Comparative pharmacokinetic study of continuous venous infusion fluorouracil and oral fluorouracil with eniluracil in patients with advanced solid tumors.

PURPOSE: To compare the pharmacokinetics of continuous venous infusion (CVI) fluorouracil (5-FU) with that of oral eniluracil/5-FU and to describe toxicities and clinical activity of prolonged oral administration of eniluracil/5-FU. PATIENTS AND METHODS: A randomized, open-label, cross-over study compared CVI 5-FU to an oral 5-FU/eniluracil combination. Seventeen patients (arm A) were randomly assigned to receive eniluracil/5-FU combination tablets (10:1 mg/m(2) BID for 7 days) during the first study period, followed by 5-FU (300 mg/m(2) CVI for 7 days) during period 2, with a 14-day washout between periods. Sixteen patients (arm B) received treatment in the opposite sequence. In period 3, all patients received eniluracil/5-FU tablets BID for 28 days. Plasma levels of 5-FU during CVI and oral administration were analyzed in periods 1 and 2. Dihydropyrimidine dehydrogenase (DPD) activity was determined by measuring plasma uracil, urinary alpha-fluoro-beta-alanine, and peripheral-blood mononuclear cell (PBMC) DPD activity. RESULTS: There were no grade 3 or 4 toxicities in either arm. Partial responses were observed in three patients. Another three patients had stable disease for > or = 3 months. Eniluracil and 5-FU pharmacokinetics were similar to those observed in previous studies and were unaffected by administration sequence. The mean +/- SD steady-state plasma concentration (C(P)) and area under the curve (AUC)(144-168h) for CVI 5-FU (104 +/- 45 ng/mL and 2,350 +/- 826 ng x h/mL, respectively) were three-fold greater than those for oral 5-FU (38.1 +/- 7.7 ng/mL and 722 +/- 182 ng x h/mL, respectively [P <.00001]). Individual 5-FU concentrations during CVI were highly variable, whereas those after eniluracil/5-FU were very reproducible. DPD activity in PBMCs before each study period was normal. CONCLUSION: Both CVI 5-FU and oral eniluracil/5-FU were well tolerated, with moderate activity in these heavily pretreated patients. However, 5-FU steady-state C(P) and AUCs achieved with oral eniluracil/5-FU were significantly less than with CVI 5-FU.     

Effects of a new clinically relevant antiestrogen (GW5638) related to tamoxifen on breast and endometrial cancer growth in vivo.

PURPOSE: Cross-resistance is an important issue for the evaluation of new antiestrogens to treat advanced breast cancer patients who have failed tamoxifen therapy. In addition, postmenopausal patients treated with long-term adjuvant tamoxifen show a 3-4-fold increase in the risk of developing endometrial cancer. Consequently, a new second line agent should be more antiestrogenic and less estrogen-like on the uterus, and be effective at controlling the growth of breast cancer after exposure to tamoxifen. The purpose was to evaluate the effects of the new tamoxifen analogue GW5638 on breast and endometrial cancer growth. EXPERIMENTAL DESIGN: Athymic mice were transplanted with an endometrial tumor model (ECC-1 E2) that is responsive to estrogen and has never been exposed to antiestrogen. In addition, we used three breast tumor models: a tamoxifen-na?ve tumor (T47D-E2) and two tamoxifen-stimulated tumors (MT2 TAM and MCF-7 TAM LT). The antiestrogen GW5638 (1.5 mg daily), tamoxifen (0.5 mg or 1.5 mg daily), and raloxifene (1.5 mg daily) were given p.o. The pure antiestrogen ICI182,780 (5 mg once a week) was given s.c. Western blots from MCF-7 TAM breast tumors were performed to demonstrate the regulation of estrogen receptor alpha expression by different ligands. RESULTS: Estradiol and GW5638 down-regulated the receptor compared with control. ICI182,780 completely degraded the receptor but tamoxifen had no effect. GW5638 did not promote tumor growth, and was effective in blocking the effects of postmenopausal estradiol on the growth of tamoxifen-na?ve breast and endometrial tumors. However, raloxifene did not completely block the effects of postmenopausal estradiol on the growth of tamoxifen-na?ve endometrial tumor after 14 weeks. GW5638 and ICI182,780 but not raloxifene were also effective in blocking the tamoxifen-stimulated breast tumor growth in athymic mice. CONCLUSIONS: GW5638 is more effective than raloxifene in blocking the effect of estrogen on tamoxifen-na?ve endometrial cancer. More importantly, GW5638, like the pure antiestrogen ICI182,780, is able to block the growth of breast cancer stimulated by tamoxifen differently from raloxifene. GW5638 down-regulates estrogen receptor but does not completely destroy the receptor. Therefore, based on our findings, GW5638 could be developed as a second line agent for advanced breast cancer patients and an important first line agent to evaluate as an adjuvant treatment or chemopreventive.     

MRI of spinal hardware: comparison of conventional T1-weighted sequence with a new metal artifact reduction sequence

Objective. This study was designed to compare diagnostic quality of MR images of patients with spinal hardware acquired using a conventional T1-weighted spin-echo sequence and a new metal artifact reduction sequence (MARS). Conclusion. The new MARS sequence effectively reduces the degree of tissue-obscuring artifact produced by spinal fixation hardware and subjectively improves image quality compared with the conventional T1-weighted spin-echo sequence. Received: 30 May 2000 Revision requested: 12 September 2000 Revision received: 27 September 2000 Accepted: 27 November 2000     

PET "reversed mismatch pattern" early after acute myocardial infarction: follow-up of flow, metabolism and function

The aim of this study was to evaluate changes of flow, metabolism and left ventricular function in patients revealing a "reversed mismatch" pattern (reduced glucose uptake relative to perfusion) on positron emission tomography (PET) early after myocardial infarction. In 19 out of 68 patients (28%), prospectively included in the GUSTO-I or STAR studies, a PET reversed mismatch pattern in the infarct-related region was found. All patients received thrombolytic therapy within 3 h after onset of pain and coronary angiography 90 min later. 2-[¹⁸F]fluoro-2-deoxy-D-glucose (¹⁸F-FDG)/nitrogen-13-labelled ammonia (¹³NH₃) PET was performed after 5 days and 3 months. In 12 of the 19 patients, functional recovery was investigated with two-dimensional echocardiography at the same time points. In the infarct-related region, normalized ¹³NH₃ uptake was 76%ᆟ% at 5 days and 85%ᆞ% at 3 months (P<0.00001). Absolute blood flow in this region was 75ᆭ ml/min per 100 g at 5 days and 80ᆧ ml/min per 100 g at 3 months. At 5 days, normalized ¹⁸F-FDG uptake in the infarct-related region was decreased (51%ᆠ%). At 3 months, ¹⁸F-FDG uptake in this region had significantly recovered (75%ᆟ%, P<0.00001). In the infarct-related region, absolute FDG metabolism was 17Lj µmol/min per 100 g at 5 days and 26Nj µmol/min per 100 g at 3 months (P<0.0001). At 5 days, normalized ¹⁸F-FDG uptake was more severely decreased as compared to the normalized ¹³NH₃ uptake (P<0.00001) in the infarct-related region, resulting in a reversed mismatch pattern (25%ᆡ% of the left ventricle). At 3 months, ¹⁸F-FDG metabolism had partially recovered, giving rise to a change into a PET match pattern. Reversed mismatch regions were present in only 7%lj% of the left ventricle at that time. The ratio of ¹⁸F-FDG uptake to ¹³NH₃ uptake in the infarct-related region increased from 0.67ǂ.8 at 5 days to 0.88ǂ.09 at 3 months (P<0.00001). No functional recovery was observed in the infarct-related region (the 5-day and 3-month wall motion scores were both 2.5ǂ.5). In patients with a myocardial infarction showing a PET reversed mismatch pattern 5 days after thrombolytic therapy, recovery of ¹⁸F-FDG uptake was found but no functional recovery was observed at 3-month follow-up.     

Evaluation and Treatment of Low Responders in Assisted Reproductive Technology: A Challenge to Meet

Purpose: To investigate the various methods of evaluationand treatment of patients with a low response to controlledovarian hyperstimulation in assisted reproductive technologies (ART). Methods: Review and analysis of relevant studies publishedin the last decade, identified through the literature and Medlinesearches. Results: While a universally accepted definition for lowresponders is still lacking, these patients are reported torepresent about 10% of the ART population. Several ovarianreserve screening techniques have been proposed; however,currently the best-characterized and most sensitive screeningtools available are the basal day 3 serum follicle-stimulatinghormone level and the clomiphene citrate challenge test.When abnormal, these tests allow physicians to counselpatients that their prognosis for conception is poor. Althoughthe presence of a normal result does indicate better long-termchances for conception, an age-related decline in fecundityremains and patient age should still be considered whencounseling patients with normal screening results. Severalstimulation protocols have been applied in the low-responsegroup with varying success. Recent studies show that theuse of a minidose gonadotropin-releasing hormone-agonistprotocol may result in significantly decreased cycle cancellationsas well as increased clinical and ongoing pregnancies,and thus is proposed as a first-line therapy. Studies evaluatingsupplementary forms of treatment to the ovulation inductionregimen show improved outcome when pretreating withoral contraceptives, whereas there seems to be no benefitfrom cotreatment with growth hormone or glucocorticoids.Blastocyst culture and transfer and assisted hatching in lowresponders are still under evaluation, whereas natural cyclein vitro fertilization may be used in cases of repeated failuresas a last option before resorting to oocyte donation or adoption.Future possible forms of treatment like in vitro maturationof immature human oocytes, cytoplasm, and nucleartransfer currently are experimental in nature and their efficacyhas still to be proven.Conclusions: The evaluation and treatment of low respondersin ART remains a challenge. Understanding of the underlyingetiology and pathophysiology of this disorder may helpthe clinician to approach it successfully.     

Cord blood and postnatal serum leptin and its relationship to steroid use and growth in sick preterm infants

OBJECTIVE: To study the effect of prenatal and postnatal glucocorticoids use on serum leptin and weight gain in sick preterm infants and its correlation with caloric intake. METHODS: Serum leptin was measured in 24 neonates at day 1 (cord), 14 and 28 by radioimmunoassay. Total caloric intake (enteral and parenteral) and weight were measured on days 14 and 28 of life. RESULTS: Mean birth weight and gestational age of study infants were 864 +/- 273 g (mean +/- SD) (range 520-1755 g), and 26.6 +/- 2.4 weeks (23-32 weeks) respectively. Cord blood leptin was greater in infants whose mothers received antenatal steroids (1.98 +/- 1.05 ng/ml vs 0.94 +/- 0.39 ng/ml, p=0.004). Serum leptin increased postnatally from 1.52 +/- 1.0 ng/ml at birth to 2.2 +/- 1.3 ng/ml on day 28 of life (p=0.03). Mean serum leptin had an inverse exponential relationship with postnatal weight gain by day 28 of life (R2=0.56). Total caloric intake on days 14 and 28 of life did not correlate with postnatal weight gain. CONCLUSIONS: Increased serum concentration of leptin following glucocorticoids may be associated with poor weight gain in sick preterm infants.     

Desired Chinese medicine practitioner capabilities and professional development needs: a survey of registered practitioners in Victoria,Australia

Background  

The State of Victoria in Australia introduced Chinese medicine practitioner registration in 2000 and issued its education guidelines in late 2002 for introduction in 2005. This study obtained practitioners' views on desired capabilities for competent Chinese medicine practice and to identify professional development needs.