of the computed tomography (CT) scans were analyzed using 3D/multiplanar imaging software, and the screw trajectories were planned. Plastic templates with screw-guiding structures were created for each lamina using 3D design and printing technology. Three types of templates were made for precise multistep guidance, and all the templates were specially designed to fit and lock onto the lamina during the procedure. In addition, plastic vertebra models were generated, and preoperative screw insertion simulation was performed. This patient-specific SGTS was used to perform the surgery, and CT scanning was used to postoperatively evaluate screw placement.

Results: Enrolled to verify this procedure were 103 patients with cervical, thoracic, or cervicothoracic pathologies. The SGTS were used to place 813 screws. Preoperatively, each template was found to fit exactly and to lock onto the lamina of the vertebra models. In addition, intraoperatively, the templates fit and locked onto the patient lamina, and the screws were inserted successfully. Postoperative CT scans confirmed that 801 screws (98.5%) were accurately placed without cortical violation. There were no injuries to the vessels or nerves.

Conclusion: The multistep, patient-specific SGTS is useful for intraoperative pedicle screw (PS) navigation in the cervical and thoracic spine. This method improves the accuracy of PS insertion and reduces the operating time and radiation exposure during spinal fixation surgery.

Level Of Evidence: 3.
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http://dx.doi.org/10.1097/BRS.0000000000002810DOI Listing
December 2018

Absorption, disposition, metabolism and excretion of [C]mizagliflozin, a novel selective SGLT1 inhibitor, in rats.

Xenobiotica 2019 Apr 28;49(4):463-473. Epub 2018 Mar 28.

a Central Research Laboratories , Kissei Pharmaceutical Co., Ltd , Azumino , Japan.

The pharmacokinetic and metabolite profiles of mizagliflozin, a novel selective sodium glucose co-transporter 1 inhibitor designed to act only in the intestine, were investigated in rats. Mizagliflozin administrated intravenously (0.3 mg/kg) and orally (3 mg/kg) declined with a short half-life (0.23 and 1.14 h, respectively). The absolute bioavailability was only 0.02%. Following intravenous administration of [C]mizagliflozin (0.3 mg/kg), radioactivity in plasma was also rapidly declined. Up to 24 h after oral administration of [C]mizagliflozin (1 mg/kg), radioactivity was recovered in the faeces (98.4%) and in the urine (0.8%). No remarkable accumulation of radioactivity in tissues was observed using tissue dissection technique and whole body autoradiography. Orally dosed [C]mizagliflozin was mostly metabolised to its aglycone, KP232, in the intestine. In the plasma, KP232 and its glucuronide were predominant. KP232 glucuronide was also prominent in the bile and was recovered as KP232 in the faeces possibly because of the deconjugation by gut microflora. Mizagliflozin was observed neither in the urine nor the faeces. These findings suggest that orally administered mizagliflozin is poorly absorbed, contributing to low systemic exposure; if absorbed, mizagliflozin is rapidly cleared from circulation.
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http://dx.doi.org/10.1080/00498254.2018.1449269DOI Listing
April 2019

Non-clinical pharmacokinetic profiles of rovatirelin, an orally available thyrotropin-releasing hormone analogue.

Xenobiotica 2019 Jan 31;49(1):106-119. Epub 2018 Jan 31.

a Central Research Laboratories, Kissei Pharmaceutical Co., Ltd , Azumino , Nagano , Japan and.

1. The non-clinical pharmacokinetic profiles of rovatirelin, a novel thyrotropin-releasing hormone (TRH) analogue, were investigated in vivo and in vitro. 2. Rovatirelin orally administered to rats and dogs was rapidly absorbed and bioavailability was estimated to be 7.3 and 41.3%, respectively. The extent of plasma protein binding of rovatirelin in rats, dogs, and humans was low in all species (∼15%). The permeability of rovatirelin from blood to brain (permeability-surface area) ranged from 1.04 ± 0.14 to 1.29 ± 0.28 μL/min/g in rats, and rovatirelin was stable in rat plasma and brain homogenates. 3. The metabolite pattern was qualitatively similar in vitro and in vivo. In animals, rovatirelin aminopentanoic acid (rovatirelin-acid), rovatirelin aminopentanone (rovatirelin-ketone), rovatirelin pyrrolidine (4S)-hydroxy (rovatirelin-OH), (thiazoylalanyl)methylpyrrolidine (TAMP), 3-(4-thiazoyl)-l-alanine (TA), and unknown metabolites were observed. In human hepatocytes, TAMP was mainly formed and no unique human metabolite was observed. 4. The radioactivity from administered [C]rovatirelin was predominantly excreted in faeces in rats and dogs, and almost all radioactivity was recovered 168 h after administration. Absorption, brain penetration, and stability of rovatirelin in the brain were greater than for taltirelin. 5. Thus, orally administered rovatirelin is a potentially improved treatment for spinocerebellar degeneration compared with taltirelin.
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http://dx.doi.org/10.1080/00498254.2017.1423130DOI Listing
January 2019

Development and validation of an LC-MS/MS method for simultaneously determining doxapram and keto-doxapram in human serum.

Bioanalysis 2017 Mar 22;9(6):503-515. Epub 2017 Feb 22.

Central Research Laboratories, Kissei Pharmaceutical Co., Ltd, 4365-1 Kashiwabara, Hotaka, Azumino, Nagano, Japan.

Aim: Doxapram, a respiratory stimulant, is used to treat apnea. A reliable method of determining doxapram in blood is required for monitoring purposes.

Results: Doxapram, keto-doxapram (active metabolite) and propranolol (internal standard) were extracted from human serum by protein precipitation and plate filtration. Molecular ions were generated by electrospray ionization in positive ion mode, and the ions were analyzed using a triple-quadrupole mass spectrometer. The calibration curves were linear from 20 to 5000 ng/ml. The method was validated and the selectivity, reproducibility and stability met the acceptance criteria.

Conclusion: An LC-MS/MS method was successfully developed for determining doxapram and keto-doxapram in human serum. The method can be used to monitor doxapram and keto-doxapram concentrations in blood.
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http://dx.doi.org/10.4155/bio-2016-0267DOI Listing
March 2017

Investigation of Drug-Drug Interactions Between Ritobegron, a Selective β3 -Adrenoceptor Agonist, With Probenecid in Healthy Men.

Clin Pharmacol Drug Dev 2016 May 29;5(3):201-7. Epub 2015 Sep 29.

Central Research Laboratories, Kissei Pharmaceutical Co., Ltd., Nagano, Japan.

We evaluated the effects of probenecid, a potent organic anion transporter 1 (OAT1) and OAT3 inhibitor, on the pharmacokinetics and safety of ritobegron, a selective β3 -adrenoceptor agonist, in healthy men. Twelve healthy men were administered a single oral dose of ritobegron (20 mg) alone or in combination with probenecid 2 hours before administration of ritobegron. In the combination sequence, additional doses of probenecid were administered 4 and 10 hours after the administration of ritobegron. Probenecid increased the Cmax of KUC-7322, an active form of ritobegron, and the AUC0-48  h by 1.39 and 2.93 times, respectively. Probenecid prolonged the t1/2 of KUC-7322 from 1.6 to 3.4 hours and decreased the renal clearance and cumulative fraction of KUC-7322 excreted in urine from 18.5 to 4.9 L/h and from 64.7% to 49.7%, respectively. Coadministration of probenecid did not influence adverse events, blood pressure, pulse rate, or heart rate relative to ritobegron alone. Although probenecid inhibited renal tubule secretion of KUC-7322 via OAT3 and increased KUC-7322 exposure, it did not influence adverse effects or vital signs. Therefore, clinically significant drug-drug interactions are unlikely to occur when probenecid is administered in combination with OAT3 inhibitors or substrates.
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http://dx.doi.org/10.1002/cpdd.212DOI Listing
May 2016

Wake up time, light, and mood in a population sample age 40-64 years.

Psychiatry Investig 2015 Apr 12;12(2):177-82. Epub 2014 Dec 12.

Department of Psychiatry, University of California, San Diego, CA, USA.

Objective: Concern that disturbances of sleep and light exposures at night might increase cancer risks have been expressed, but little actual exposure data has been collected. Measurements from a representative population sample were examined to understand the magnitude of in-bed light exposure at night and possible correlates.

Methods: From 1990 to 1994, a home survey of sleep disorders among adults ages 40-64 was conducted in the City of San Diego California, using stratified representative sampling techniques. Along with questionnaires, sleep logs, and 3-night wrist activity and pulse oximetry measures, bedside illumination was measured with a computer recording system. Questionnaires included the CESD depression scale and a scale of symptoms typical of winter depression.

Results: Complete data were available from 286 men and women, whose mean in-bed intervals averaged 7 hours and 42 minutes. The mean room illumination during the first part of the night was mean 12.7 lux (median 3.2 lux) and during the last 2 hours in bed averaged 28.7 lux (median 18.9 lux). Nocturnal light exposure was positively correlated with age, male gender, summer season, time in bed, wake-up time, and depressive symptoms.

Conclusion: Complex bi-directional interactions may take place between sleep disturbances, depression, time in bed, wake-up-time, and in-bed illumination. The most crucial light exposures appear to occur in the last 2 hours in bed, largely after dawn, so daylight exposure may be an important factor.
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http://dx.doi.org/10.4306/pi.2015.12.2.177DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4390587PMC
April 2015

Depletion of Cryptosporidium parvum oocysts from contaminated sewage by using freshwater benthic pearl clams (Hyriopsis schlegeli).

Appl Environ Microbiol 2012 Oct 17;78(20):7420-8. Epub 2012 Aug 17.

Section of Drinking Water Chemistry, Division of Environmental Hygiene, Hokkaido Institute of Public Health, Sapporo, Japan.

The freshwater benthic pearl clam, Hyriopsis schlegeli, was experimentally exposed to Cryptosporidium parvum oocysts, and it was verified that the oocysts were eliminated predominantly via the fecal route, retaining their ability to infect cultured cells (HCT-8). The total fecal oocyst elimination rate was more than 90% within 5 days after exposure to the oocysts. H. schlegeli was able to survive in the final settling pond of a sewage plant for long periods, as confirmed by its pearl production. In the light of these findings, the clam was placed in the final settling pond in a trial to test its long-term efficacy in depleting oocysts contaminating the pond water. The number of clams placed was set to ensure a theoretical oocyst removal rate of around 50%, and the turbidity and the density of feed microbes in the overflow trough water of the pond were about 35% and 40 to 60% lower, respectively, than in the control water throughout the year. It was found that the clam feces containing oocysts were sufficiently heavy for them to settle to the bottom of the pond, despite the upward water flow. From these results, we concluded that efficient depletion of oocysts in the sewage water of small or midscale sewage treatment plants can be achieved by appropriate placement of H. schlegeli clams.
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http://dx.doi.org/10.1128/AEM.01502-12DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3457110PMC
October 2012

Early sleep psychiatric intervention for acute insomnia: implications from a case of obsessive-compulsive disorder.

J Clin Sleep Med 2012 Apr 15;8(2):191-3. Epub 2012 Apr 15.

Department ofPsychophysiology, National Institute of Mental Health, National Center of Neurology and Psychiatry, 4-1-1 Ogawa-Higashi, Kodaira, Tokyo 187-8553, Japan.

Insomnia is a common problem among patients with obsessive-compulsive disorder (OCD), and patients suffering from acute insomnia with psychiatric comorbidity are more likely to develop chronic insomnia without appropriate intervention. Here we report a case of obsessive-compulsive disorder with acute insomnia, successfully treated with early sleep psychiatric non-pharmacological intervention. The augmentation of medication runs a risk of exacerbating daytime impairment. Clinicians usually prescribe medication, such as antidepressants and hypnotics without reflections for such complaints. However, the use of these sedative agents is often problematic, especially when patients have kept a good QOL activity in daily life. The rapid recovery from acute insomnia in this case suggests that the appropriate use of actigraphy is a favorable non-pharmacological intervention in acute insomnia.
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http://dx.doi.org/10.5664/jcsm.1778DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3311417PMC
April 2012

A rapid detection method using flow cytometry to monitor the risk of Legionella in bath water.

J Microbiol Methods 2011 Jul 2;86(1):25-32. Epub 2011 Apr 2.

Nagasaki Prefectural Institute for Environmental Research and Public Health, 2-1306-11 Ikeda, Omura, Nagasaki 856-0026, Japan.

Legionella species are the causative agents of human legionellosis, and bathing facilities have been identified as the sources of infection in several outbreaks in Japan. Researchers in Japan have recently reported evidence of significant associations between bacterial counts and the occurrence of Legionella in bathing facilities and in a hot tub model. A convenient and quantitative bacterial enumeration method is therefore required as an indicator of Legionella contamination or disinfection to replace existing methods such as time-consuming Legionella culture and expensive Legionella-DNA amplification. In this study, we developed a rapid detection method (RDM) to monitor the risk of Legionella using an automated microbial analyzing device based on flow cytometry techniques to measure the total number of bacteria in water samples within two minutes, by detecting typical patterns of scattered light and fluorescence. We first compared the results of our RDM with plate counting results for five filtered hot spring water samples spiked with three species of bacteria, including Legionella. Inactivation of these samples by chlorine was also assessed by the RDM, a live/dead bacterial fluorescence assay and plate counting. Using the RDM, the lower limit of quantitative bacterial counts in the spiked samples was determined as 3.0×10(3)(3.48log)counts mL(-1). We then used a laboratory model of a hot tub and found that the RDM could monitor the growth curve of naturally occurring heterotrophic bacteria with 1 and 2 days' delayed growth of amoeba and Legionella, respectively, and could also determine the killing curve of these bacteria by chlorination. Finally, samples with ≥3.48 or <3.48log total bacterial counts mL(-1) were tested using the RDM from 149 different hot tubs, and were found to be significantly associated with the positive or negative detection of Legionella with 95% sensitivity and 84% specificity. These findings indicated that the RDM can be used for Legionella control at bathing facilities, especially those where the effectiveness of chlorine is reduced by the presence of Fe(2+), Mn(2+), NH(4)(+), skin debris, and/or biofilms in the water.
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http://dx.doi.org/10.1016/j.mimet.2011.03.012DOI Listing
July 2011

Intraductal ultrasonography in the diagnosis of bile duct stones: when and whom?

Dig Endosc 2011 Apr 13;23(2):173-5. Epub 2010 Dec 13.

Department of Gastroenterology, Sendai City Medical Center, Sendai, Japan.

Background And Aim: Biliary intraductal ultrasonography (IDUS) is highly sensitive in visualizing bile duct stones (BDS). Indications for IDUS, however, in cases of suspected BDS have not yet been established. The aim of the present study was to elucidate adequate indications for IDUS in cases that undergo endoscopic retrograde cholangiopancreatography (ERCP) due to suspected BDS.

Methods: A total of 213 patients who were suspected of having BDS were included in this retrospective study. The patients were divided into two groups: Group A in which BDS was visualized by ERCP; and Group B in which BDS was demonstrated only by IDUS. Comparison between the groups was carried out.

Results: ERCP successfully visualized BDS in 166 patients. Forty-seven patients underwent IDUS, which revealed BDS and biliary sludge in 12 and eight patients, respectively. The diameter of the largest stone was 13 ± 6 mm in Group A and 5 ± 1 mm in Group B (P < 0.001). The sensitivity, specificity, and accuracy of ERCP in the diagnosis of BDS were 93%, 100%, and 94%, respectively. The sensitivity was influenced by the size of BDS: 100% in cases of stones ≥ 8 mm in size, but 74% in those with stones < 8 mm. In cases with stones < 8 mm, the sensitivity was significantly affected by the bile duct diameter (≥ 12 mm vs < 12 mm, P < 0.05).

Conclusion:   When ERCP fails to visualize stones in patients with suspected BDS, IDUS is recommended, especially in those with a bile duct ≥ 12 mm in diameter.
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http://dx.doi.org/10.1111/j.1443-1661.2010.01071.xDOI Listing
April 2011

Comparison of ultraflex and niti-s stents for palliation of unresectable malignant gastroduodenal obstruction.

Dig Endosc 2010 Apr;22(2):83-9

Department of Internal Medicine, Toho University Ohashi Medical Center, Meguro-ku, Tokyo, Japan.

Aim: Self-expandable metallic stents are widely used for palliation of malignant gastric outlet obstruction (GOO), but clinical outcomes of different stents have not been compared. Here, we compared outcomes in patients with a GOO receiving either an Ultraflex (UF) or a Niti-S (NS) stent.

Methods: Prospective outcomes in 53 patients receiving palliative placement of an NS stent for symptomatic GOO over a 3-year period were compared with those obtained retrospectively in 31 patients receiving a UF stent in a previous 5-year period. Main outcome measurement was between-group comparison of clinical outcome, complications, and reintervention.

Results: Baseline characteristics between the groups were comparable. No difference in technical or clinical success rate was observed. Median procedure time for NS placement was shorter than for UF (15 vs 40 min; P < 0.0001). Complications were more frequent with NS than with UF placement, albeit without statistical significance (16% vs 25%). Although two severe complications occurred in each group, neither was stent related in the NS group. Reintervention was more frequent in the NS group (3% vs 21%; P = 0.0485). Median survival time was 53 versus 88 days for UF versus NS stents, respectively.

Conclusion: Although no significant difference was seen with regard to feasibility, reintervention was less frequent with UF stents than with NS stents. However, UF stents require much more procedure time, and a complicated and difficult placement procedure. These observations suggest that although NS stents placed using a through-the-scope technique may be more patient friendly than UF stents, further optimization of through-the-scope stents is still required. Further prospective comparison of NS and UF stents in GOO treatment is warranted.
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http://dx.doi.org/10.1111/j.1443-1661.2010.00942.xDOI Listing
April 2010

Efficacy of the revised Vienna Classification for diagnosing colorectal epithelial neoplasias.

World J Gastroenterol 2009 May;15(19):2351-6

Division of Gastroenterology, Department of Internal Medicine, Toho University Ohashi Medical Center, 2-17-6 Ohashi, Meguro-ku, Tokyo, Japan.

Aim: To prospectively investigate the efficacy of the revised Vienna Classification for diagnosing colorectal epithelial neoplastic lesions in cold biopsy specimens.

Methods: Patients were selected for inclusion if they had colorectal epithelial lesions that were not considered suitable for direct endoscopic resection. These included colorectal polyps > or = 10 mm and lesions suspected of being carcinomas capable of invading the colorectal submucosa or beyond, including strictures, based on the cold biopsies obtained from each lesion prior to resection. We investigated the relationship between diagnoses based on cold biopsy samples using the revised Vienna Classification and resected specimens of the same lesions, and the therapeutic implications of diagnoses made using the revised Vienna Classification. The same cold biopsy specimens were also examined using the Japanese Group Classification guidelines, and compared with the resected specimens of the same lesions for reference.

Results: A total of 179 lesions were identified. The sensitivity, specificity, positive and negative predictive values of the revised Vienna Classification for distinguishing between intramucosal lesions and submucosal invasive carcinomas in cold biopsy specimens was 22.2%, 100%, 100%, and 71.4%, respectively, and for distinguishing between intramucosal lesions and those invading the submucosa or beyond was 59.7%, 100%, 100%, and 37.6%, respectively. The sensitivity, specificity, positive and negative predictive values of the Japanese Group Classification for distinguishing between intramucosal lesions and submucosal invasive carcinomas in cold biopsy specimens was 83.3%, 91.4%, 83.3%, and 91.4%, respectively, and for distinguishing between intramucosal lesions and those invading the submucosa or beyond was 95.1%, 91.4%, 97.9%, and 82.1%, respectively. A total of 137 of 144 carcinomas that had invaded the submucosa or beyond and three high-grade intraepithelial neoplasias were diagnosed as "carcinoma" using the Japanese Group Classification system.

Conclusion: The revised Vienna Classification for cold biopsy specimens has high positive predictive value in the diagnosis of colorectal carcinoma invasive to the submucosa or beyond.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2684601PMC
http://dx.doi.org/10.3748/wjg.15.2351DOI Listing
May 2009

[Successful endoscopic removal of pancreatic catheter after Whipple resection being effective for improving repeated pancreatitis-a case report].

Nihon Shokakibyo Gakkai Zasshi 2009 Feb;106(2):228-32

Department of Internal Medicine, Toho University Ohashi Medical Center, Japan.

A 54-year-old man had repeated pancreatitis since three years after pylorus-preserving pancreatoduodenectomy (PpPD) and reconstruction by the modified Child method. Since abdominal pain appeared after meals, a pancreatic duct tube was removed endoscopically, which resulted in an improvement. It has been postulated that a pancreatic duct tube, used at the anastomosis between the pancreas and gastrointestinal tract, is spontaneously dislodged or creates a spatial gap with the wall of the main pancreatic duct enough to let the pancreatic juice outflow. However, endoscopic removal of the tube remained in place was significantly effective. We here discussed this case with reference of previous published reports.
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February 2009

A liquid chromatography/tandem mass spectrometry method for detecting UGT-mediated bioactivation of drugs as their N-acetylcysteine adducts in human liver microsomes.

Rapid Commun Mass Spectrom 2009 Mar;23(5):564-70

Pharmacokinetics Research, Kissei Pharmaceutical Co., Ltd., 19-48 Yoshino Matsumoto City, Nagano 399-8710, Japan.

The detection of the reactive metabolites of drugs has recently been gaining increasing importance. In vitro trapping studies using trapping agents such as glutathione are usually conducted for the detection of reactive metabolites, especially those of cytochrome P450-mediated metabolism. In order to detect the UDP-glucuronosyltransferase (UGT)-mediated bioactivation of drugs, an in vitro trapping method using N-acetylcysteine (NAC) as a trapping agent followed by liquid chromatography/tandem mass spectrometry (LC/MS/MS) was developed in this study. After the test compounds (diclofenac and ketoprofen) had been incubated in human liver microsomes with uridine diphosphoglucuronic acid (UDPGA) and NAC, the NAC adducts formed through their acyl glucuronides were analyzed using LC/MS/MS with electrospray ionization (ESI). The NAC adduct showed a mass shift of 145 units as compared to its parent, and the characteristic ion fragmentations reflected the parent. This is a concise and high-throughput method for evaluating reactive metabolites by UGT-mediated bioactivation.
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http://dx.doi.org/10.1002/rcm.3912DOI Listing
March 2009

Metallic stents for gastric outlet obstruction: reintervention rate is lower with uncovered versus covered stents, despite similar outcomes.

Gastrointest Endosc 2009 Apr 10;69(4):806-12. Epub 2009 Jan 10.

Department of Internal Medicine, Division of Gastroenterology, Toho University Ohashi Medical Center, Tokyo, Japan.

Background: Self-expandable metallic stents (SEMSs) are widely used for palliation of malignant gastric outlet obstruction (GOO). A common complication of their use, however, is stent obstruction caused by tumor ingrowth or hyperplasia. The covered SEMS was designed to prevent these problems.

Objective: We compared the performance of uncovered and covered SEMSs in patients with GOO.

Design: A retrospective study, single center.

Setting: A tertiary-referral center.

Patients: Sixty patients with symptomatic malignant GOO.

Interventions: All patients received an uncovered or covered knitted nitinol stent by using the over-the-wire placement procedure.

Main Outcome Measurement: Comparison of the clinical outcome, complications, and the reintervention rate between uncovered and covered stents.

Results: Thirty-one patients (mean [+/-SEM] age 72.2 +/- 2.1 years; 16 men) received uncovered SEMSs, and 29 (mean [+/-SEM] age 70.6 +/- 1.7 years; 17 men) received covered SEMSs. The technical success rate was 100% in both groups. No difference in clinical success was seen (90.3% uncovered group vs 86.2% covered group). Regarding early complications (<1 week), one mild case of pancreatitis from the stent covering the papilla occurred in each group. Late complications included reobstruction, migration, bleeding, stent fracture, and perforation. The occurrence of reobstruction did not differ between the 2 groups (3.2% uncovered group vs 10.3% covered group). No difference in migration (0% uncovered group vs 6.9% covered group) was seen. The uncovered group required less frequent reinterventions for stent reobstruction, migration, or stent fracture (3.2% uncovered group vs 20.7% covered group, P = .0490). The uncovered group had 2 major late complications: bleeding and perforation. All 60 patients died, with a median survival time of 51 days and 62 days, respectively.

Limitations: Small-sized, single-center, retrospective study.

Conclusions: In palliation for malignant GOO, covered stents were associated with a more frequent need for reintervention than uncovered stents, despite similar outcomes and complications. These results require confirmation in a larger randomized comparison.
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http://dx.doi.org/10.1016/j.gie.2008.06.009DOI Listing
April 2009

Left renal pseudocyst associated with alcoholic chronic pancreatitis.

BMJ Case Rep 2009 14;2009. Epub 2009 Apr 14.

Toho University Ohashi Medical Center, Division of Gastroenterology, Department of Internal Medicine, 2-17-6 Ohashi, Meguro-ku, Tokyo, 153-8515, Japan.

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http://dx.doi.org/10.1136/bcr.08.2008.0608DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3029552PMC
November 2011

Prevalence rates of Giardia and Cryptosporidium among diarrheic patients in the Philippines.

Southeast Asian J Trop Med Public Health 2008 Nov;39(6):991-9

Research and Biotechnology Division, St Luke's Medical Center, 279 E Rodriguez Sr Avenue, Quezon City 1102, Philippines.

The prevalence of Giardia and Cryptosporidium among 3,456 diarrheic patients corrected from May 2004 to May 2005 in the Philippines was determined. Of 133 (3.8%) positive samples, 69 (2.0%) were positive for Giardia and 67 (1.9%) for Cryptosporidium. Three samples had co-infection with Giardia and Cryptosporidium. Luzon had the highest positive samples (5.0%) followed by Mindanao (4.9%), then Visayas (2.2%). Giardia was most prevalent in Mindanao (3.6%) while Cryptosporidium was most prevalent in Luzon (3.1%). The prevalence of Giardia (2.0%) among pediatric patients (0-18 years) did not significantly differ from that (1.9%) among adults (> 18 years old). However, for Cryptosporidium, the prevalence (2.9%) among pediatric patients was significantly higher compared to that (0.2%) among adult patients. In the pediatric population, the highest percentage of patients with Giardia was the 5-9 year old age group, while that of Cryptosporidium was in the 0-4 year old group. The prevalence of Giardia, but not Cryptosporidium, was significantly higher in male than female adults. Seasonality had a distinct peak in September with Cryptosporidium more prevalent in the rainy (2.6%) than dry season (0.9%).
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November 2008

Distinct difference of flaA genotypes of Legionella pneumophila between isolates from bath water and cooling tower water.

Microbiol Immunol 2008 Sep;52(9):460-4

Department of Bacteriology, National Institute of Infectious Diseases, Tokyo, Japan.

To investigate the genetic difference of Legionella pneumophila in human-made environments, we collected isolates of L. pneumophila from bath water (n = 167) and cooling tower water (n = 128) primarily in the Kanto region in 2001 and 2005. The environmental isolates were serogrouped and sequenced for a target region of flaA. A total of 14 types of flaA genotypes were found: 10 from cooling tower water and nine from bath water. The flaA genotypes of isolates from cooling tower water were quite different from those of bath water.
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http://dx.doi.org/10.1111/j.1348-0421.2008.00060.xDOI Listing
September 2008

Genetic evidence for Plasmodium falciparum resistance to chloroquine and pyrimethamine in Indochina and the Western Pacific between 1984 and 1998.

Am J Trop Med Hyg 2008 Oct;79(4):613-9

Department of Parasitology, National Institute of Infectious Diseases, Tokyo, Japan.

Plasmodium falciparum resistance to chloroquine and pyrimethamine is widely distributed in malaria-endemic areas. The origin and geographic spread of this drug resistance have been inferred mainly from records of clinical resistance (treatment failure). Identification of the Plasmodium falciparum chloroqunie resistance transporter (pfcrt) gene and the dihydrofolate reductase (dhfr) gene as target genes of chloroquine and pyrimethamine, respectively, has made it possible to trace the history of genetic resistance to these two drugs. However, evidence for genetic resistance has been limited because of scarcity of archival specimens. We examined genotypes of pfcrt and dhfr in Indochina (Thailand, Myanmar, and Laos) and the Western Pacific (the Philippines, Indonesia, and Papua New Guinea) between 1984 and 1998 by testing samples obtained from malaria cases imported to Japan. Results show that 96% (28 of 29) and 77% (20 of 26) of samples had resistant genotypes of pfcrt and dhfr, respectively, substantiating the inferred history of clinical resistance in these geographic areas during this period.
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October 2008

Genetic polymorphisms of CYP2A6 affect the in-vivo pharmacokinetics of pilocarpine.

Pharmacogenet Genomics 2008 Sep;18(9):761-72

Department of Pharmacokinetics Research, R&D, Kissei Pharmaceutical Co. Ltd., Nagano, Japan.

Objective: Pilocarpine is metabolized to pilocarpic acid by plasma esterase and to 3-hydroxypilocarpine by CYP2A6. The objective of this study was to identify the determinants of interindividual differences in pilocarpine pharmacokinetics after oral administration and to investigate the possible involvement of genetic polymorphisms of CYP2A6.

Methods: The pharmacokinetic parameters of pilocarpine, pilocarpic acid, and 3-hydroxypilocarpine after oral administration of pilocarpine hydrochloride in 28 Japanese participants were calculated based on the data obtained from two phase-1 clinical studies. Probit analysis was carried out for the pharmacokinetic parameters, and participants were accordingly classified into two groups: poor metabolizers and nonpoor metabolizers of pilocarpine. The poor metabolizers were genotyped for CYP2A6, and the pharmacokinetic parameters in this group were compared with those in the nonpoor metabolizers.

Results: Relatively large interindividual differences were observed in the pharmacokinetic parameters of pilocarpine, pilocarpic acid, and 3-hydroxypilocarpine. Probit analysis of the pharmacokinetic parameters revealed that seven of the 28 participants exhibited significantly low plasma concentrations and urinary recovery of 3-hydroxypilocarpine and were classified as poor metabolizers. Genotyping analysis revealed that these poor metabolizers had two inactive CYP2A6 alleles, CYP2A6*4A, CYP2A6*7, CYP2A6*9, or CYP2A6*10. The apparent pilocarpine clearance was significantly lower in the poor metabolizers than in the nonpoor metabolizers (P<0.05).

Conclusion: We demonstrated that CYP2A6 genotype is a contributor to pilocarpine pharmacokinetics, although the impact of the CYP2A6 polymorphism may be pharmacologically and toxicologically tolerable.
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http://dx.doi.org/10.1097/FPC.0b013e328303c034DOI Listing
September 2008