Pharmacokinetics, oral bioavailability, and metabolism in mice and cynomolgus monkeys of (2'R,5'S-)-cis-5-fluoro-1-[2-(hydroxymethyl)-1,3-oxathiolan-5-yl] cytosine, an agent active against human immunodeficiency virus and human hepatitis B virus

(2'R,5'S-)-cis-5-Fluoro-1-[2-(hydroxymethyl)-1,3-oxathiolan-5-yl] cytosine (524W91) is a nucleoside analog with potent anti-human immunodeficiency virus and anti-human hepatitis B virus activities in vitro. The pharmacokinetics and bioavailability of 524W91 after oral dosing were studied in mice dosed with 10, 100, and 600 mg of 524W91 per kg of body weight by the oral and intravenous routes. Cynomolgus monkeys were dosed with 10 and 80 mg of 524W91 per kg. In both species, the clearance of 524W91 was rapid, via the kidney, and was independent of dose. In monkeys, the total body clearance of 10 mg of 524W91 per kg was 0.7 +/- 0.1 liter/h/kg, and the volume of distribution at steady state was 0.8 +/- 0.02 liter/kg. The terminal elimination half-life was 1.0 +/- 0.2 h. The absolute bioavailability after oral dosing was 63% +/- 4% at 10 mg/kg. Concentrations of 524W91 in the cerebrospinal fluid were 4% +/- 0.7% of the corresponding levels in plasma. In mice, the total clearance of 10 mg of 524W91 per kg was 2.3 liters/kg/h, and the volume of distribution at steady state was 0.9 liter/kg. Absolute bioavailability in mice after oral dosing was 96% at a dose of 10 mg/kg. The metabolism of orally administered [6-3H]524W91 was studied in cynomolgus monkeys at a dose of 80 mg/kg and in mice at a dose of 120 mg/kg. Monkeys excreted 41% +/- 6% of the radioactive dose in the 0- to 72-h urine, 33% +/- 10% in the feces, and 10% +/- 7% in the cage wash. Unchanged 524W91 was 64% of the total radiolabeled drug recovered in the urine. The glucuronide was a minor urinary metabolite. 5-Fluorouracil was not detected (less than 0.02% of the dose). Mice dosed orally with 120 mg of [6-3H]524W91 per kg excreted 67% +/- 7% of the radiolable in the )- to 48-h urine. Small amounts of the 3' -sulfoxide and glucuronide metabolites were observed in the urine, but 5-fluorouracil was not detected. Good bioavailability after oral dosing and resistance to metabolism recommend 524W91 for further preclinical evaluation.     

Chemoprevention of pulmonary carcinogenesis by aerosolized budesonide in female A/J mice

This investigation is part of a continuing effort to develop effective chemoprevention for carcinogenesis of the lung. The present study explores the use of aerosol administrations for this purpose. The agent selected for initial study was the synthetic glucocorticoid budesonide. This selection was based on previous work in which budesonide added to the diet was found to inhibit pulmonary adenoma formation in female A/J mice. However, high dose levels were required, i.e., of the order of 300 microg/kg, of body weight [L. W. Wattenberg and R. D. Estensen, Carcinogenesis (Lond.), 18: 2015-2017, 1997]. For aerosol administration of budesonide, a nose-only technique has been developed that entails nebulization of the compound dissolved in ethanol and subsequent stripping off of the solvent (less than 3 microl ethanol/liter of air remaining at the site of inhalation). The budesonide particles produced by the apparatus had a mass median aerodynamic diameter of less than 1 microm. An experiment has been carried out in which the inhibitory effects of aerosolized budesonide, given for 1 min six times a week, were studied. Concentrations of budesonide of 26, 81, and 148 microg/liter of air (calculated doses of 23, 72, and 126 microg/kg of body weight) were used. The aerosols were started 1 week after three oral administrations of benzo(a)pyrene (2 mg/20 g of body weight) to female A/J mice. All three doses of budesonide resulted in more than 80% inhibition of pulmonary tumor formation compared to the aerosol control and 90% or greater compared to mice not exposed to aerosol. The difference in inhibition is due to the aerosol procedure itself, which produces a reduction in tumor formation. A decrease in splenic weight (evidence of a systemic effect) occurred at all doses of budesonide. To the best of our knowledge, this is the first published effort at the use of aerosol administration to prevent neoplasia of the respiratory tract. The results of the present study show that administration of a potential chemopreventive agent by aerosol at a low dose can inhibit the occurrence of pulmonary carcinogenesis in female A/J mice.     

Treatment of gastritis in cheetahs (Acinonyx jubatus)

Three cheetahs (Acinonyx jubatus) had a clinical history of chronic spiral bacteria-associated gastritis and three cheetahs had no clinical history of gastritis. Gastric biopsies were obtained from all six cheetahs prior to treatment for gastritis and 3 wk and 1 yr posttreatment. The cheetahs were treated with tetracycline hydrochloride 500 mg p.o. q.i.d., metronidazole 250 mg p.o. q.i.d., and bismuth subsalicylate 300 mg p.o. q.i.d. Each drug was administered concurrently for 7 days. Following this treatment, each cheetah was maintained on 300 mg bismuth subsalicylate p.o. s.i.d. for 1 yr. The three cheetahs with a history of gastritis were culture positive for Helicobacter acinonyx and remained positive during the entire study. The three cheetahs with no clinical history of gastritis were culture negative for H. acinonyx, but gastric biopsies revealed Gastrospirillum-like bacteria (tentatively named Helicobacter heilmannii) pretreatment. Gastric biopsies were negative for H. heilmannii on subsequent examinations. Although the treatment did not eradicate H. acinonyx, it did provide symptomatic relief from the vomiting, anorexia, and weight loss associated with clinical gastritis. The use of endoscopically guided gastric mucosal biopsies for urease testing and histopathologic examination of Warthin-Starry-stained sections is a sensitive and specific method of diagnosing spiral bacteria-associated gastritis. Treatment of spiral bacteria-associated gastritis in cheetahs should include the rational use of antibiotics (tetracycline or amoxicillin and metronidazole), bismuth compounds, and omeprazole and evaluation of husbandry methods to reduce stress.     

Breast cancer among women exposed to polybrominated biphenyls

We conducted a nested case-control study with 1,925 women enrolled in a polybrominated biphenyl (PBB) registry to examine the association between breast cancer and serum PBBs. Twenty women who developed breast cancer were matched to 290 control subjects on sex, race, and age. Women with serum PBB levels of 2.0-3.0 parts per billion (ppb) [odds ratio (OR) = 3.5; 95% confidence interval (CI) = 0.9-13] or 4.0 ppb or greater (OR = 3.1; 95% CI = 0.8-12) had a higher estimated risk for breast cancer than women with less than 2.0 ppb. The odds ratios were unchanged when available breast cancer risk factors were included in the analysis.     

There are no racial, age, sex, or weight differences in the effect of salt on blood pressure in salt-sensitive hypertensive patients

STUDY DESIGN: A bench-top trauma sled was used to apply four intensities of whiplash trauma to human cadaveric cervical spine specimens and to measure resulting intervertebral rotations using high-speed cinematography. OBJECTIVES: To determine the cervical spine levels most prone to injury from whiplash trauma and to hypothesize a mechanism for such injury. SUMMARY OF BACKGROUND DATA: Whiplash injuries traditionally have been ascribed to hyperextension of the head, but other mechanisms such as hypertranslation also have been suggested. METHODS: Six occiput to T1 (or C7) fresh cadaveric human spines were studied. Physiologic flexion and extension motions were recorded with an Optotrak motion analysis system by loading up to 1.0 Nm. Specimens then were secured in a trauma sled, and a surrogate head was attached. Flags fixed to the head and individual vertebrae were monitored with high-speed cinematography (500 frames/sec). Data were collected for 12 traumas in four classes defined by the maximum sled acceleration. The trauma classes were 2.5 g, 4.5 g, 6.5 g, and 8.5 g. Significance was defined at P < 0.01. RESULTS: In the whiplash traumas, the peak intervertebral rotations of C6-C7 and C7-T1 significantly exceeded the maximum physiologic extension for all trauma classes studied. The maximum extension of these lower levels occurred significantly before full neck extension. In fact, the upper cervical levels were consistently in flexion at the time of maximum lower level extension. CONCLUSIONS: In whiplash, the neck forms an S-shaped curvature, with lower level hyperextension and upper level flexion. This was identified as the injury stage for the lower cervical levels. A subsequent C-shaped curvature with extension of the entire cervical spine produced less lower level extension.     

Bixin and norbixin in human plasma: determination and study of the absorption of a single dose of Annatto food color

A procedure was developed for the detection and determination of bixin and norbixin in human plasma by reversed-phase HPLC with a sensitivity limit of 5 micrograms l-1. A group of seven volunteers ingested a single dose of 1 ml of a commercial Annatto Food Color (16 mg of cis-bixin in soybean oil). The presence of bixin (cis and trans) and norbixin (cis and trans) was demonstrated in the plasma at average levels of 11.6, 10.1, 2.8 and 0 micrograms l-1 of bixin and 48, 58, 53 and 29 micrograms l-1 of norbixin after 2, 4, 6 and 8 h, respectively. Considerable individual variations were observed. Complete plasma clearance generally occurred for bixin by 8 h and for norbixin by 24 h after ingestion of cis-bixin.