Four-week toxicity study

A toxicity screening in late 1985 compared six compounds, including BY 319 and pantoprazole. The results for pantoprazole were very promising. In a four-week toxicity study in early 1986, pantoprazole displayed the most promising data from the series of dimethoxy pyridine compounds. Based on the various animal models, pantoprazole was found to be approximately equipotent to omeprazole [37b], much more stable at neutral and weakly acidic pH, and displayed higher selectivity in enzyme models (pantoprazole is more selective to the H+/K+- as opposed to the Na+/K+-ATPase than omeprazole). Pantoprazole was not the only possible candidate compound at this time. Smith Kline French also had a potential candidate compound, SK F95601 (see Fig. 3.7), which was a 4-amino-3-chloropyridine compound [38]. 

IPEC-Europe (intended clinical route)b ADME Acute toxicity (intended route) and skin sensitization. Ames, chromosome damage and micronucleus. Four weeks toxicity (2 species by intended route) Short-term use studies. Three-month toxicity (most appropriate species). Teratology (rat and rabbit). Genotoxicity assays Short-/midterm studies. Segment I reproduction. Six to nine months toxicity (rodent and nonrodent), segment III reproduction, and carcinogenicity (conditional)... 

Four-week toxicology studies in rodent and nonrodent The four-week studies are designed for subchronic exposure of rodents and nonrodents to the test article. These studies also look at reversibility of any toxicity observed. Many times these are the pivotal studies used to support the first in human dosing. Toxicokinetic assessments are generally included in repeat-dose toxicity studies. When testing biopharmaceuticals, studies also include assessment and characterization of immune response (immunogenicity). 

Parenteral lethality was determined by injecting rabbits of mixed sexes intraperitoneally with 31.6, 63, 126, 252, and 500 /xg/kg of 2,3,7,8-TCDD as a 0.01% corn oil suspension control rabbits were injected with corn oil. The rabbits were housed in individual holding cages and were observed for signs of toxicity for four weeks. The LDso s were calculated by the Weil modification of the Thompson method 14, 15) or by the Litchfield and Wilcoxon method (9). The acute lethality studies were terminated when it was evident that the survivors were not showing signs of toxicity. 

TABLE 16.2. Four-Week Dog or Cynomolgus Monkey Toxicity Study... 

Haggerty, G.C., Miller, G., Port, C. and Gad, S. (1989). Four-week oral toxicity study of diclofenac in the ferret. Presented at the National Meeting of the American College of Toxicology, Williamsburg, Virginia. 

Four-Week Oral Toxicity Study in Female Rats with Mixtures of Nephrotoxicants Having Similar Modes of Action... 

Mobil Oil Corporation. TSCA sec. 8(e) Submission 8EHQ-0381-0366 Follow-up. 4 Four Week Inhalation Toxicity Study in the Rat. Prepared by Bio/dynamics, Inc, Washington, DC, Office of Toxic Substances, US Environmental Protection Agency, 1981... 

Henry SP Bolte H, Auletta C, Komburst DJ. Evaluation of the toxicity of ISIS 2302, a phosphorothioate oligonucleotide, in a four week study in cynomolgus monkeys. Toxicology 1997 120 145-155. 

In a 13 week oral study, piperazine dihydrochloride was administered to dogs (four per sex per dose) at concentrations up to 3692 ppm in the diet. Clinical chemistry changes indicative of mild liver effects were the only sign of systemic toxicity. The no-observed-adverse-effect level in the study was 1477 ppm, which is 25 mg kg of piperazine base. In another 13 week oral study, piperazine was administered to rats (10 per sex per dose) at concentrations of 50, 150, or 500 mg kg in the diet. Histopathological changes were seen in the liver and kidneys in the two higher dose groups. The no-effect level in the study was 50 mg kg... 

Odagiii, Y., N. Wataii, T. Suga, and T. Masuyama. 2006. Four-week oral toxicity study of functional food containing superfine dispersed lentinan (P-l,3-glucan) in rats. Biotherapy 20(6) 568-577. 

Mitsuya, M., N. Suegara, Y. Kojima, et al. 2001. Four-week oral toxicity studies of the leaf powder of mulberry (Morus alba L.) in rats. Pharmacometrics 61(1) 169-176. 

Hagiwara, A. Sano, M. Ichihara, T. Yoshino, H. Miyata, E. Tamano, S. Aoki, H. Yukawa, C. Koda, T. Nakamura, M. Shirai, T. Four-week oral toxicity study of l-carboxy-5,7-dibromo-6-hydroxy-2,3,4-trichloroxanthone (HXCA), an impurity of phloxine B, in F344 rats. J. Toxicol. Sci. 2003, 28,445-453. 

In the recently reported Phase 1 study [114], MAG-CPT was administered as a 30 min infusion on three consecutive days every four weeks. The starting dose was 17 mg/m /day and this was escalated to 130 mg/m /day total dose per cycle = 390 mg/m. Haematological toxicity was rare, but cumulative bladder toxicity was dose-hmiting at doses of 68 mg/m or greater. This could only be resolved by withdrawal of treatment. Of the 16 patients entered in this trial, 11 were evaluable for chnical responses after two courses. These two Phase I studies were the first involving HPMA copolymer conjugates in which no objective clinical responses were seen. However, one patient with renal cell carcinoma had tumour shrinkage and a colon patient had stable disease for 62 days. 

The complexity of the chemistries present in metal etcher exhausts has led researchers to develop experimental methods for investigating the toxicity of these mixtures.Application of these methods in inhalation studies where rats were exposed to etcher effluent six hours per day, five days per week, for four weeks, showed no significant indications of organ toxicity or behavioral effect. There were, however, statistically significant increases in chromosomal aberrations and sister chromatid exchanges in bone marrow cells indicating these chemical mixtures are suspected mutagens. ... 

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