Pharmacological And Toxicological Studies Of Compound Boric Acid Mouthrinse (CBAM)

Mouthrinses are used in mouth odor removal, reduction of oral bacteria and preventing tooth decay. They usually have good anti-inflammatory and analgesic effects. Mouthrinse was regared as an adjuvant therapy for oral diseases, such as periodontitis, gingivitis, pericoronitis and oral mucosa disease, etc. These components in the mouthrinse preparation can effectively inhibit the plaque formation, improve the status of gingival inflammation.Compound boric acid mouthrinse (CBAM) was used in Guangdong Provincial Stomatological Hospital as a hospital pharmacy preparation. The prescription of the mouthrinse was based on the traditional oral compound borax solution ("Duo'er Solution), in which the glycerin, thymol, procaine and other components were added. CBAM is a hospital pharmacy preparation in our hospital for several years. The clinical effect is obvious and singnificant. No serious adverse reactions were shown. Compared to those mouthrinses available in the market sales, also from the as well as feedback of the patients treated by CBAM in our hospital, the effect of CBAM is higher than the traditional boric acid gargle and others.To make the CBAM serve for more patients, and to provide the theoretical basis and clinical application of boric acid as a mouthrinse, the experiment was conducted and to further development CBAM as new drug for oral dental usage.Objectives:The components of boric acid mouthrinse preparation contains some antiseptic and disinfectant ingredients, which may have some toxicity. To verify the safety and efficacy of CBAM, we conducted the acute toxicity, topical toxicity, and pharmacodynamic effects studies. These expeiments may not only provide the theory basis of CBAM clinical application, but also provide the useful data for developing CBAM as a national new drug from the present hospital pharmacy prepation.Methods:Analgestic effects of compound boric acid mouthrinse were observed with pain model of mice induced with acetic acid or hot plate. The anti-inflammatory effects were studied with acute ear edema induced with dimethylbenzene in mice and rat foot edema induced with carrageen. The minimal inhibitory concentration (MIC) against nine clinical isolates was determined with tube dilution test. The minimal bactericidal concertration (MBC) was measured with the agar dilution method.According to Drug Registration Regulations and the related regulatory requirements, the acute toxicity of CBAM was tested in rats and mice, respectively. The maximum tolerated dose and the mice administered oral median lethal dose (LD50) were calculated using software. In these experiments, a condensed CBAM solution (106.4 mg/ml) was used in rats by oral administration, while the normal CBAM solution (20.75 mg/ml) was used orally to mice. Several parameters were observed before and after administration.The local oral mucosa irritation tests and allergy tests of CBAM were done on rats and guinea pigs, respectively. Normal saline was used as placebo in the oral mucosal irritation test. For allergy testing,2,4-Dinitrochlorobenzene was added as positive control.SPSS 13.0 statistical software was used for statistical analysis. Homogeneity of variance among groups was analysised by ANOVA. The pairwise comparisons was conducted using LSD software. Welch test was used to analysize the variance arrhythmia. The comparison od two groups was conducted by Tamhane method.Results:In the pharmacodynamic study, we found that boric acid rinse on xylene-induced mouse ear edema and carrageenan-induced paw edema was significantly inhibited, suggesting that there are anti-inflammatory effect. Compared with the control group, there were significant differences (F= 41.429, P= 0.000). All of the low, medium and high dose groups of CBAM, can increase the pain threshold. Compared with the control group, there were also significant differences (F= 96.635, P= 0.000). CBAM at high, medium and low doses could inhibit writhing times induced by acetic acid in mice. Compared with the control group there were significant differences (F= 20.688, P= 0.000). It suggests that CBAM has significant analgesic effect. In vitro antibacterial test confirmed that CBAM can inhibit or kill the growth of Streptococcus, Staphylococcus aureus, Streptococcus pneumoniae, Streptococci, Klebsiella pneumoniae, Candida albicans, Streptococcus mutans, Actinomyces and Lactobacilli. These pharmacological effects of CBAM provide the experimental basis for its effect on gingivitis, periodontitis, oral erosion, adjuvant therapy after oral cancer depleting operation.In acute toxicity tests, we found that the mouse LD50 of CBAM is 3.95 g/kg. The death time after drug adminisrtration are usually 1 to 2 hours, but the autopsy found no abnormal change in heart, liver, spleen, lung, kidney and other organs. Although the oral mouthrinse has some toxicity, but if we extrapolated the mice LD50 dose to the human adult dose, is 237 g/person. The clinical application of CBAM for oral topical mouth rinse is the concentration of only 2% in one day with about 60 ml. Considering the small amount of drug absorbed to the body, the usage of CBAM is in the safe range. The maximum dose used in rats by oral administration, is of 3.1g/kg (110 times of clinical adult dosage). In this dosage, the body condition, diet, water intake and body weight were normal, no pathological changes were seen in tissues and organs, suggesting the oral topical use of CBAM is safe.Local oral mucosa irritation test and allergy test showed that rats have no abnormal oral mucosa and no oral mucosa irritation when given CBAM orally Meanwhile, the guinea pig allergy test results also show that CBAM does not cause allergic reactions when adminstrated on skin.Conclusions:Pharmacodynamics experiments show that compound boric acid mouthrinse (CBAM) has antibacterial and anti-inflammatory, analgesic effects. The acute toxicity test showed that the mice LD50 of CBAM is 3.95 g/kg when administered orally. Rats can still tolerate the maximum amount of 3.1 g/kg CBAM when administered orally. The topical toxicity test showed that CBAM has no oral mucosal irritation and sensitization. These results suggest that compound boric acid mouthrinse (CBAM) is safe when used orally. Also, its antibacterial, anti-inflammatory and analgesic effect provides the theory basis of CBAM clinical application. It also provide the useful data for developing CBAM as a national new drug from the present hospital pharmacy prepation.