Cephaloridine-induced nephrotoxicity in the Fischer 344 rat: proton NMR spectroscopic studies of urine and plasma in relation to conventional clinical chemical and histopathological assessments of nephronal damage

The acute toxicological effects of the nephrotoxic antibiotic cephaloridine (CPH, 0–1500 mg/kg) in male Fischer 344 (F344) rats, have been investigated over 48 h using clinical chemistry, histopathology and proton nuclear magnetic resonance (¹H NMR) spectroscopy of urine and plasma. High field (400 and 600 MHz)¹H NMR urinalysis revealed increased excretion of lactic acid, acetoacetate, alanine, valine, lysine, glutamine and glutamate and a severe, time-dependent glycosuria. A major change observed in urine of CPH-treated animals was the dose-dependent increase in HB which may relate to altered energy metabolism. CPH also caused dose-dependent decreases in the urinary excretion of hippurate, allantoin and protein (conventional assay). This abnormal metabolic profile is consistent with a functional defect in the S₁/S₂ regions of the proximal tubule, and was confirmed by histologypost mortem. Functional changes observed included elevations in blood urea nitrogen (BUN) and urine flow rate (UFR) and dose-related decreases in urine osmolality. Spin-echo¹H NMR spectroscopic analysis of lyophilised plasma, reconstituted with²H₂O revealed an abnormal phase modulation of the methyl signal from free alanine and it is postulated that this is due to the release of transaminases from damaged tissue which via a reversible conversion to pyruvate, cause variable deuteration of alanine at the -CH position. This observation suggests that¹H NMR spectral patterns are also dependent on the level of plasma transaminases and this may provide a novel indicator of tissue damage.     

Variations in Prkdc and susceptibility to benzene-induced toxicity in mice.

Benzene, a carcinogen that induces chromosomal breaks, is strongly associated with leukemias in humans. Possible genetic determinants of benzene susceptibility include proteins involved in repair of benzene-induced DNA damage. The catalytic subunit of DNA-dependent protein kinase (DNA-PKcs), encoded by Prkdc, is one such protein. DNA-PKcs is involved in the nonhomologous end-joining (NHEJ) pathway of DNA double-strand break (DSB) repair. Here we compared the toxic effects of benzene on mice (C57BL/6 and 129/Sv) homozygous for the wild-type Prkdc allele and mice (129/SvJ) homozygous for a Prkdc functional polymorphism that leads to diminished DNA-PK activity and enhanced apoptosis in response to radiation-induced damage. Male and female mice were exposed to 0, 10, 50, or 100 ppm benzene for 6 h/d, 5 d/week for 2 weeks. Male mice were more susceptible to benzene toxicity compared with females. Hematotoxicity was evident in all male mice but was not seen in female mice. We observed similar, large increases in both micronucleated erythrocyte populations in all male mice. Female mice had smaller but significant increases in micronucleated cells. The p53-dependent response was induced in all strains and genders of mice following benzene exposure, as indicated by an increase in p21 mRNA levels in bone marrow that frequently corresponded with cell cycle arrest in G2/M. Prkdc does not appear to be a significant genetic susceptibility factor for acute benzene toxicity. Moreover, the role of NHEJ, mediated by DNA-PK, in restoring genomic integrity following benzene-induced DSB remains equivocal.     

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.     

Chemopreventive effects of alpha-santalol on skin tumor development in CD-1 and SENCAR mice.

Studies from our laboratory have indicated skin cancer chemopreventive effectsof sandalwood oil in CD-1 mice. The purpose of this investigation was to study the skin cancer chemopreventive effects of alpha-santalol, a principal component of sandalwood oil in CD-1 and SENCAR mice. alpha-Santalol was isolated from sandalwood oil by distillation under vacuum and characterized by nuclear magnetic resonance and gas chromatography-mass spectrometry. Chemopreventive effects of alpha-santalol were determined during initiation and promotion phase in female CD-1 and SENCAR mice. Carcinogenesis was initiated with 7,12-dimethylbenz(a)anthracene and promoted with 12-O-tetradecanoylphorbol-13-acetate (TPA). The effects of alpha-santalol treatment on TPA-induced epidermal ornithine decarboxylase (ODC) activity and (3)H-thymidine incorporation in epidermal DNA of CD-1 and SENCAR mice were also investigated. alpha-Santalol treatment during promotion phase delayed the papilloma development by 2 weeks in both CD-1 and SENCAR strains of mice. alpha-Santalol treatment during promotion phase significantly (P < 0.05) decreased the papilloma incidence and multiplicity when compared with control and treatment during initiation phase during 20 weeks of promotion in both CD-1 and SENCAR strains of mice. alpha-Santalol treatment resulted in a significant (P < 0.05) inhibition in TPA-induced ODC activity and incorporation of (3)H-thymidine in DNA in the epidermis of both strains of mice. alpha-Santalol significantly prevents papilloma development during promotion phase of 7,12-dimethylbenz(a)anthracene-TPA carcinogenesis protocol in both CD-1 and SENCAR mice, possibly by inhibiting TPA-induced ODC activity and DNA synthesis. alpha-Santalol could be an effective chemopreventive agent for skin cancer. Additional experimental and clinical studies are needed to investigate the chemopreventive effect of alpha-santalol in skin cancer.     

Australia's notifiable diseases status, 2002: Annual report of the National Notifiable Diseases Surveillance System.

There were 57 infectious diseases notifiable at the national level in Australia in 2002. States and territories reported 100,278 cases of infectious diseases to the National Notifiable Diseases Surveillance System (NNDSS), a fall of 4 per cent compared to the number of notifications in 2001. In 2002, the most frequently notified diseases were, sexually transmitted infections (31,929 reports, 32% of total notifications), gastrointestinal infections (26,708 reports, 27% of total notifications) and bloodborne infections (23,741, 24%). There were 11,711 (12% of total) cases of vaccine preventable diseases, 3,052 (3% of total) cases of vectorborne diseases, 1,155 (1% of total) cases of zoonotic infections, two cases of quarantinable diseases (Vibrio cholerae O1) and 1,980 cases of other bacterial diseases, notified to NNDSS. Compared to 2001, notifications of sexually transmitted infections increased by 16 per cent and gastrointestinal infections by 2 per cent while bloodborne infections fell by 18 per cent. The number of notifications of chlamydial infection and Q fever were the highest since 1991 and 1995 respectively. By contrast, the number of notification for hepatitis A and measles were the lowest since 1991. For other notifiable diseases, the number of notifications was within the range of the five years between 1997 and 2002 (range = five-year mean plus or minus two standard deviations). This report also includes 2002 summary data on communicable diseases from other surveillance systems including the Laboratory Virology and Serology Reporting Scheme and sentinel general practitioner schemes.