Pharmacokinetics of fluticasone propionate multidose, inhalation-driven, novel, dry powder inhaler versus Diskus and metered-dose inhalers.

BACKGROUND: A novel inhalation-driven multidose dry powder inhaler (MDPI) that eliminates the need for the patient to coordinate device actuation with inhalation has been developed for delivery of inhaled asthma medications. OBJECTIVE: To characterize the pharmacokinetics of single-dose fluticasone propionate (Fp) MDPI compared with single doses of Fp Diskus (a dry powder inhaler) and a metered-dose inhaler (MDI) in healthy subjects. METHODS: This was a single-center, open-label, randomized, three-period crossover, single-dose pilot study in healthy adults ages 18 to 45 years. Eligible subjects (N = 18) were randomized to one of six treatment sequences that contained three treatment arms: Fp MDPI 400 micrograms/inhalation X two inhalations (800 micrograms total dose); Fp Diskus 250 micrograms/inhalation X four (1000 micrograms total dose); and Fp MDI 220 micrograms/inhalation X four (880 micrograms total dose). Pharmacokinetics (area under concentration-versus- time curve [AUC], maximum plasma concentration [Cmax], time to Cmax [tmax], and elimination half-life [t1/2]), safety, and tolerability were assessed for each treatment. RESULTS: Plasma Fp concentration-versus-time curves were comparable across treatments. Geometric mean AUC 0-t and Cmax for Fp MDPI 800 micrograms were 19% and 18% higher, respectively, compared with Fp Diskus 1000 micrograms, and 47% and 82% higher, respectively, compared with Fp MDI 880 micrograms. Median tmax (60.0-60.6 minutes) and median t1/2 (9.1-9.8 hours) were comparable across the three treatments. Single-dose Fp was well tolerated, with no new safety issues noted. CONCLUSION: Single-dose administration of Fp MDPI 800 micrograms produced systemic exposure comparable with those for Fp Diskus 1000 micrograms and Fp MDI 880 micrograms.

Bladder tumors in rats fed cyclohexylamine or high doses of a mixture of cyclamate and saccharin.

Papillary transitional cell tumors were found in the urinary bladders in 8 rats out of 80 that received 2600 milligrams per kilogram of body weight per day of a mixture of sodium cyclamate and sodium saccharin (10:1) for up to 105 weeks. From week 79 on, several of these rats received cyclohexylamine hydrochloride (125 milligrams per kilogram per day, the molecular equivalent of the conversion of about 10 percent of the cyclamate dosage to cyclohexylamine) in addition to the sodium cyclamate and sodium saccharin. In another study in which 50 rats were fed daily 15 milligrams of cyclohexylamine sulfate per kilogram of body weight for 2 years, eight males and nine females survived. One of the eight males had a tumor of the urinary bladder. In neither study were bladder tumors found in the control rats or in rats treated with lower doses of the compounds.

Single-Stranded DNA Curtains for Studying Homologous Recombination.

Homologous recombination is an important pathway involved in the repair of double-stranded DNA breaks. Genetic studies form the foundation of our knowledge on homologous recombination. Significant progress has also been made toward understanding the biochemical and biophysical properties of the proteins, complexes, and reaction intermediates involved in this essential DNA repair pathway. However, heterogeneous or transient recombination intermediates remain extremely difficult to assess through traditional ensemble methods, leaving an incomplete mechanistic picture of many steps that take place during homologous recombination. To help overcome some of these limitations, we have established DNA curtain methodologies as an experimental platform for studying homologous DNA recombination in real-time at the single-molecule level. Here, we present a detailed overview describing the preparation and use of single-stranded DNA curtains in applications related to the study of homologous DNA recombination with emphasis on recent work related to the study of the eukaryotic recombinase Rad51.

Discharge-flow kinetics measurements using intracavity laser absorption spectroscopy.

Intracavity laser absorption spectroscopy ("ICLAS") has been demonstrated as a feasible detection method for trace species in a discharge flow tube. This implementation has been used to measure the rate of the reaction between atomic hydrogen and NO to form HNO in helium carrier gas. A reaction rate constant of (4.3 +/- 0.4) x 10(-32) cm(6) molecule(-2) s(-1) at 295 K was measured for the reaction H + NO + M --> HNO + M (M = He). The pressure and concentration range enabled by ICLAS detection has allowed us to limit reactive pathways that would inhibit the formation of HNO. The sensitivity of ICLAS, coupled with the versatility of the discharge flow technique, suggests that intracavity absorption spectroscopy will be a useful technique for kinetics measurements on free radicals and other reactive species.

Hepatitis B vaccination in pregnancy: factors influencing efficacy.

OBJECTIVE: To determine seroprotective antibody response after hepatitis B vaccination during pregnancy and to assess factors influencing the rate of maternal seroprotection. METHODS: Records of 80 healthy gravidas who elected hepatitis B vaccination during pregnancy, after being identified as hepatitis B surface antigen (HbsAg) and antibody (HbsAb) negative on initial prenatal screen, were analyzed retrospectively. Each gravida was begun on a series of three recombinant hepatitis B vaccines at 0, 1, and 6 months. At 36-40 weeks' gestation, all gravidas were rescreened for seroprotective levels of HbsAb using qualitative enzyme-linked immunosorbent assay analysis. The women were grouped by maternal age (less than 25 years or at least 25 years), smoking history, maternal weight, body mass index (BMI) (less than 30, at least 30, less than 34, or at least 34), number of vaccinations received, race-ethnicity, gestational age at vaccination, and vaccination-to-rescreening interval. Data were compared by t test, chi2 test, or Fisher exact test. Stepwise logistic regression analysis was done. RESULTS: At rescreening, 39 (49%) of the 80 women had seroprotective HbsAb conversion. After two vaccinations, obese women (BMI at least 30) (P = .04), women at least 25 years old (P = .04), and women with smoking histories (P = .005) were significantly less likely to respond to the vaccine. Logistic regression analysis for predicting failure of seroprotective response after two vaccinations showed significantly increased odds for severe obesity with BMI at least 34 (odds ratio [OR] 16.2; 95% confidence interval [CI] 1.7, 154.7), smoking history (OR 7.5; 95% CI 2.0, 27.7), and age at least 25 years (OR 3.9; 95% CI 1.1, 14.4). CONCLUSION: Maternal obesity, advancing age, and smoking have negative influences on the efficacy of hepatitis B vaccination in pregnant women.

Acute intentional iron overdose in pregnancy.

BACKGROUND: Although iron is the second most common overdose agent in pregnancy, the obstetric literature does not reflect current management of this emergency. CASE: A 27-year-old woman, para 0-3-4-3, at 27 weeks' gestation ingested 24 mg/kg of elemental iron in a suicide attempt. Therapy with crystalloid hydration, gastric lavage, and intravenous deferoxamine chelation treated the overdose without maternal or fetal complications. CONCLUSION: Pregnancy should not alter therapy for acute iron overdose. Deferoxamine administered in the third trimester is not associated with perinatal complications and is potentially life saving.

Neonatal morbidity at 34-37 weeks: the role of ruptured membranes.

OBJECTIVE: Evaluate neonatal morbidity in deliveries occurring between 34 0/7 and 36 6/7 weeks' gestation, comparing outcomes in pregnancies complicated by preterm premature rupture of membranes with those in which delivery occurred with intact membranes prior to the onset of labor. METHODS: The obstetric database was reviewed for a 5-year period. Healthy gravidas delivering nonanomalous singleton gestations from vertex presentations were evaluated, with corticosteroid or antibiotic administration or both noted. The neonatal database was reviewed for the following complications: admission to the neonatal intensive care unit, need for assisted ventilation, and development of hyaline membrane disease, bronchopulmonary dysplasia, intraventricular hemorrhage, necrotizing enterocolitis, or culture-proven sepsis. Groups were compared using chi2 tests. The power of this study to detect a ten-fold decrease in the likelihood of neonatal complications at the P<.05 significance level was greater than 90%. RESULTS: Of 853 eligible pregnancies, 414 (48.5%) gravidas had ruptured membranes prior to the onset of active labor. No difference existed between groups in the number of patients who had received corticosteroids during pregnancy, but patients with ruptured membranes were more likely to have received antibiotics prior to delivery. No neonatal deaths occurred, and neonatal morbidity was low in both groups. CONCLUSION: No clinically significant difference exists in neonatal outcome between 34 0/7 and 36 6/7 weeks' gestation as the result of membrane status prior to the onset of labor.

The utility of the TDx test in the assessment of fetal lung maturity.

Accurate assessment of fetal lung maturity is essential in the management of high-risk obstetric patients. New rapid techniques have been developed to supplement time-consuming chromatographic methods. We compared one of these newer methods, the TDx-FLM, to the standard tests for fetal pulmonary maturity. There was an excellent correlation between the TDx and the lecithin-sphingomyelin ratio (r = 0.78). Although a TDx value of 70 or greater is considered mature, we found a value of 50 or greater predictive of fetal lung maturity in 100% of cases, and have chosen to redefine a mature value as 50 or greater in our institution. This value has greatly enhanced the clinical applicability of the test, allowing use of a large number of specimens from the previously poorly understood and often disregarded borderline category.

Prenatally diagnosed sacrococcygeal teratoma: a unique expression of trisomy 1q.

Partial duplication of the long arm of chromosome 1 has been observed in fetal intracranial teratomas. We sonographically diagnosed a 19-week fetus with sacrococcygeal teratoma, cerebral ventriculomegaly, and cerebellar hypoplasia. Chromosomal analysis of amniocytes showed an unbalanced translocation between chromosomes 1 and 15, resulting in trisomy 1q21-->1 qter. Duplication or over expression at more than one locus on the long arm of chromosome 1 may be required for the development of an extra-gonadal teratoma.

Fetal intracardiac echogenic foci: current understanding and clinical significance.

The detection of fetal intracardiac echogenic foci (ICEF) by ultrasound was first reported in 1987. Despite many investigations, the relationship of ICEF with congenital heart malformations and chromosomal abnormalities remains unclear. This review describes the current understanding of ICEF based on a literature search from 1980 to the present. ICEF are observed in 0.5 to 20 percent of fetuses, with an overall frequency of 5.6 percent. These small, discrete structures near the papillary muscles and chordae tendinae move in synchrony with the intraventricular valves. They likely represent microcalcification of the papillary muscles. ICEF are most commonly seen in the left ventricle and occasionally in the right ventricle or bilaterally. Intra-atrial or diffuse ICEF are rare. In the chromosomally normal fetus, ICEF are not associated with congenital heart defects. The presence of ICEF in fetuses at high risk for chromosomal abnormalities suggests an increased possibility of aneuploidy, especially if other sonographic markers are noted. A similar association is observed with trisomy 21 in particular. The significance of ICEF in fetuses at low risk for aneuploidy is less clear and represents an area for future research.

Prenatal detection and management of quadruple nuchal cord. A case report.

As imaging techniques improve, nuchal cords are often being identified prior to labor. Nuchal cords are encountered in up to 25% of deliveries and are usually not clinically significant. They may, however, have devastating results. Nuchal cords may be associated with abnormal fetal activity and testing, but there is often no clinical warning of a nuchal cord during pregnancy, labor or delivery. We report a case of a quadruple nuchal cord discovered after the mother complained of decreased fetal movement. The clinical course of this patient highlights many of the difficulties encountered in the management of antenatally diagnosed nuchal cords, particularly in the preterm fetus.

The relative proportions of type I and type II muscle fibers in the external sphincter ani muscle at different ages and stages of development--observations on the development of continence.

The external sphincter ani muscles were partially or completely removed from 11 fetuses, 3 infants, 2 children and 12 adults, none of whom had had anorectal disease and all of whom had died of diseases not affecting the anorectal organ of continence. Muscle fiber-typing was carried out. In the fetuses ages 26-40 weeks, we found a predominance of Type II (rapid) fibers. With increasing gestational age Type II fibers started to diminish along with a simultaneous increase in Type I (slow) fibers. At the same time, stromal restructuring took place. Three infants, ages 1, 2 and 10 months, showed further increases of Type I fibers, until finally, in the two older children studied (5 and 8 years), there was a predominance of Type I fibers. This persisted in adults between ages 56 to 70, but after age 70 Type I fibers diminished, so that the ratio of slow to rapid fibers in the 78 to 81 year-old group was 3:2. This study shows that in contrast to other skeletal muscles the fiber distribution in the external sphincter ani muscle is not established from the beginning, but is the result of a developmental process. The predominance of Type II (twitching) fibers explains the state of reflex continence of the young infant. With increasing maturation of tonic Type I fibers, an additional voluntary component to continence is made possible with the help of the supporting pelvic musculature. This maturation is determined by the increasing strain on the pelvic floor as the child learns to sit and walk.(ABSTRACT TRUNCATED AT 250 WORDS)

Intentional iron overdose in pregnancy--management and outcome.

The objectives of our study were to 1) determine if peak maternal serum iron level or toxicity stage after intentional overdose is associated with adverse maternal-fetal outcome, and 2) describe the use of deferoxamine antidote therapy in obstetric patients. A computer search of the English language literature from 1966-1998 used the key words iron toxicity, iron poisoning, deferoxamine, and pregnancy to identify peer-reviewed papers reporting intentional iron overdoses in pregnancy. Two investigators independently extracted data from articles and their references including stage of toxicity (0 = asymptomatic, 1 = gastrointestinal symptoms, 2 = metabolic disturbance, 3 = organ failure), with differences resolved by consensus. Statistical analysis used the Student t-test, Fisher exact test, or ANOVA, as appropriate. Fourteen publications were identified, describing 61 cases of obstetric iron overdose, including one recent case at our institution. Compared with women who had lower peak levels, women with peak serum iron levels > or =400 mcg/dL were more frequently symptomatic (12/13 vs. 5/10, respectively, p = 0.05). Peak iron level > or =400 mcg/dL was not associated with increased risk of spontaneous abortion, preterm delivery, congenital anomalies, or maternal death. However, patients with stage 3 toxicity were more likely to spontaneously abort (1/3 vs. 1/56, respectively), deliver preterm (2/3 vs. 6/56, respectively), or experience maternal death (3/3 vs. 0/56, respectively). The proportions of patients treated with deferoxamine and total dosages of deferoxamine were similar by peak iron level (> or =400 vs. <400 mcg/dL) and toxicity stage (0-3). Peak iron levels > or =400 mcg/dL are associated with symptomatic iron overdose. Stage 3 toxicity is associated with spontaneous abortion, preterm delivery, and maternal death.

Meralgia paresthetica: an unusual complication of post-cesarean analgesia.

Intramuscular (IM) injections may be associated with nerve injury, classically the sciatic nerve after intragluteal injection. We describe an unusual injury of the lateral femoral cutaneous nerve following an IM injection of 100 mg meperidine and 25 mg promethazine in the anterolateral right thigh. Although the thigh is advocated as a relatively safe site for IM injection, iatrogenic neuropathy may result. Awareness of the anatomy of the lateral femoral cutaneous nerve and avoiding injections into a partially anesthetized extremity may decrease the likelihood of recurrences.

Twin vaginal birth after cesarean.

OBJECTIVE: To determine both success rate and maternal-fetal outcome of vaginal birth after cesarean in twin gestations. METHODS: We identified all women from a single center attempting vaginal birth of twins after cesarean from 1988-98. Twin pairs were excluded for delivery < or = 25 weeks gestation, monoamnionicity, nonvertex twin A, or major anomaly or death of either twin. Cases were matched to the next three consecutive twin gestations attempting vaginal delivery without a prior cesarean. Variables matched were gestational age at delivery (+/- 1 week), presentations of both fetuses, labor onset (spontaneous or induced), and prior vaginal delivery (yes or no). The primary outcome was successful vaginal delivery of both fetuses. Secondary maternal outcomes included chorioamnionitis, hemorrhage requiring transfusion, hysterectomy, uterine rupture, and length of stay. Neonatal outcomes included one and five minute Apgars, NICU admission, and length of NICU stay. RESULTS: Twelve parturients were matched to 36 controls. There were no differences between the groups with respect to maternal demographics, intrapartum variables, fetal genders, birthweights, or chorionicity. Women with a prior cesarean (10/12) delivered both twins vaginally compared to 31/36 parturients without a prior cesarean (P = 1.0). There were no differences between cases and controls with respect to maternal morbidity (1/12 vs 4/36, P = 1.0), or postpartum stay (2.5 +/- 1.0 vs 2.5 +/- 2.3 days, P = .25). Neonatal outcomes were similar by birth order, except that second-born twins of cases had significantly longer NICU stays than controls (22.7 +/- 3.8 vs 10.4 +/- 7.8 days, P = .04). CONCLUSION: Twin trial of labor after cesarean is associated with a high success rate of vaginal delivery but may be associated with a more lengthy NICU stay for the second twin.