A phase I study of SR-4554 via intravenous administration for noninvasive investigation of tumor hypoxia by magnetic resonance spectroscopy in patients with malignancy.

PURPOSE: To perform a Phase I study of SR-4554, a fluorinated 2-nitroimidazole noninvasive probe of tumor hypoxia detected by (19)F magnetic resonance spectroscopy (MRS). EXPERIMENTAL DESIGN: SR-4554 administration, on days 1 and 8, was followed by plasma sampling for pharmacokinetic studies and by three MRS studies performed over 24 h on days 8 and 9. Unlocalized MR spectra were acquired from tumor (10- or 16-cm dual resonant 1H/19F surface coil; 1.5 T Siemens Vision MR system; 2048 transients acquired over 34 min; 1.28-ms adiabatic pulse; repetition time, 1 s). Plasma drug concentrations were measured with a validated high-performance liquid chromatography method. Noncompartmental pharmacokinetic analysis was performed. RESULTS: Eight patients underwent pharmacokinetic studies, receiving doses of SR-4554 of 400-1600 mg/m(2). Peak plasma concentrations increased linearly with the SR-4554 dose (r(2) = 0.80; P = 0.0002). The plasma elimination half-life was relatively short (mean +/- SD, 3.28 +/- 0.59 h), and plasma clearance was quite rapid (mean +/- SD, 12.8 +/- 3.3 liters/h). Urinary recovery was generally high. SR-4554 was well tolerated. A single patient experienced dose-limiting toxicity (nausea and vomiting) at 1600 mg/m(2). The maximum tolerated dose was 1400 mg/m(2). SR-4554 was detected spectroscopically in tumors immediately after infusion at doses of 400-1600 mg/m(2). At the highest dose (1600 mg/m(2)), SR-4554 was detectable in tumor at 8 h, but not at 27 h. CONCLUSIONS: SR-4554 has plasma pharmacokinetic and toxicity profiles suitable for use as a hypoxia probe. It can be detected in tumors by unlocalized MRS. Additional clinical studies are warranted.     

Long-term cholesterol-lowering effects of psyllium as an adjunct to diet therapy in the treatment of hypercholesterolemia

BACKGROUND: Hypercholesterolemia is a major risk factor for coronary heart disease and nutrition management is the initial therapeutic approach. OBJECTIVE: This multicenter study evaluated the long-term effectiveness of psyllium husk fiber as an adjunct to diet in the treatment of persons with primary hypercholesterolemia. DESIGN: Men and women with hypercholesterolemia were recruited. After following an American Heart Association Step I diet for 8 wk (dietary adaptation phase), eligible subjects with serum LDL-cholesterol concentrations between 3.36 and 4.91 mmol/L were randomly assigned to receive either 5.1 g psyllium or a cellulose placebo twice daily for 26 wk while continuing diet therapy. RESULTS: Serum total and LDL-cholesterol concentrations were 4.7% and 6.7% lower in the psyllium group than in the placebo group after 24-26 wk (P < 0.001). Other outcome measures did not differ significantly between groups. CONCLUSIONS: Treatment with 5.1 g psyllium twice daily produces significant net reductions in serum total and LDL-cholesterol concentrations in men and women with primary hypercholesterolemia. Psyllium therapy is an effective adjunct to diet therapy and may provide an alternative to drug therapy for some patients.     

Dietary fibre and the occurrence of gut symptoms in cystic fibrosis

Accepted 26 October 1996
OBJECTIVE—To evaluate the effect of currently recommended energy rich cystic fibrosis diets on fibre intake and to investigate the relationship between fibre intake and the occurrence of gut symptoms.
METHOD—Prospective completion of non-weighed five day food diaries by 28 children with cystic fibrosis and comparison of mean daily fibre intake with age matched controls who did not have cystic fibrosis. Prospective completion of similar diaries to a total of 68 children with cystic fibrosis and comparison of fibre and lipase intake with the occurrence of gut symptoms.
RESULTS—Mean daily fibre intake in children with cystic fibrosis was 7.00 g compared with 14.65 g in controls (p<0.001). Mean daily fibre intake in eight patients troubled with moderate or severe abdominal pain was 0.144 g/kg. This was significantly lower (p<0.01) than mean values for 22 patients with occasional but mild symptoms (0.249 g/kg) and 38 with no gut symptoms (0.312 g/kg). There was a trend towards higher pancreatic enzyme doses (lipase/kg/day) in children with abdominal pain.
CONCLUSIONS—Currently recommended cystic fibrosis diets have a low fibre content. A low residue diet might be an important factor in the pathogenesis of gastrointestinal symptoms.

     

Randomised controlled double blind study of role of recombinant erythropoietin in the prevention of chronic lung disease

AIM—To evaluate the role of recombinant human erythropoietin (R-HuEpo) in reducing iron infusion, which may exacerbate free radical damage, leading to chronic lung disease.METHODS—A multicentre, randomised, placebo controlled, double blind study was carried out in four neonatal intensive care units in Yorkshire. Infants were randomly allocated and received either R-HuEpo (480 U/kg/wk) or placebo by twice weekly subcutaneous injection. The primary outcome measure was the number of days on respiratory support and a secondary outcome the number of blood transfusions required.RESULTS—Forty two very low birthweight (VLBW) infants were randomly allocated. There was little difference in the need for respiratory support one month after randomisation, but subsequently there was a trend towards a reduction in the proportion requiring respiratory support in the R-HuEpo group (difference at three months ?0.50, 95% confidence interval ?1.00, 0.17). During stay in hospital, the median number of blood transfusions was lower for infants in the R-HuEpo group (difference in medians ?2, 95% CI ?4, 0). The study was stopped early because of failure to recruit babies at the expected rate.CONCLUSIONS—R-HuEpo seems to reduce the number of days in oxygen for ill VLBW infants. These data could be used to construct a larger multicentre study to evaluate this effect further.     

Long-chain polyunsaturated fatty acid transport across the perfused human placenta

The role of the placenta in controlling the supply of fatty acids to the fetus was investigated in term placentae (n=9) from normal pregnancies. The maternal side was perfused ex vivo for 90 min with a modified Krebs Ringer solution containing a physiological mixture of fatty acids and ratio of fatty acid to human albumin. There was no evidence of chain elongation and desaturation of the essential fatty acids. Relative to the value for oleic acid, the rate of transfer to the fetal circulation was: 1.30±0.02 (P<0.001) for linoleic acid, 1.61 ± 0.09 (P=0.002) for α-linolenic acid, 0.67 ± 0.10 (P=0.033) for arachidonic acid and 2.I0 ± 0.16 (P=0.003) for docosahexaenoic acid. For tissue accumulation the values were 1.47 ± 0.39 (P<0.001) for linoleic acid, 2.24 ± 0.37 (P=0.027) for α-linolenic acid, 9.84 ± 1.03 (P=0.001) for arachidonic acid, and 3.01 ± 0.79 (P=0.064) for docosahexaenoic acid. The order of selectivity for transfer from the maternal to the fetal circulation was docosahexaenoic>α-linolenic>linoleic>oleic>arachidonic acid. Such a mechanism would allow the preferential transfer of docosahexaenoic acid and the essential fatty acids to the fetal circulation, thereby protecting the polyunsaturated fatty acid supply to the fetus during a critical period of development.     

Dietary sulfur amino acid requirement of juvenile yellow perch fed the maximum cystine replacement value for methionine

We conducted three separate experiments designed to determine the dietary methionine requirement, ability of cyst(e)ine to spare methionine, and the total sulfur amino acid requirement (TSAA) of juvenile yellow perch when fed the maximal amount of cyst(e)ine. The purified basal diet used in each experiment contained 33.6 g of crude protein/100 g diet and 12.0 g of lipid/100 g diet. In the first experiment,;>L-methionine was added to eight diets providing methionine concentrations ranging from 0.37 to 1.77 g/100 g diet in gradations of 0.2 g/100 g diet. Diets were fed for 12 wk to juvenile yellow perch initially weighing 4.7 g/fish. Broken-line analyses of weight gain and feed efficiency data indicated that the dietary methionine requirement was 1.0 g/100 g diet (3.1 g TSAA/100 g dietary protein) and 1.1 g/100 g diet (3.4 g TSAA/100 g dietary protein), respectively. In the second experiment, various ratios of L-cyst(e)ine and L-methionine were added to the basal diet and fed for 12 wk to determine the cyst(e)ine replacement value of yellow perch initially weighing 19.3 g/fish. Weight gain and feed efficiency (FE) data indicated that cyst(e)ine spared up to 51% of the methionine requirement. In the final experiment, graded levels of cyst(e)ine plus methionine in a ratio of 51:49 were added to the basal diet in gradations of 0.1 g/100 g diet (0.5 to 1.2 g TSAA/100 g diet) to determine the dietary total sulfur amino acid requirement. Diets were fed to satiation for 10 wk to fish initially weighing 8. 1 g. Broken-line analyses of weight gain, feed intake and FE data indicated that the dietary TSAA requirement was 0.85, 0.87 and 1.0 g of TSAA/100 g diet (2.5 to 3.0 g of TSAA/100 g of dietary protein), respectively. The majority of dietary TSAA requirements of fish are in the range of 2 to 4 g/100 g of dietary protein and are generally similar to those of both birds and swine, but lower than estimates for rodents.     

Strontium-90 in newborns and childhood disease

Radioactive strontium-90 concentrations in baby teeth obtained from Suffolk County, New York, rose steadily during the 1980s. Recent levels of strontium-90 are similar to those reported for babies born in the late 1950s-at the height of atmospheric nuclear weapons testing in Nevada. Strontium-90 concentrations increased concomitantly with increases in cancer incidence among Suffolk children under the age of 5 y, a result that mimicked parallel trends observed in the 1950s and early 1960s. Given that effects of strontium-90 on developing cells are most pronounced during the fetal and infant periods, escalating levels should be viewed as a factor in the recent decline in various child health status measures.