**5.3 Clinical hypersensitivity studies with either theobromine or fluoride-containing toothpastes**

Hypersensitivity is a short and sharp pain arising from exposed dentin by an external stimulus [39]. The prevalence of hypersensitivity varies [40]. The therapeutic approach is to occlude dentin tubules [41].

Clinical studies were conducted in four different samples. The detail of the experimental design has been already described [26, 42]. Importantly theobromine-based toothpaste has shown that the hypersensitivity disappeared within a week [42]. On the other hand, fluoride-based toothpastes indicated practically no effects to alleviate sensitivity without much occlusion on the dentinal tubes during this experimental period of 1 week.

#### **5.4 Preventive effect of dental caries by theobromine**

A study using an established in vitro caries pH cycling model [43] was conducted [44]. Treatment with theobromine results in resistance to acid attack. A recent study has shown that theobromine gel had more effective remineralizing potential than fluoride gel [45].

In the oral environment, remineralization and demineralization are happening constantly. The hardness test conducted on the enamel surface [26] clearly showed that theobromine was much more effective than fluoride. However, in another study using pH cycling method, theobromine does not appear to offer any anti-caries benefits [46]. Applied theobromine to the demineralized enamel surface caused recrystallization and increased surface microhardness.

Crystallite size is the main factor that controls the dissolution of HAP. Small crystallites have a much higher surface area/volume ratio compared to larger crystallites. Dissolution is more rapid on smaller crystallites than on larger ones. Thus, larger crystallites of HAP in the enamel resist dissolution under cariogenic conditions better than smaller ones.

From the comparative studies between theobromine and fluoride each parameter measured indicated that theobromine is superior to fluoride. Recently, a clinical study on the evaluation of the anticaries activity of either theobromine or fluoridebased toothpaste against *plaque S. mutans* in children of age group from 6 to 9 years was conducted [47]. It was concluded that theobromine-based toothpaste is beneficial as a safe anti-cariogenic agent. Furthermore, theobromine showed more antimicrobial effects against *S. mutans*, *Lactobacillus acidophilus*, and *Enterococcus faecalis* in the in vitro study. Theobromine showed greater zones of inhibition than other commercially available fluoridated children's toothpastes [48].

In addition, a recent in vitro study indicated that theobromine is an effective cariostatic agent and a safe alternative to fluoride in preventive dental care [36, 49]. The theobromine group is superior compared to the fluoride group in each parameter studied.
