Pancreatic toxicity case study

The initial hazard identification of pancreatic toxicity in a prechnical study is always concerning because of the potentially serious human health risks, which may include fulminant, hfe-threatening cases of DIAP or a lifelong iUness, such as CP, type 1 diabetes, or pancreatic neoplasia. Because both the exocrine and the endocrine pancreas have enormous reserve capacities and there are limited sensitive and specific biomarkers to detect pancreatic injury in both animals and humans, there is always the concern that subclinical DIAP may initially go undetected in humans. Further, AP may progress until a threshold of severity is evident in minimally or asymptomatic healthy human volunteers exposed to drug candidates with unknown risks and/or in previously healthy patients that receive standard-of-care agents with marked... 

The lesson learned from these case studies was that in vitro models can be used as screening tools when investigating direct injury to a relevant single cell type, but traditiontd two-dimensional (2D) cell culture models often bear little physical, molecular, or physiological similarity to the pancreas in vivo. This highhghts a need to continue efforts to define more complex multicell systems, such as organotypic and ex vivo models, for assessment of drug candidate-induced pancreatic toxicity. 

Multiple time points are included in study designs to assess acute and late effects as well as the reversibility of any adverse effects. The route of administration should reflect the intended clinical use. Repeated-dose toxicity studies are only relevant if the clinical use includes multiple dosing. For example, in the case of p pancreatic islet cells, toxicity studies should mimic the clinical scenario of retransplantation assessment of acute toxicities and cumulative effects that would preclude retransplantation. 

Female rats are also more susceptible than males to such organophosphorus insecticides as azinphosme-thyl and parathion. Castration or estrogen treatment of the male reverses this difference. The male rat is far more susceptible to carcinoma than the female as shown in the following examples Males are more susceptible to the induction of pancreatic tumors by azaserine, colonic carcinoma by dime-thylhydrazine, intestinal tumors by dimethylnitrosa-mine, renal tumors by decalin, and liver cirrhosis by AAF. In the case of hydroquinone, which is present in photographic material, acute exposure produced renal toxicity in the female but in a chronic 2 year study, the male and not the female was found to have tubular degeneration and adenoma. 

In the case of LC-PUFAs, care must be taken to ensure no toxicity from these compounds. Manufacturers must study the effects of fats, minerals, enzymes, or other factors on LC-PUFA bioavailability and processing. For example, newborn fat absorption can be highly variable because of the immaturity of several lipases, including pancreatic lipase (for review, see Hamosh, 1988). Human milk contains lipases that compensate for the lack of pancreatic lipases. Thus human-milk fat is more bioavailable than the vegetable oils found in infant formulas. 

Saw palmetto is generally regarded as safe with high long-term tolerability. " One case, however, was recently reported in which saw palmetto appeared to be responsible for development of recurrent pancreatitis in a 55-year-old male." A study to investigate its effect on liver functions in rat showed that saw palmetto did not result in any toxicity at 5 x the maximum recommended human doses. The pharmacology and therapeutic signifi-... 

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