Quetiapine Excretion Into Human Breast Milk.

BACKGROUND: Risk assessment of the use of quetiapine during breastfeeding is challenging owing to a paucity of data. METHODS: A pharmacokinetic study was conducted in lactating women who were taking quetiapine. The primary endpoint was to determine quetiapine concentration profiles in milk and estimated infant exposure levels. Multiple milk and a single blood quetiapine concentrations were determined using a highly sensitive liquid chromatography with tandem mass spectroscopy method. RESULTS: Nine subjects receiving fast-release quetiapine (mean dose, 41 mg/d) were analyzed at steady state. The mean milk/plasma drug concentration ratio at 2-hour postdose was 0.47 (SD, 0.50; range, 0.13-1.67). The mean milk concentration of each patient was 5.7 ng/mL (SD, 4.5; range, 1.4-13.9 ng/mL). The mean infant quetiapine dose via milk per body weight relative to weight-adjusted maternal dose was 0.16 % (SD, 0.08; range, 0.04%-0.35%). CONCLUSIONS: Infant exposure levels to quetiapine via milk are predicted to be very small.

Unintended pregnancy during radiotherapy for cancer.

BACKGROUND: A 27-year-old woman with upper mediastinum stage IIA Hodgkin lymphoma was treated with six cycles of doxorubicin, bleomycin, vinblastine, and dacarbazine chemotherapy. Two months later she received a total of 4,250 cGy to the upper mediastinum and left clavicular region over a 1-month period. One week after completion of radiotherapy she was found to be 13-weeks pregnant. Her physician advised her to terminate pregnancy. She contacted a teratology information service for further information regarding the risks of radiation exposure for her fetus. INVESTIGATIONS: Estimation of fetal radiation exposure, literature review and synthesis of published cases and effects of fetal radiation exposure. DIAGNOSIS: Estimated fetal radiation dose between 5 and 18 cGy. MANAGEMENT: Counseling on the possible risks to the fetus as a result of radiation exposure.

Pregnancy outcome following in utero exposure to bisphosphonates.

BACKGROUND AND AIM: The safety of bisphosphonates in human pregnancy has not been well established. To characterize pregnancy outcome in women receiving bisphosphonates, we conducted a multi-centre, prospective cohort study with a comparison group. METHODS: Patients were recruited through 3 teratogen information centres in Canada and South Korea. We followed 21 women exposed to bisphosphonates during or <3 months before pregnancy, and 21 matched-comparison group women without exposure to known teratogens. Pregnancy/neonatal outcome data were collected by interview. The primary endpoint was neonatal outcome including major birth defects. The secondary endpoints included other pregnancy outcomes such as spontaneous abortions. RESULTS: Indication of the therapy was osteoporosis in all patients. There was no difference in the maternal demographics between the 2 groups. In the bisphosphonate group, there were 18 live births, 2 spontaneous abortions and 1 therapeutic abortion, which were not significantly different from the comparison group. The mean gestational age (mean+/-SD) of the bisphosphonate group was 38.7+/-1.9 weeks (comparison group: 39.3+/-1.9 weeks; P=0.42), and the mean birth weight was 3.1+/-0.3 kg (comparison group: 3.3+/-0.5 kg; P=0.11). In the bisphosphonate group, there was a child diagnosed with Apert syndrome, an autosomal dominant acrocephalosyndactyly, with a fibroblast growth factor 2 mutation. CONCLUSION: Coupled with existing data in the literature, our findings suggest that preconceptional and first-trimester use of bisphosphonates may not pose substantial fetal risks.

The effect of amitriptyline, gabapentin, and carbamazepine on morphine-induced hypercarbia in rabbits.

BACKGROUND: Severe exacerbation of chronic neuropathic pain often requires morphine in patients already treated with drugs such as tricyclic antidepressants, carbamazepine and gabapentin. However, it is unclear if a combination of these drugs intensifies the effects of morphine on the respiratory system and, if so, whether these effects are due to pharmacokinetic or pharmacodynamic interaction. METHODS: We gave rabbits (n=6 per group) the following drugs daily for 4 days: subcutaneous normal saline 1 mL (control); amitriptyline subcutaneously 7 mg/kg; carbamazepine orally 100 mg/kg; gabapentin subcutaneously 25 mg/kg; and all three drugs concurrently (combination). On the fifth day, morphine 5 mg/kg was given IV, and Paco2, Pao2 and pH were measured. Morphine, morphine 3-glucoronide and morphine 6-glucoronide concentrations were measured in the plasma over the 4 h period after morphine injection. RESULTS: Compared with controls, premorphine baseline Paco2 was significantly higher (P<0.05) in the amitriptyline group. Postmorphine Paco2 was significantly higher in the amitriptyline and combination groups at all time points over the 240 min, and in the gabapentin group at 10 and 30 min after morphine injection (P<0.05). Peak Paco2 was significantly higher in the amitriptyline group (58.4+/-1.6 mm Hg; mean SD, P<0.005) and in the combination group (57.4+/-1.0 mm Hg, P<0.02) than in the control group (50.2+/-5.2 mm Hg). Similarly, the area under the curve of Paco2 from zero to 240 min was significantly higher in the amitriptyline and combination groups than in the control (P<0.001). There were no significant differences among the groups in plasma concentrations of morphine and its metabolites. CONCLUSIONS: We conclude that pretreatment with amitriptyline increases morphine- induced hypercarbia through pharmacodynamic processes. The effects of carbamazepine or gabapentin were not obvious in this model.

Prenatal exposure to HMG-CoA reductase inhibitors: effects on fetal and neonatal outcomes.

BACKGROUND: Use of HMG-CoA reductase inhibitors (statins) is becoming increasingly common. However, a recent study based on a series of cases reported to FDA suggests possible teratogenic effects of statins on embryogenesis, such as limb defects and severe central nervous system anomalies. METHODS: In a prospective, observational cohort study with a comparison group to examine a fetal toxicity risk of statins, we followed 64 pregnant women taking statins, and 64 comparison group women without exposure to known teratogens. The statin group women were exposed to atorvastatin (n=46), simvastatin (n=9), pravastatin (n=6), or rosuvastatin (n=3) during the first trimester. RESULTS: There was no difference in the rate of major malformations between the statin group (1/46 live birth: 2.2%) and the comparison group (1/52 live birth: 1.9%, p=0.93). Similarly, there were no statistical differences between the statin and comparison groups in live births (71.9% vs 81.2%), spontaneous abortions (14: 21.9% vs 11: 17.2%), therapeutic abortions (3: 4.7% vs 0: 0%) and stillbirths (1: 1.5% vs 1: 1.6%). Gestational age at birth (38.4+/-2.8 weeks vs 39.3+/-1.3 weeks: M+/-S.D., p=0.04) and birth weight (3.14+/-0.68kg vs 3.45+/-0.42kg, p=0.01) were lower in the statin group. CONCLUSIONS: The absolute risk of teratogenicity of statins, if any, appears relatively small. A large-scale study is needed to further characterize the teratogenic potential.

Benzamil, a blocker of epithelial Na(+) channel-induced upregulation of artery oxygen pressure level in acute lung injury rabbit ventilated with high frequency oscillation.

The epithelial Na(+) transport via an epithelial Na(+) channel (ENaC) expressed in the lung epithelium would play a key role in recovery from lung edema at acute lung injury by removing the fluid in lung luminal space. The lung edema causes dysfunction of gas exchange, decreasing oxygen pressure level of artery [P(aO(2))]. To study if ENaC plays a key role in recovering P(aO(2)) from a decreased level to a normal one in acute lung injury, we applied benzamil (20microM, a specific blocker of ENaC) to the lung luminal space in acute lung injury treated with high frequency oscillation ventilation (HFOV) that is a lung-protective ventilation with a lower tidal volume and a smaller pressure swing than conventional mechanical ventilation (CMV). Benzamil facilitated the recovery of P(aO(2)) in acutely injured lung with HFOV but not CMV. The observation suggests that in acutely injured lung treated with HFOV an ENaC blocker, benzamil, can be applied as a therapeutic drug for acute lung injury combing with HFOV.

Paternal use of ribavirin-interferon alpha 2B combination therapy before conception.

QUESTION: One of my male patients is receiving ribavirin-interferon alpha 2B (Pegetron) combination therapy for chronic hepatitis C. His wife recently found out she is 6 weeks pregnant. They are concerned that the medications might have affected his sperm. How should I advise them? ANSWER: To the best of our knowledge, paternal exposure to ribavirin-interferon alpha 2B has no adverse effects on reproduction. Although we do not have sufficient information to confirm this, several pregnancies where the father had been exposed to these medications turned out fine. If an unexpected pregnancy occurs while the father is receiving this therapy, there is no medical indication for terminating the pregnancy.

Cardiac output measurement by pulse dye densitometry using three wavelengths.

OBJECTIVES: Pulse dye densitometry (PDD), based on the principles of pulse oximetry and dye-dilution technique, is a less invasive method of measuring cardiac output (CO). We have developed prototype equipment to measure CO in pediatric patients using this technique. The purpose of our study was to evaluate the accuracy of this new PDD system using three wavelengths for pediatric application by comparing measurement with an ultrasound flowmeter. DESIGN: Laboratory investigation. SETTING: Hospital physiology research laboratory. SUBJECTS: A total of 15 young piglets weighing approximately 10 kg each. INTERVENTIONS: Measurement of CO by PDD was performed using general anesthesia. Indocyanine green, 0.2 mg/kg, was administered intravenously, and CO was calculated from the dye dilution curve obtained by the PDD system. The ultrasound flowmeter probe was placed on the ascending aorta in the animal, and CO was simultaneously calculated. MEASUREMENTS AND MAIN RESULTS: The two CO values, simultaneously obtained by the ultrasound flowmeter and PDD, were compared during various hemodynamic states. The bias between the CO measured by the ultrasound flowmeter and the CO measured by the PDD system using the reflection-type probe at the central site was 33.8 mL/min and the precision was 293.4 mL/min, indicating that CO measured by PDD had a good correlation with measurements obtained with the ultrasonic method. CONCLUSION: We measured CO in young piglets at an acceptable level of bias and precision using a prototype PDD device. CO measurement by this new PDD system using three wavelengths can be useful and beneficial for critically ill infants and children. It is simple to perform, requiring an injection of dye into a peripheral intravenous catheter, and it will provide a less invasive bedside measurement of CO.