Inhibitory and stimulative effects of amiodarone on metabolism of carvedilol in human liver microsomes.

It was reported that coadministration of amiodarone with carvedilol increased the serum concentration to dose (C/D) ratio of S-carvedilol in patients with heart failure, but not of R-carvedilol. The aim of the present study was to investigate the effect of amiodarone and its metabolite on the metabolism of R- and S-carvedilol in human liver microsomes (HLM). Oxidation of carvedilol in HLM was evaluated in the presence of reduced nicotinamide adenine dinucleotide phosphate (NADPH), whereas glucuronidation was evaluated in the presence of uridine 5'-diphosphate (UDP)-glucuronic acid. The oxidation and glucuronidation activities of HLM for S-carvedilol were approximately 2- and 4-fold greater, respectively, than those for R-carvedilol. In the presence of amiodarone (50 microM) and/or desethylamiodarone (25 microM), the oxidation activity for R- and S-carvedilol decreased significantly. In contrast, the glucuronidation activity for R-carvedilol was increased 1.6- and 1.4-fold by amiodarone and desethylamiodarone, respectively, whereas the glucuronidation of S-carvedilol was only slightly changed by amiodarone and desethylamiodarone. These results suggested that inhibition of S-carvedilol oxidation by amiodarone and/or desethylamiodarone is implicated in the increased C/D ratio of S-carvedilol associated with coadministration of amiodarone. On the other hand, the stimulative effect of amiodarone and/or desethylamiodarone on the glucuronidation of R-carvedilol may compensate for the inhibitory effect of those on R-carvedilol oxidation.

Huge fetal ovarian cyst.

Most fetal ovarian cysts increase in size during the late stages of pregnancy. Early treatment of a huge neonatal cyst may reduce the risk of gastrointestinal obstruction.

A simulation study to evaluate limited sampling strategies to estimate area under the curve of drug concentration versus time following repetitive oral dosing: limited sampling model versus naive trapezoidal method.

The area under the curve (AUC) can be associated with the therapeutic or toxic effect of a drug. The limited sampling model (LSM) is an approach that is gaining popularity due to its simplicity for the estimation of AUC using 1-3 blood samples. The aim of the present simulation study was to compare the performance of LSM for various hypothetical drugs with that of the naive trapezoidal method (Trap). The 3-point (trough, peak, and downhill) sampling design following repetitive oral dosing was assumed for LSM (LSM3) and Trap (Trap3). The 2-point (trough and peak) sampling design was also assumed for LSM (LSM2) and Trap (Trap2). In addition, trough-sampling and peak-sampling designs for LSM were designated as LSM1 and LSM1', respectively. As a result, the rank order of precision of the AUC estimation designs/methods was summarized as follows: LSM3 asymptotically equal to Trap3> or =LSM2> or =Trap2 asymptotically equal to LSM1>LSM1'. The finding suggested that LSM can not always improve the estimation performance of AUC in the 3-point sampling design, and that LSM1' is insufficient to estimate the performance of AUC for the hypothetical drugs evaluated in the present study. Accordingly, LSM2 and LSM1 may be an efficient approach for estimating AUC following repetitive oral dosing. In addition, Trap3 and Trap2 may be promising alternatives, because Trap does not require a high investment to recruit a full-sampling model-development group.

Mechanisms responsible for the altered pharmacokinetics of bosentan: analysis utilizing rats with bile duct ligation-induced liver dysfunction.

The purpose of this study was to evaluate the mechanisms responsible for the pharmacokinetic variability of bosentan utilizing rats with liver dysfunction induced by 7-day bile duct ligation (BDL). Bosentan was administered intravenously at a constant infusion rate (I) of 24, 40 or 60 microg/min/kg. The blood bosentan concentration (BBC) following infusion was measured by HPLC, and apparent clearance (CL) of the drug was estimated as I/BBC. The CL values in normal rats were 30.5 and 19.3 ml/min/kg at infusion rates of 24 and 60 microg/min/kg, respectively, suggesting non-linear pharmacokinetics of bosentan. The BBC in BDL rats was much higher than that in normal rats, and the CL values in BDL rats were 3.80 and 3.08 ml/min/kg at infusion rates of 24 and 60 microg/min/kg, respectively. The CL value of bosentan at an infusion rate of 40 microg/min/kg in normal rats was decreased significantly by the coadministration of taurocholic acid or bilirubin. In addition, the hepatic mRNA expression of CYP2C6, CYP3A2, Oatp1a1, Oatp1a4 and Oatp1b2 in BDL rats decreased to 77.6%, 34.0%, 65.4%, 84.8% and 44.2% of that in normal rats, respectively. These results suggested that bile acids and/or bilirubin accumulated in BDL rat plasma inhibited the hepatic uptake of bosentan, and that the decreased bosentan clearance in BDL rats was caused at least partly by the impaired expression of hepatic drug-metabolizing enzymes and uptake transporters. Moreover, because the pharmacokinetics of bosentan was non-linear at the tested doses, the increased BBC in BDL rats might further induce the saturation of hepatic uptake and/or metabolism of bosentan.

Management of pregnancy complicated by ankylosing spondylitis: A case report and literature review.

Pregnancy complicated by ankylosing spondylitis is rare. Labor assistance and instrumental delivery may be difficult due to hip stiffness. Restriction in lumbar flexion may cause difficulties in administering neuraxial analgesia. Difficult intubation for general anesthesia due to limited neck mobility is another potential risk that must be considered.

Incidence of residual bacterial contamination of transvaginal ultrasound probes.

PURPOSE: The aim of the study was to investigate if ultrasound probes are reusable medical devices that risk becoming contaminated after a patient examination in Japan. METHODS: The level of bacterial contamination on transvaginal ultrasound (TVU) probes following current routine probe cleaning at a university hospital (site A) and a clinic (site B) in Japan was investigated. RESULTS: A total of 98.1% of probes were found to be contaminated at site A (median CFU 40, IQR 10, 132.5) and 94.1% were found to be contaminated at site B (median CFU 50, IQR 20, 85). Of the contaminated probes, 52.9% at site A and 64.6% at site B harbored potentially pathogenic bacteria including methicillin-resistant Staphylococcus aureus (MRSA). CONCLUSION: These findings suggest that there is a high rate of ultrasound probe residual bacterial contamination in Japan.

Background Factors Determining the Introduction and Dosage of Insulin in Women With Gestational Diabetes Mellitus.

BACKGROUND: Gestational diabetes mellitus (GDM) is a risk for perinatal complication, and appropriate diagnosis of and intervention in this condition are important. This study aimed to identify patient factors associated with introduction and dosage of insulin, which is the main drug for treatment of GDM. METHODS: In total, 114 patients who had been diagnosed with GDM at our hospital were included in this study. We retrospectively collected clinical parameters of GDM patients, including how many times positive glucose tolerance test results were obtained, whether insulin was introduced, dosage of insulin, body weight, and infant weight. Background factors differing between the insulin introduction and non-introduction groups of GDM patients and parameters associated with the insulin dosage were analyzed. RESULTS: Insulin was introduced in 51 GDM patients (45%). In the insulin introduction group, the six-divided diet was less common and the 75-g glucose tolerance test result was positive a significantly greater number of times compared with the non-introduction group. The factor associated with the insulin introduction status was the number of positive 75-g glucose tolerance test results (odds ratio (OR) 2.04, 95% confidence interval (CI): 1.09 - 3.81, P value = 0.025). In addition, the insulin dosage was found to positively correlate with body weight in the non-pregnant state (P value = 0.005). CONCLUSIONS: The six-divided diet was effective for blood glucose control in GDM women. A positive correlation found between the insulin dosage and body weight in the non-pregnant state suggests the importance of proper pre-pregnancy body weight control.

Rupture of hidden abnormal myometrial vessels during cesarean delivery of a patient with subserosal leiomyoma: A possible pathogenesis of sudden-onset disseminated intravascular coagulation.

We report a case of sudden-onset disseminated intravascular coagulation during cesarean delivery for a patient with a subserosal leiomyoma. Rupture of hidden anastomotic vessels resulted in a significant decrease in fibrinogen levels and uncontrolled bleeding. Uterine venous flow disturbance caused by subserosal leiomyoma compression can possibly cause such a situation.

Preoperative administration of eculizumab to prevent surgery-triggered hemolysis during cesarean section with paroxysmal nocturnal hemoglobinuria.

Eculizumab in pregnancy has been reported to be effective in improving outcomes in patients with paroxysmal nocturnal hemoglobinuria. However, a cesarean section may result in surgery-triggered hemolysis. An additional dose of eculizumab just prior to delivery is an appropriate choice to prevent postoperative hemolysis.

Detection of Asherman's syndrome after conservative management of placenta accreta: a case report.

BACKGROUND: We present a case involving conservative treatment of placenta accreta, with a subsequent diagnosis of Asherman's syndrome. CASE PRESENTATION: A 41-year-old Japanese woman (G2P0A2) delivered a healthy male infant via cesarean section due to preeclampsia. The placenta did not spontaneously separate and was manually removed. Adhesion was tight and placenta accreta was diagnosed. During the procedure, no uterine inversion or perforation, and no uterine cavity adhesion, were observed. Four months postoperatively, hysteroscopy was performed. Adhesion was detected at the fundus of her uterus where the placenta had adhered to the uterus. Asherman's syndrome was diagnosed. CONCLUSIONS: Asherman's syndrome might occur after conservative management of placenta accreta, which may be a direct cause of placenta accreta recurrence. When Asherman's syndrome is diagnosed, the site of the placenta and adhesion should be monitored during subsequent pregnancies.

Open fan sign: An ultrasound finding suggesting postpartum intrauterine forgotten gauze.

Gauze counting is regarded as the most essential way to prevent forgotten gauze inside the body during any surgery. However, incident may still occur due to artificial mistake. An open fan sign on ultrasonography may indicate a gauze left in the intrauterine cavity.

UGT2B7*3 did not affect the pharmacokinetics of R- and S-carvedilol in healthy Japanese.

We previously investigated the pharmacokinetics of R- and S-carvedilol in 54 healthy Japanese subjects, and reported that the oral clearance (CL/F) and apparent volume of distribution (V/F) of both enantiomers in subjects with the CYP2D6*10 allele were significantly lower than those in subjects without the CYP2D6*10 allele. In the present study, we examined the genotype of UGT2B7 in these 54 subjects, and investigated the effect of UGT2B7*3 on the pharmacokinetics of R- and S-carvedilol. Forty-three subjects did not have the UGT2B7*3 allele, and 11 subjects had one UGT2B7*3 allele. CL/F and V/F values of R- and S-carvedilol in the subjects with one UGT2B7*3 allele were similar to those without the UGT2B7*3 allele, indicating that the UGT2B7*3 allele did not significantly affect the systemic clearance (CL) and bioavailability (F) of the two enantiomers.

Can biparietal diameter-to-femur length ratio be a useful sonographic marker for screening thanatophoric dysplasia since the first trimester? A literature review of case reports and a retrospective study based on 10,293 routine fetal biometry measurements.

OBJECTIVE: The aim of the study was to determine whether the biparietal diameter/femur length (BPD/FL) ratio can be used to detect thanatophoric dysplasia in the first trimester of pregnancy. MATERIALS AND METHODS: Twenty-four reported cases of thanatophoric dysplasia diagnosed based on ultrasonographic results with molecular or radiographic diagnosis were included. All sonographic measurement records were extracted and reviewed, and the BPD/FL ratio was calculated for each gestational week. In addition, 10,293 routine fetal biometry measurements from 1395 cases of patients without skeletal dysplasia were compared. RESULTS: The BPD/FL ratio in the control group decreased to less than 3 prior to gestational week 13, and to less than 2 prior to week 18. Of the 27 BPD/FL ratios obtained from 24 cases of thanatophoric dysplasia, none was in the control range. CONCLUSION: The BPD/FL ratio may be used to detect lethal skeletal dysplasias such as thanatophoric dysplasia since the first trimester.

Managing vulvovaginal hematoma by arterial embolization as first-line hemostatic therapy.

OBJECTIVE: A puerperal vulvovaginal hematoma may continue to grow after a surgical procedure and may require blood transfusion. Thus, we selected arterial embolization for hemostasis as the first-line management in two cases of large vulvovaginal hematoma. MATERIALS AND METHODS: Case 1 was a 32-year-old pregnant woman. After delivery, a 10-cm vulvar hematoma developed. An enhanced computed tomography (CT) scan revealed active bleeding. Arterial embolization was performed and complete hemostasis was obtained. Case 2 was a 34-year-old woman with a recurring hematoma after delivery. An enhanced CT scan revealed extravasation in the hematoma. Gelatin sponges were applied and complete hemostasis was obtained. In both cases, arterial embolization was successful without requiring blood transfusions. RESULTS AND CONCLUSION: We successfully managed two cases of puerperal vulvovaginal hematoma by arterial embolization based on the evaluation of an enhanced CT scan. In conclusion, we suggest arterial embolization to be a viable option for first-line treatment in the management of vulvovaginal hematomas.

Site and incidence of birth canal lacerations from instrumental delivery with mediolateral episiotomy.

OBJECTIVE: Instrument-assisted vaginal delivery is a significant risk factor for birth canal lacerations. Although many obstetricians recently are recommending restrictive rather than a routine episiotomy, reports have shown restrictive episiotomy to be associated with more extensive anterior birth canal trauma compared with routine episiotomy. MATERIALS AND METHODS: We retrospectively reviewed 110 cases of forceps and vacuum deliveries and investigated the site of birth canal lacerations. Birth canal lacerations were divided into four sites according to direction-anterior, ipsilateral, contralateral, and posterior. RESULTS: The frequency of lacerations were, from most to least, posterior (34%), lateral (21.7%), and anterior (1.9%). Moreover, among the lateral lacerations, they were more frequent in the contralateral side of episiotomy than the ipsilateral side (18.9% vs. 4.7%, p < 0.01). CONCLUSION: Our results indicate that caution is also needed concerning not only the anterior site, but also the contralateral site of an episiotomy to prevent laceration in an instrument-assisted vaginal delivery.

A pregnancy-associated nonfamilial case of PAPA (pyogenic sterile arthritis, pyoderma gangrenosum, acne) syndrome.

Little is known about the influence of pregnancy on pyogenic sterile arthritis, pyoderma gangrenosum, acne (PAPA) syndrome. We experienced a rare case of pregnancy complicated with PAPA syndrome. The patient had various histories of skin and joint disorders and experienced subarachnoid hemorrhage during pregnancy; however, her skin lesion was unaffected.

Use of intra-arterial nitroglycerin during uterine artery embolization for severe postpartum hemorrhage with uterine artery vasospasm.

OBJECTIVE: Uterine artery embolization (UAE) is a standard method for treating postpartum hemorrhage (PPH), although uterine artery vasospasm during UAE may lead to failure of hemostasis. Here, we report our experience with a case of PPH in which the bleeding was successfully controlled by intra-arterial administration of nitroglycerin during the second UAE. CASE REPORT: A 30-year-old woman experienced PPH following a successful cesarean section, and a UAE was performed. However, 6 hours later, vaginal bleeding restarted; the reason for unsuccessful embolization during the first UAE was vasoconstriction due to hypovolemic shock. We performed a second UAE, but uterine bleeding continued. After intra-arterial administration of nitroglycerin, hemostasis was confirmed, and there was no reperfusion of the uterine artery. After these two UAE procedures, no recurrence of bleeding was observed. CONCLUSION: Thus, use of intra-arterial nitroglycerin was effective for controlling uterine artery vasospasm during UAE. However, larger studies are required to confirm these findings.

Birth of healthy neonates after intracytoplasmic injection of ejaculated or testicular spermatozoa from men with nonmosaic Klinefelter's syndrome: a report of 2 cases.

BACKGROUND: Klinefelter's syndrome is one of the major causes of azoospermia, cryptozoospermia and severe oligozoospermia with either a nonmosaic (47,XXY) or mosaic (47,XXY/46,XY) ICSI treatment with cryopreserved testicular spermatozoa failed, but after the third attempt, 6 of 8 oocytes injected with cryopreserved sperm were fertilized and karyotype. Men with Klinefelter's syndrome generally have difficulty having children. CASES: Patient 1 had motile spermatozoa in the ejaculate, which were injected into 3 oocytes, resulting in fertilization and cleavage. Two good-quality embryos were transferred into his wife's uterine cavity. She conceived and, following a normal pregnancy, delivered a healthy female infant. Two years later she conceived for the second time with motile spermatozoa in the ejaculate and delivered a healthy male infant uneventfully. To our knowledge, this was the first case in which a nonmosaic Kleinefelter's syndrome patient fathered 2 children through intracytoplasmic sperm injection (ICSI) using motile spermatozoa in the ejaculate. Patient 2, with azoospermia, was subjected to testicular biopsy to collect spermatozoa. The first 2 attempts at ICSI treatment with cryopreserved testicular spermatozoa failed, but after the third attempt, 6 of 8 oocytes injected with cryopreserved sperm were fertilized and cleaved. Two of these embryos were transferred into the wife's uterine cavity. She conceived and, following a normal pregnancy, delivered a healthy male infant. In all cases, amniocentesis followed by genetic analysis showed a normal karyotype. CONCLUSION: Two infertile men with nonmosaic Klinefelter's syndrome successfully fathered normal children after intracytoplasmic injection of ejaculated or testicular spermatozoa.