Evaluation of the toxicologic and teratogenic potentials of sodium fluorescein in the rat.

Sodium fluorescein (10%) when injected intravenously (5 ml/kg) in pregnant albino rats crossed the placental barrier and appeared to be distributed throughout the fetus within 15 min. It was detectable in the fetus up to 4 h after injection but not beyond 24 h. A single intravenous administration of sodium fluorescein did not produce embryotoxic or teratogenic effects. Oral LD50 studies using sodium phenobarbital on rats which received sodium fluorescein during their fetal development showed no apparent effects of sodium fluorescein on their drug detoxification systems.

Comparative analgetic testing of various compounds in mice using writhing techniques.

Anti-writhing assays to detect analgesia or specific activity against selected agonists were performed on albino mice. Acetylcholine Cl, bradykinin triacetate, phenylquinone, and serotonin creatinine sulfate were used as agonists. 10 compounds, including 5 standard analgetics, were tested against each agonist. Attempts to study histamine phosphate as an agonist were not successful. Results of these investigations showed satisfactory analgetic acitivity for codeine phosphate and acteyl salicylic acid (ASA) in all assays. weaker analgetics displayed varying degrees of activity depending on the agonist tested. Acute oral toxicities were determined for the 10 test compounds and the analgetic ED50 vs the LD50 of each compound was compared. The data confirmed the nonspecificity for writhing assays as well as a variability in activity of the test compounds against the various agonist.

Antiinflammatory activity: evaluation of a new screening procedure.

Acetaminophen, ascorbic acid, aspirin, dexamethasone, indomethacin, and phenylbutazone were tested to evaluate a new antiinflammatory screen. The basic methodology of Rassaert (1) was employed with slight modifications. The technique employs a 50-mm length of cotton twine instead of a cotton pellet. The data confirm the ability of this technique to rapidly screen activity of a variety of chemicals having antiinflammatory activity. It appears that statistically significant reductions in granuloma weight range between 10% and 50%, depending on the test compound and dose employed. This technique demonstrates activity for compounds such as aspirin and acetaminophen only at extremely high doses. However, more potent agents are detectable at more reasonable dose levels. Ascorbic acid, which has been shown to have activity in other models, was inactive in this assay. Dexamethasone was the most active agent, followed by indomethacin and phenylbutazone. Duplicate assays of selected agents showed a satisfactory degree of reproducibility.

Antipyretic testing of commercial aspirin formulations in rats.

Four commercial aspirin formulations and aspirin powder USP were assayed in yeast-fevered rats for antipyretic activity. Tablets allowed to disintegrate spontaneously prior to dosing yielded aggregates of various sizes which failed to produce uniform patterns of antipyresis. When tested at smaller, more uniform particle sizes of total product, consistent, statistically significant antipyresis was observed with no significant variation among formulations. The ED50 values and parallel line assays were homogeneous.

Acute toxicity testing of erythrosine and sodium fluorescein in mice and rats.

Erythrosine and sodium fluorescein, two colors used as a dental plaque disclosing agents, have similar chemical structures differing only in that erythrosine has four iodine atoms in the molecule while sodium fluorescein has no iodine. A comparative toxicological profile was made on both compounds employing oral dose ranges and acute oral toxicity tests in mice and rats. The results show erythrosine to be approximately twice as toxic as sodium fluorescein with LD50 values of 2558 +/- 1.35 mg/kg in mice and 2891 +/- 1.02 mg/kg in rats for erythrosine and 4738 +/- 1.23 mg/kg in mice and 6721 +/- 1.26 mg/kg in rats for sodium fluorescein. The major toxic manifestations of both compounds were those indicative of central nervous system depression.

Anticalculus and antiplaque activity of 8-hydroxyquinoline sulfate.

The effect of 8-hydroxyquinoline sulfate on the formation of artificial calculi, rat calculus, and dog plaque plus its ability to remove dog plaque were studied. Several chemically related agents were also evaluated for their anticalculus effects. The most effective anticalculus agent was 8-hydroxyquinoline sulfate. At concentrations of 4 or 5%, swabbed over molar teeth, it was essentially equally effective in retarding the formation of rat calculus. Significant (1% level) reduction occurred with concentration as low as 3% in rats. When used so as to mimic mouthrinse use, 4% 8-hydroxyquinoline sulfate also significantly (5% level) reduced formation of calculus in rats. All rats showed normal behavioral and weight-gain patterns. Visual evaluation of oral tissues in the swabbing tests plus visual and histopathological evaluation of oral tissues in the mouthrinse procedure showed 8-hydroxyquinoline sulfate had no irritating or toxic effects. In dogs, the teeth treated with 4% 8-hydroxyquinoline sulfate nine times during a five-day period had 93.7 to 98.4% less buccal plaque than vehicle-treated teeth. The antiplaque effect was considerable in both canines and fourth premolars. In older dogs, teeth treated with 4% 8-hydroxyquinoline sulfate 15 times during a ten-day period had 33 to 46.1% less plaque than when treated with the vehicle. The effect was considerable on canines but slight on fourth premolars. In older dogs after 24 treatments during a 15-day period, 4% 8-hydroxyquinoline sulfate removed 25 to 57.5% of established plaque whereas the vehicle removed 2.5 to 22.5%. Again, 8-hydroxyquinoline sulfate was more effective on canine buccal plaque. These results show that 8-hydroxyquinoline sulfate is an effective anticalculus and antiplaque agent that is nontoxic to animal oral tissue. The results also indicate that the dog is a suitable animal model for the evaluation of antiplaque agents.

Conjunctival temperature: a measure of ocular decongestant and anti-inflammatory activity.

A new experimental method is presented that permits objective evaluation of ocular decongestant and anti-inflammatory activity following systemic or local administration of drugs to the rabbit eye inflamed with mustard oil. The inflammation produced by mustard oil is characterized by conjunctival hyperemia and chemosis and is measured by the conjunctival sac temperature. Although a 2% suspension of acetylsalicylic acid (0.1 ml) applied topically to the eye did not markedly reduce conjunctival temperature compared to the control eye, oral administration of 300 mg/kg showed a significant reduction throughout the duration of the experiment. In addition to the anti-inflammatory agent, acetylsalicylic acid, the antihistaminic, antazoline phosphate 0.5% and a vasoconstrictor or decongestant, naphazoline hydrochloride 0.05% were applied individually and in combination (Vasocon-A) locally in the conjunctival sac. Both antazoline phosphate and naphazoline hydrochloride reduced congestion and conjunctival sac temperature while the combination reflected the action of the individual ingredients. The palliative effect of antazoline phosphate indicates that this drug administered topically readily antagonizes histamine in the inflamed eye. There was no corneal anesthesia after instillation of Vasocon-A into the rabbit eye. Antazoline hydrochloride administered in up to 8 times the concentration in Vasocon-A did not induce corneal anesthesia which could be readily obtained with tetracaine hydrochloride.