Histopathology enhanced

Balb c mice and Wistar rats were used in the experiments. The administration of single doses of 1, 2 and 2 caused mainly necrotic changes in the liver, measured by GPT and histopathology. The extent of necrosis depended on doses and on time of observation (1-4 days after injections). In shorter time interval (2-4 hrs) 1, 2 and 2 caused depletion of hepatic GSH (even up to 10 % of control). 4 and 5 did not generate necrotic changes. Increased GPT activity was observed after 3 doses of fi. Single doses of 4, 5 and fi mostly increased the level of malondialdehyde (MDA-indicator of lipid peroxidation) in the liver. Repeated injections (3-7) of the investigated compounds enhanced the activity of ALA-D or ALA-S in the liver and caused steatosis. 

In contrast to mice, male rats treated with trichloroethylene by com oil gavage at 1,100 mg/kg/day for 3 weeks failed to exhibit histopathology in the liver, although enhanced hepatic DNA synthesis (175% of control) was detected (Stott et al. 1982). No treatment-related nonneoplastic lesions of the liver were described for male or female rats treated with 1,000 mg/kg/day trichloroethylene for 2 years (NTP 1988, 1990), with 1,097 mg/kg/day for 78 weeks (NCI 1976), or with 250 mg/kg/day for 52 weeks (Maltoni et al. 1986). Except for enlarged livers, liver effects were not reported in mice treated by gavage with trichloroethylene in com oil for 18 months at a dose of 1,978 mg/kg/day for males and 1,483 mg/kg/day for females (Henschler et al. 1984). Hepatic effects were not reported in mice treated by gavage with trichloroethylene in com oil at doses up to 1,739 mg/kg/day for 78 weeks (NCI 1976) or at 1,000 mg/kg/day for 103 weeks (NTP 1990). 

Marttin, E., et al. 1996. Acute histopathological effects of benzalkonium chloride and absorption enhancers on rat nasal epithelium in vivo. Int J Pharm 141 151. 

Buadu, L.D., Murakami, J., Murayama, S., et al. (1996) Breast lesions correlation of contrast medium enhancement patterns on MR images with histopathologic findings and tumor angiogenesis. Radiology, 200, 639-649. 

Lashmar UT, Hadgraff J, Thomas N. Topical application of penetration enhancers to the skin of nude mice a histopathological study. ] Pharm Pharmacol 1989 41(2) 118-122. 

The potential link of formaldehyde-inactivated vaccines adjuvanted with aluminium and observed with the RSV prototype vaccines raised concerns that the influenza H5N1 pandemic formaldehyde-inactivated adjuvanted vaccine could cause an immunopathological effect. As a result, a challenge study in macaque monkeys was conducted it measured both humoral and cell-mediated immune responses and evaluated lung histopathology as an endpoint. The study concluded that there was no disease enhancement.95... 

Much has been made of the enhanced histopathology concept. In reality, this is simply a reminder to pay close attention to the histology of immune system tissues. ICH S8 recommends that a semiquantitative description of observed changes be used. This reflects the fact that lymphoid tissues demonstrate cellular dynamics indicative of potential functional changes. Once again. 

Before describing the overall approach, two basic principles need to be stated. First, it is of value to clarify that enhanced histopathology is not (i) lymphoid tissue immunohistochemistry (ii) bhnd scoring of lymphoid tissues ... 

Enhanced histopathology involves the semiquantitative description of lymphoid tissue changes and is considered central to the Best Practice Guideline for lymphoid tissue microscopic examination. This approach is rooted in the concept that (i) each lymphoid organ has separate compartments that support specific immune functions (ii) these compartments can and should be evaluated individually for changes and (iii) descriptive, rather than interpretative terminology, should be used to characterize changes within these compartments. 

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