Mucosal tolerance effects

Procarbazine -alkylating agent cell cycle independent -bone marrow suppression—prolonged -nausea and vomiting—severe tolerance often develops with repeated dosing -mucocutaneous effects (mucositis, stomatitis, diarrhea) -rash, hives, photosensitivity -interstitial pneumonitis -CNS toxicity—seizures, lethargy, headache, ataxia -flu-like syndrome -azoospermia and amenorrhea almost universal... 

It is of particular clinical relevance to test the effects of mucosal allergen application in already sensitized organisms. The obvious advantage of the use of so-called hypoallergenic molecules lies in their risk-free application. Thus, the practical consequences from such experimental studies could include the development of low-risk mucosal vaccines based on the induction of tolerance - with or without the use of certain mucosal antigen delivery systems. 

PURPOSE AND RATIONALE Drags developed for local application to mucosal membranes of the eye, mouth, membranes of the penis, vagina and rectum have to be tested for local tolerance as well. However, for testing of locally irritating effects findings from toxicology studies with repeated administration to mucosal membranes are more suitable than acute studies developed mainly for testing of industrial chemicals. 

In chronic studies, male and female rats and mice tolerated up to 2.5 ppm chlorine gas for 6 h/day, 5 days/week for 2 years (CUT, 1993 Wolf et al, 1995). Concentration-dependent lesions confined to the nasal passages were observed in all animals. These lesions were most severe in the anterior nasal cavity and included respiratory and olfactory epithelial degeneration, septal fenestration, mucosal inflammation, respiratory epithelial hyperplasia, squamous metaplasia and goblet cell hypertrophy and hyperplasia, and secretory metaplasia of the transitional epithelium of the lateral meatus. Body weight was depressed compared to controls but no early deaths occurred. A similar lack of lower respiratory tract effects was seen in monkeys exposed to 2.3 ppm chlorine for 6 h/day, 5 days/week, for 1 year (Klonne et al, 1987). At these concentrations, chlorine is effectively scrubbed in the anterior nasal passages as indicated by the absence of lesions in the lung. 

Omeprazole, in a starting dose of 0.7 mg/kg/day, was effective in the treatment of severe esophageal reflux after failed fundoplication in 18 children (mean age at presentation 7.8 years) over a mean follow-up period of 4.4 years (30). It was also well tolerated. A hyperplastic polyp was noted in one child after 38 months of treatment and persisted without any dysplastic change. One to three gastric nodules were seen in three children after a mean of 45 months histology of the nodules showed only mucosal edema. 

In 21 patients with squamous cell carcinomas of the head and neck randomized to tretinoin 45, 50, or 150 mg/ m either once daily or as divided doses every 8 hours for 1 year, severe adverse effects included headache in five patients, hypertriglyceridemia in six, mucositis in two, and hyperbilirubinemia, raised alkaline phosphatase, colitis, raised lipase, xerostomia, eczema, and arthritis in one patient each (9). The dose had to be reduced in seven of eight patients with severe toxicity at 90 mg/m / day. Three of nine patients taking 45 mg/m /day required dose reductions. The plasma AUC of tretinoin did not correlate with the severity or frequency of adverse effects. From these results it can be concluded that 15 mg/m /day every 8 hours is a tolerable dose for 1 year in patients with squamous cell carcinomas of the head and neck. 

In dogs, high doses of BCNU resulted in severe bone marrow hypoplasia with delayed, reversible thrombocytopenia. The other major toxicides observed were cardiopulmonary (pulmonary edema, myocardial infarction, and pericardial hemorrhage), intestinal mucosal damage with hemorrhage, renal toxicity, and delayed hepatotoxicity. Similar toxicity was seen in monkeys except that cardiopulmonary toxicity did not occur. In rats, initially well-tolerated doses may cause death later. There is sufficient evidence for the carcinogenicity of BCNU in rats. BCNU is embryo-and fetolethal in rats and rabbits at doses nontoxic to the mother and can induce a variety of teratogenic effects in rats. 

In commercially available topical formulations (0.03% and 0.1%), tacrolimus ointment (PROTOFnc) is effective in and approved for the treatment of atopic dermatitis in adults (0.03% and 0.1%) and children (0.03%). Other uses in dermatology include intertriginous psoriasis, vitiligo, mucosal lichen planus, graft-versus-host disease, allergic contact dermatitis, and rosacea. It is applied to the affected area twice a day and generally is well tolerated. 

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