Distribution and excretion of fluoxetine and norfluoxetine in human milk

AIMS: To characterize milk/plasma (M/P) ratio and infant dose, for fluoxetine and norfluoxetine, in breast-feeding women taking fluoxetine for the treatment of depression, and to determine the plasma concentration of these drugs in their infants. METHODS: Fourteen women (mean age 32.2 years) taking fluoxetine (mean dose 0.51 mg kg-1 day-1 ) and their infants (mean age 3.4 months) were studied. Fluoxetine and norfluoxetine in plasma and milk were measured by high-performance liquid chromatography over a 24 h dose interval in four patients, and by single point data collection in 10 patients. Infant exposure was estimated as the product of estimated milk production, and average drug concentration in milk, normalized to body weight and expressed as a percentage of the weight-adjusted maternal dose. RESULTS: Mean M/P values of 0.68 (95% CI 0.52-0.84) and 0.56 (95% CI 0.35-0.77) were calculated for fluoxetine and norfluoxetine, respectively. Mean total infant exposure (fluoxetine equivalents) was estimated to be 6.81% (range 2.15-12%) of the weight-adjusted maternal dose of fluoxetine. Contributions from fluoxetine and norfluoxetine were approximately equal. Fluoxetine (range 20-252 microgram l-1 ) was detected in five of the nine infants from whom samples were collected, and norfluoxetine (range 17-187 microgram l-1 ) was detected in seven of the nine infants. The highest of these concentrations was about 70% of the maternal plasma concentrations. CONCLUSIONS: The mean combined dose of fluoxetine and norfluoxetine transmitted to infants via breast milk is below the 10% notional level of concern. However, there was considerable interpatient variability in estimated infant dose and in some of the patients, the dose was >10%. Further, since adverse effects have been observed in breast-fed infants, careful monitoring of the infants is mandatory. Neonates exposed to these drugs in utero had higher concentrations of fluoxetine and norfluoxetine and are at greater risk of adverse effects.     

Presynaptic calcium currents evoking quantal transmission from avian ciliary ganglion neurons

Using whole-cell patch clamp techniques, we simultaneously recorded presynaptic Ca++ current and excitatory postsynaptic currents (EPSCs) from avian neuromuscular junctions in culture. Quantal synaptic transmission was proportional to evoked presynaptic Ca++ current except with large stimuli, which evoked bursts of quanta, reflecting a shift to synchronized release. Synaptic delay, measured from the onset of presynaptic depolarization to the appearance of the first postsynaptic quantal response, was often greater than 100 msec for weak depolarizations but declined as stimulus intensity was increased. Quantal events evoked by Ca++ tail currents had a mean synaptic delay of 1.67 msec. The single type of presynaptic Ca++ current observed displayed an inactivation time constant of greater than 100 msec and tail currents well fit by a single exponential function.     

新缩瞳剂包公藤甲素人工合成研究

包公藤甲素是从包公藤(Erycibe obtusifolia Benth.)茎中提得的一个新莨菪烷生物碱,具有强烈的缩瞳作用,临床用于治疗青光眼。本文报道用合成的6β-乙酰氧基托品酮为原料,经卤代、水解、还原和N-去甲基化等反应合成包甲素(8)。经光谱测定证实8与天然包甲素的结构完全一致。合成品系外消旋体,其作用机理与天然品相同,而强度则减半。     

Screening for gestational diabetes with the one-hour 50-g glucose test

A one-year experience of screening for gestational diabetes is reported. Patients with any of seven risk factors were screened at the time of prenatal registration. Those without risk factors, and those not found to be diabetic by 24 weeks' gestation, were tested later in pregnancy. Of 4116 patients, 77% had at least one risk factor. The prevalence of diabetes in patients with risk factors was significantly greater than among those with no risk factors (P less than .001). Of 936 patients who had no risk factors, four were found to have diabetes. Multiple logistic regression analysis suggested that family history, obesity, and age over 25 years contributed significantly to the prediction of gestational diabetes. More than 10% of gestational diabetics had screening values between 135-139 mg/dL. Among patients whose early screening values were elevated and whose initial glucose tolerance tests were normal, the odds of being classified ultimately as a gestational diabetic were 7.3 times that of patients whose initial screening tests were normal. Selective screening based on risk factors including maternal age may enhance detection of diabetes early in gestation.     

Generation of a functional and durable vascular niche by the adenoviral E4ORF1 gene

Vascular cells contribute to organogenesis and tumorigenesis by producing unknown factors. Primary endothelial cells (PECs) provide an instructive platform for identifying factors that support stem cell and tumor homeostasis. However, long-term maintenance of PECs requires stimulation with cytokines and serum, resulting in loss of their angiogenic properties. To circumvent this hurdle, we have discovered that the adenoviral E4ORF1 gene product maintains long-term survival and facilitates organ-specific purification of PECs, while preserving their vascular repertoire for months, in serum/cytokine-free cultures. Lentiviral introduction of E4ORF1 into human PECs (E4ORF1⁺ ECs) increased the long-term survival of these cells in serum/cytokine-free conditions, while preserving their in vivo angiogenic potential for tubulogenesis and sprouting. Although E4ORF1, in the absence of mitogenic signals, does not induce proliferation of ECs, stimulation with VEGF-A and/or FGF-2 induced expansion of E4ORF1⁺ ECs in a contact-inhibited manner. Indeed, VEGF-A-induced phospho MAPK activation of E4ORF1⁺ ECs is comparable with that of naive PECs, suggesting that the VEGF receptors remain functional upon E4ORF1 introduction. E4ORF1⁺ ECs inoculated in implanted Matrigel plugs formed functional, patent, humanized microvessels that connected to the murine circulation. E4ORF1⁺ ECs also incorporated into neo-vessels of human tumor xenotransplants and supported serum/cytokine-free expansion of leukemic and embryonal carcinoma cells. E4ORF1 augments survival of PECs in part by maintaining FGF-2/FGF-R1 signaling and through tonic Ser-473 phosphorylation of Akt, thereby activating the mTOR and NF-κB pathways. Therefore, E4ORF1⁺ ECs establish an Akt-dependent durable vascular niche not only for expanding stem and tumor cells but also for interrogating the roles of vascular cells in regulating organ-specific vascularization and tumor neo-angiogenesis.     

Changing from a mixed to self-selected vegetarian diet – influence on blood lipids

Objective To observe any changes in serum concentrations of lipids, when UK meat‐eaters switch to a self selected vegetarian diet for 6 months. Design Observational study using capillary blood samples and 3‐day estimated dietary diary. Setting Free‐living subjects in the North‐West of England. Subjects Twelve male and 31 female adult volunteers aged between 18 and 42 years. Outcome measures Serum lipids; nutrient intake and anthropometric measurements at baseline and 6 months after switching to a self‐selected vegetarian diet. Results Total energy intake and amount of energy derived from saturated fatty acids decreased significantly after changing to a vegetarian diet (P < 0.05) whereas energy derived from carbohydrate, and intakes of nonstarch polysaccharide intake increased. On switching to a vegetarian diet, total cholesterol and triacylglycerol concentrations were not significantly changed, but HDL‐C was 21% higher than at baseline (1.21 mmol L^?1 vs. 1.47 mmol L^?1; P = 0.001). Conclusions These results suggest that beneficial changes to diet occurred on changing to a self‐selected vegetarian diet. Changing to a self‐selected vegetarian diet appears to be one way of achieving a better blood lipid profile.     

Operation Everest II: ventilatory adaptation during gradual decompression to extreme altitude

To assess the ventilatory adaptation during gradual ascent to extreme altitude, we studied seven healthy males as part of the 40 d simulated ascent of Mt. Everest in a hypobaric chamber. We measured resting ventilation (VE, l.min-1), arterial oxygen saturation (SaO2%), the ventilatory response to oxygen breathing, isocapnic hypoxic ventilatory response (HVR), and hypercapnic ventilatory response (HCVR) at sea level prior to the ascent (760 torr), 14,000 feet (428 torr), 24,000 feet (305 torr), and within 24 h of descent (765 torr). VE increased from 9.3 +/- 1.1 l.min-1 at 760 torr to 23.4 +/- 1.3 l.min-1 at 305 torr and remained elevated at 14.7 +/- 0.7 l.min-1 after descent. Oxygen breathing decreased VE by 9.6 +/- 1.3 l.min-1 at 305 torr. Isocapnic HVR (expressed as a positive slope of VE/SaO2, l.min-1.%SaO2(-1) increased from 0.18 +/- 0.07 at 760 torr to 0.34 +/- 0.11 and 0.38 +/- 0.5 at 428 torr and 305 torr (P less than 0.05) respectively. HVR was elevated further upon return to sea level (0.8 +/- 0.09, P less than 0.05). HCVR (S = VE/PETCO2, l.min-1.torr-1) increased from sea level (S = 4.4 +/- 0.09) to 305 torr (S = 18.7 +/- 3.5, P less than 0.01) and remained elevated upon return to sea level (S = 10.7 +/- 4.6, P less than 0.001). This study is the first to investigate the ventilatory response to such extreme altitude and so soon after descent and shows that hypoxic and hypercapnic responses increase during prolonged progressive hypoxic exposure and remain significantly elevated from pre-ascent levels immediately upon descent.     

Preliminary correlations of clinical outcome with in vitro chemosensitivity of second passage human breast cancer cells

These studies describe the clinical correlations of 63 in vitro chemosensitivity assays on breast cancer cells after short-term monolayer culture. Forty-five of the assays were single agent correlations. Based on cut-off values determined empirically, the test accurately predicted resistance for 36 of 41 patients (88%) who did not respond to the drug. It also predicted sensitivity with a high degree of accuracy: 21 of 22 patients (95%) who responded to the drug tested had a sensitive assay. In five cases, two biopsies were evaluated from the same patient. Whenever assays were performed before and after treatment with a given drug, tumor cells from the second biopsy were more resistant in vitro if the patient failed on therapy. If the patient did not fail, but stopped therapy for other reasons, or if there was no intervening therapy with the tested drug, the two biopsies remained similar in drug sensitivity. These results suggest that in vitro chemosensitivity assays which accurately predict both sensitivity and resistance can be obtained with breast cancer cells after short-term culture and that further prospective trials are warranted.