Mucosal tissue irritation

Irritation is veiy subjective and may differ widely from treatment to control subjects. Most irritation occurs as a result of penetration enhancers. Evaluation of toxicity and irritation should be concerned with mucosal tissue irritation, the extent of damage to the mucosal cells, and the rate of recovery. 

Turning to the subject of many an adventure story, ichthyothereol is the active ingredient of a poisonous substance used in arrowheads by the Indians of the Lower Amazon River Basin. It causes convulsions in mammals. And histrionicotoxin is isolated from the skin of poison arrow frog, a highly colorful species of the genus Dendrobates. The frog secretes this compound and similar ones as defensive venoms and mucosal-tissue irritants against both mammals and reptiles. 

Adverse Effects. Topical application of acyclovir may produce local irritation of cutaneous and mucosal tissues. Prolonged systemic administration of acyclovir or valacyclovir may cause headaches, dizziness, skin rashes, and gastrointestinal problems (nausea, vomiting, diarrhea). 

Buccal tissue is a robust tissue owing to its continuous exposure to a multitude of substances and its high cellular turnover rate.92 93 The absence of Langerhans cells in the oral mucosal tissues reduces sensitivity to potential allergens.94,95 Hence irritation and hypersensitivity reactions due to drugs and their formulation excipients may be minimal in the short term as well as chronic treatment by this route. 

Dermal Effects. Chromium compounds can produce effects on the skin and mucous membranes. These include irritation, burns, ulcers, an allergic type of dermatitis. Irritation of the nasal mucosa and other mucosal tissues of the respiratory system, and nasal septum ulcers, and perforation were considered under Respiratory Effects discussed above. Dermatitis is considered under Immunological Effects discussed below. 

Rats that were administered 2,000 mg/kg/day unleaded gasoline by gavage for 4 weeks were found to have gastric erythema, erosion of the gastric mucosa, and ulceration of the epithelium (Haider et al. 1985). The combined findings in humans and animals demonstrate the irritating effect of gasoline on mucosal tissue. 

Because of its potential damage to the membrane, permeation enhancers elicit great safety concern, especially in chronic therapy. Some of these include (l)potential tissue irritation and damage, (2) effect of the enhancer on structural integrity of the mucosal membrane, (3 Reversibility of membrane perturbation, (4) long-term effect of continued exposure to the enhancer, and (5)potential to also enhance absorption of any potential harmful substances that are also present in the intestine. All these issues may have significant toxicity ramifications. Therefore, the FDA has not approved any permeation enhancer, although use of some common excipients that are reported to enhance absorption may be acceptable (Table 18.8). 

Postmortem Procedures. Rabbits are euthanized by lethal dose of a barbiturate soon after the last vaginal irritation scores are collected. The vagina is opened by longitudinal section and examined for evidence of mucosal damage such as erosion, localized hemorrhage, and so on. No other tissues are examined. No tissues are collected. After the macroscopic description of the vagina is recorded, the animal is discarded. 

Nicolazzo et al. [52] considered the use of the lipophilic skin penetration enhancers, octisalate and padimate (both used in sunscreens), in comparison to Azone on the buccal absorption of various drugs in vitro. They were found to have limited effect in enhancing the permeation of triamcinolone acetonide (although some increase in tissue uptake was proposed in some cases) relative to Azone, while reducing the penetration of estradiol and caffeine. One interesting report is that of the effect of capsaicin from capsicum, a commonly used food ingredient, which has been reported to enhance the permeability of sulfathiazole in human volunteers [53] presumably by a direct irritation effect on the mucosa. This raised an interesting issue of the effect of diet on oral mucosal permeability. 

In tests designed to evaluate the primary irritation of mucous membranes, the tissues of choice (wherever possible) should be the specific mucosal to which the chemical is applied. Differences in histology, absorptive capacity, and pH ranges of the mouth, eye, genitourinary, and rectal mucosa are great enough that results obtained on one mucosa may not apply for the other. 

With drugs for external use, an investigation of skin irritation due to deteriorated drugs formed in stress tests is necessary. Mucosal irritation tests are required for ophthalmological drugs and suppositories. Tissue damage tests should be performed for drugs in intramuscular administration. 

The FDA has made several modifications to the tests required by Part 1 of the ISO 10993 standard for the category of surface devices that permanently contact mucosal membranes. The ISO does not require acute, subchronic, or chronic implantation tests as does FDA. FDA requires irritation, systemic toxicity, acute, subchronic, and chronic tests for external communicating devices, tissue/bone/ dentin with prolonged and permanent contact. Device manufacturers are advised to consider tests to detect chemical components of device materials that may be pyrogenic. This matrix is a framework and not a checklist and it is stressed by the FDA that necessary safety testing will be decided on a case-by-case basis. 

The toxicity of hypochlorite arises from its corrosive activity on skin and mucous membranes. Corrosive burns may occur immediately upon exposure to concentrated bleach products. Most of this corrosiveness stems from the oxidizing potency of the hypochlorite itself, a capacity that is measured in terms of available chlorine . The alkalinity of some preparations may contribute substantially to the tissue injury and mucosal erosion. Sodium hypochlorite when combined with an acid or ammonia may produce chlorine or chloramine gas, respectively. An inhalation exposure to these gases may result in irritation to mucous membranes and the respiratory tract, which may manifest itself as a chemically induced pneumonitis. 

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