Dental erosion following clopidogrel administration in a dog: A case‐based study

Abstract

A 10‐year‐old neutered male Chihuahua presented with unilateral dental erosion that occurred after several months of oral medications mixed with honey. A pH test was performed on all oral medications administered to the dogs to determine the cause of enamel erosion. Among the medications, the only acidic medication was clopidogrel (pH 2.65). To evaluate the effect of clopidogrel on the tooth surface under the same conditions as in the present patient, an additional preliminary study was designed in which two extracted teeth of another dog were immersed in a clopidogrel–honey mixture or only in honey. After a 3‐week soaking of the extracted tooth in the clopidogrel–honey mixture, field‐emission scanning electron microscope analysis revealed a rougher surface, whereas energy‐dispersive X‐ray spectroscopy analysis showed a reduced Ca/C ratio compared to the control tooth. In this case, prolonged exposure of the tooth surface to clopidogrel may be a cause of dental erosion.

A 10‐year‐old neutered male Chihuahua was presented with unilateral dental erosion that occurred after several months of oral medications mixed with honey. Among the medications, the only acidic medication was clopidogrel (pH 2.65). Additionally, it was demonstrated in an independent experiment that a clopidogrel–honey mixture could cause dental erosion when administered to a patient with low salivation. This result suggested prolonged exposure of the tooth surface to clopidogrel may cause dental erosion in dogs.

Figure legends

Macroscopic and microscopic features of tooth surface that immersed into clopidogrel–honey mixture (left) vs. honey alone (right).

1. INTRODUCTION

Disorders of dental hard tissues in dogs are mainly caused by trauma but can also be caused by genetics, infection and acidic degradation. Acquired loss of dental hard tissue in dogs includes crown wear in dogs with inherited enamel hypocalcification, dental caries and abrasion/attrition (Niemiec, 2014). Dogs with enamel defects, regardless of the cause, are more likely to develop tooth fractures, periodontal disease, dentin sensitivity, pulpitis and pulp necrosis (Shope et al., 2019).

Dental erosion refers to the loss of enamel due to acquired causes, and the most prominent etiological factor in humans is known to be low pH (Barbour et al., 2011). Dog saliva has a pH of 8.5, making it more alkaline and resulting in a higher buffering capacity compared to human saliva (pH 6.2–7.6) (Al‐ahmad et al., 2018; Lavy et al., 2012). This difference in saliva composition between humans and dogs is thought to be the reason why caries or erosion are less common in dogs (Pasha et al., 2018). In general, saliva acts as a buffer in the oral cavity of healthy individuals; however, this ability is reduced when its secretion is insufficient due to age or disease (Fenoll‐Palomares et al., 2004).

Clopidogrel has been used as an antiplatelet agent in dogs as an extralabel use (Plumb, 2018). A recent paper reported that the use of clopidogrel in combination with long‐term prescription of prednisolone could protect against glucocorticoid‐induced platelet reactivity in dogs (Thomason et al., 2020). Commercially available clopidogrel bisulphate is known to be practically insoluble in neutral water and has a pH‐dependent solubility (Kolbe et al., 2002; Plumb, 2018). The pH of clopidogrel bisulphate in aqueous solution is very low, less with a pH <1 at a concentration of 100 mg/mL (Kolbe et al., 2002).

This report presents a case of tooth erosion in a dog where the enamel loss may have been induced by clopidogrel. The hypothesis was supported by the experimentally identified enamel loss as a result of teeth incubation in clopidogrel solution.

2. CASE DESCRIPTION

A 10‐year‐old castrated male Chihuahua weighing 3 kg presented with noticeably smaller left maxillary third incisor (203) and canine (204) over 2 months, as observed by the owner (Floyd, 1991). The patient had been diagnosed with a meningoencephalitis of unknown aetiology (MUE) 11 months prior and was taking anticonvulsants, immunosuppressants and hepatic supplements. However, his symptoms did not improve after treatment; thus, prednisolone 0.5 mg/kg twice a day was started 3 months before the presentation. The patient showed symptoms of Cushing's syndrome while under steroid treatment, and 1 mg/kg/day of oral clopidogrel was added 2 months prior to presentation. In addition to MUE, his grade 4 tracheal collapse was controlled with theophylline (10 mg/kg, twice daily), and the patient was being monitored for left facial nerve paralysis, which had first manifested 8 months earlier. As the owner was right‐handed, the medications were mixed with honey and administered using the space between the patient's teeth 203 and 204. The patient was living indoors and was fed mainly dry kibble and soft treats such as chicken, frozen vegetables and boiled chestnuts. In the history, the patient did not use hard toys or chews, and there were no clinical signs of pain, such as drooling or decreased chewing ability.

On physical examination, the patient was slightly sedated due to the zonisamide, which was being taken for the underlying disease. The patient had a grade 4/6 murmur on cardiac auscultation, and echocardiography revealed severe mitral valve regurgitation with dilatation of the left ventricle, moderate tricuspid regurgitation and severe pulmonary hypertension. The neurological examination revealed a decreased palpebral reflex on the left eye. Serum chemistry results showed elevated overall liver enzyme levels (ALT = 702 U/L, reference range [RR]: 5.3–83.3 U/L; AST = 62 U/L, RR: 11.7–42.5 U/L; ALP = 838 U/L, RR: 0–97.9 U/L; and gamma‐GT = 96 U/L, RR: 0–14 U/L), which were not significantly different from previous test results, except for a decrease in gamma‐GT levels. Other serum chemistry test results, including calcium (9.8 mg/dL, RR: 9.0–11.9 mg/dL) and electrolytes, were all within normal limits.

Upon awake oral examination, the patient exhibited normal occlusion with minimal visible calculus and gingival inflammation. Notably, teeth 202–206 displayed complete loss of the outer layer of the supragingival crown (Figure 1a,b and Figure S1). The symmetrically positioned teeth (103, 104) in the right maxilla showed no loss of the outer crown layer (Figure 1c). Interestingly, the patient did not show any pain response to percussion of the affected teeth, and no other trauma or ulcerative changes in the oral mucosa were observed. Two dental radiographic images were taken with the bisecting angle technique using a portable X‐ray generator (Rextar X, Posdion Co. LTD; exposure setting: 2 mA at 70 kVp for 0.10 s with a 10‐cm focal film distance) and a computed radiography system (CR7 VET, IM3) to assess the status of the affected teeth. Intraoral radiograph revealed enamel loss in the coronal crown of the teeth ranging from 202 to 206 without endodontic and periodontal lesions (Figure 1d). The patient was diagnosed with dental erosion, and the owner declined restorative treatment due to the anaesthetic risk due to the severe tracheal collapse. As the symptoms of MUE improved, prednisolone and clopidogrel were discontinued from that day, and the owner was advised not to mix the medication with honey. After this point, there was no further progression of enamel erosion.

FIGURE 1.

A case of dental erosion in a dog. (a and b) Smaller left maxillary crowns (tooth 204) with a distinct border (red arrows) at the level of the gingival margin. These changes were observed after repeated administration of an oral medication containing clopidogrel mixed with honey using the space between the patient's teeth 203 and 204. (c) Contralateral incisors and a canine were not affected by dental erosion. (d) Tooth erosion was identified by intraoral radiography (yellow arrows).

3. PRELIMINARY STUDY

3.1. pH evaluation of the medications

To identify the cause of the enamel erosion, screening of the approximate pH of all medications taken by the patient was performed using pH test strips (Universal Test Paper; Yingmed). The patient was taking the following medications: clopidogrel, levetiracetam, silymarin, ursodeoxycholic acid, zonisamide, potassium bromide, misoprostol, theophylline and prednisolone, which were ground and placed into coded 1.5 mL Eppendorf tubes, with each containing 0.25 mg of medication and 0.5 mL of distilled water for injection (pH 7.13). A pH test strip was dipped into each suspension of the medication, and the only agent identified as acidic was clopidogrel. The pH values of clopidogrel and theophylline were within pH 2–3 and pH 8–9, respectively. The pH values of the other drugs ranged from 6 to 7. To identify the exact pH of clopidogrel (Clavixin Tab., Korea United Pharm.) ingested by the patient, 3 mg of clopidogrel was dissolved in 0.5 mL of distilled water, and the pH was measured using a pH meter (AquaSearcher AB23PH, Ohaus). The exact pH value of the dissolved clopidogrel was 2.65.

3.2. Effect of clopidogrel on the tooth surfaces: clinical test

A clinical test was designed to assess the effect of clopidogrel on tooth surfaces. Two maxillary canines from another dog, which were extracted due to bilateral oronasal fistulae, were prepared by removing the calculus using an ultrasonic scaler and polishing with pumice. Tooth surfaces were disinfected with 0.12% chlorhexidine and stored in sterile saline until further use. Before and after the experiment, the tooth surfaces were washed with sterile distilled water, air‐dried for 1 h and weighed. To create similar conditions for the patient in this case, two Eppendorf tubes were filled with 0.25 mL of natural honey, and one tube was mixed with 3 mg clopidogrel. Each tooth was immersed with the crown side down in each tube and stored in a humidified incubator at 37°C for 3 weeks. The honey and clopidogrel mixture in the Eppendorf tube was changed every 2 days. After 3 weeks, the teeth were thoroughly dried using a vacuum desiccator and coated with platinum using an ion sputter for 80 s. The coated specimens were mounted on a specimen bench using carbon tape and observed under a field‐emission scanning electron microscope (FE‐SEM; GeminiSEM 560, Zeiss) at 2000× magnification. Using the same specimen, enamel components, such as calcium, phosphorus, carbon, oxygen, sodium and chloride (Ca, P, C, O, Na and Cl), were analysed based on their weight percentages using energy‐dispersive X‐ray spectroscopy (EDS).

The dry net weight of the canine dipped in a honey mixture with clopidogrel (T‐clo) decreased from 534 to 531 mg, whereas the control tooth (T‐con) maintained the same weight. Upon gross examination, the enamel surface of the T‐clo lost its lustre and became chalky compared to the T‐con (Figure 2a,b). In the SEM micrographs, the surfaces of the T‐clo appeared to be markedly rougher and more porous than those of the T‐con (Figure 2c,d). In the mineral composition analysis using EDS, the T‐clo had a higher ratio of organic elements, such as C and O, and lower contents of inorganic elements such as Ca and P compared to the T‐con (Table 1). Additionally, the Ca/C ratio was higher in the T‐con (3.08) than in the T‐clo (2.62).

FIGURE 2.

Macroscopic and microscopic features of the experimental teeth. (a) Tooth surfaces before immersion in a clopidogrel and honey mixture and after 3 weeks of application (T‐clo). The enamel surface was chalky and demonstrated noticeably reduced gloss. (b) Tooth surfaces before and after the honey immersion for 3 weeks (T‐con). The enamel surface remained smooth and glossy. (c) Scanning electron micrograph of the T‐clo (bar = 5 μm, magnification ×2000). (d) Scanning electron micrograph of the T‐con (bar = 5 μm, magnification ×2000).

TABLE 1.

Mineral composition of experimental tooth by energy‐dispersive X‐ray spectroscopy (EDS) analysis.

Element	Weight percentage (%)
	T‐clo	T‐con
C	11.57	10.70
O	42.65	39.72
Na	0.47	0.43
P	14.47	15.63
Cl	0.57	0.53
Ca	30.29	33.00
Total	100.00	100.00

Abbreviations: C, carbon; Ca, calcium; Cl, chloride; EDS, energy‐dispersive X‐ray spectroscopy; Na, sodium; O, oxygen; P, phosphorus; T‐clo, tooth immersed in clopidogrel‐honey mixture; T‐con, tooth immersed in honey.

4. DISCUSSION

It was proven that the dental erosion in this case might have been caused by clopidogrel by the supplemental experiments. Considering that the dental hard tissue loss in this case was limited to the crown above the gingiva, the absence of a lesion suggestive of fracture and the unilateral occurrence, it could be presumed that it had not been caused by tooth resorption, traumatic fracture or enamel disorders due to systemic lesions or genetic causes, respectively.

Dental erosion is an irreversible chemical process that begins with the diffusion of acidic substances to the tooth surface, removing calcium and phosphorus ions (Wang & Lussi, 2010). It is known that the solubility of apatite included in enamel increases below pH 4 (Morgado et al., 2022). In humans, most acidic foods and beverages cause dental erosion, and medications and oral hygiene products with low pH are also possible contributors (Zero, 1996). In addition, intrinsic factors such as gastroesophageal reflux disease reportedly contribute to the occurrence of dental erosion (Picos et al., 2020). The pH of clopidogrel dissolved in the physiologically neutral solution identified in this report was 2.65, which suggested that prolonged exposure of the tooth surface to this solution might lead to enamel damage.

Studies have shown that dog saliva is more alkaline than human saliva; therefore, it may have a higher buffering capacity for acids (Al‐Ahmad et al., 2018; Lavy et al., 2012). The lack of reports on significant enamel loss in dogs treated with clopidogrel is attributed to the buffering ability of saliva. In the present case, it is possible that the acidity of clopidogrel was not neutralised due to decreased tear and salivary secretions, along with left facial nerve paralysis. In addition, as the owner administered the oral medication mixed with honey into the interdental spaces of the patient's teeth 203 and 204, the sticky nature of the honey may have caused prolonged adhesion of the clopidogrel to the adjacent tooth surface, resulting in erosion of the unilateral tooth surface.

To facilitate oral administration in many veterinary patients, medications are sometimes mixed with favourite foods, such as syrup, honey and treats. Honey has an average pH of 3.9, which is relatively acidic; however, honey has been reported to cause minimal damage to the tooth surface and microhardness due to its levels of calcium, phosphorus and fluoride (Grobler et al., 1994). In this study, there was no surface change or weight loss indicative of enamel erosion in the teeth dipped in pure honey; however, the T‐clo exhibited a porous and very rough surface. This difference was attributed to the high solubility of clopidogrel in low‐pH solvents such as honey, thereby resulting in the high acidity of the clopidogrel‐honey mixture and contributing to the changes in tooth surface texture.

EDS can analyse components without damaging the sample and provides high sensitivity for major elements of dental hard tissue (Das et al., 2016). A previous study showed that enamel experiences a reduction in microhardness as the mineral content and Ca/C ratio decrease (Fagrell et al., 2010). As symmetrical teeth were employed in the experimental part of this study, the elemental composition of the enamel of the two teeth was expected to be almost the same as that before the experiment. However, the Ca/C ratio of the T‐clo was considerably lower than that of the T‐con after the experiment. This indicates that the microhardness of the tooth surface decreased due to the loss of calcium caused by the acidic clopidogrel.

In this case‐based preliminary study, an independent experiment demonstrated that a clopidogrel–honey mixture could cause dental erosion. However, this was a preliminary test to assess reproducibility based on a single case, and the number of teeth tested was limited. This experiment was also limited by the use of two symmetrically positioned teeth extracted from the same dog to provide identical condition, so it was not possible to compare teeth stored in a clopidogrel aqueous solution to teeth stored in a clopidogrel–honey mixture. Therefore, further studies with a larger number of teeth are needed, and dental precautions for administrating clopidogrel should be studied.

In this case, prolonged exposure of the dog's tooth surface to clopidogrel might be one of the causes of dental erosion. Therefore, monitoring for enamel damage should be necessary for the long‐term administration of clopidogrel to small‐breed dogs that require powdered formulations. Care should be taken, especially, to avoid mixing and feeding the clopidogrel with supplements with a high viscosity and acidity, such as honey.

AUTHOR CONTRIBUTIONS

Se Eun Kim: Conceptualization; data curation; formal analysis; investigation; methodology; project administration; resources; visualization; writing—original draft.

CONFLICT OF INTEREST STATEMENT

There are no conflicts of interest to declare.

FUNDING INFORMATION

This work was not supported by any funding source or institution.

ETHICS STATEMENT

The author confirmed that the ethical policies of the journal, as noted on the journal's author guidelines page, have been adhered to. The owners of the dogs were fully informed of the experiments and consented to the use of the animals’ data and the teeth for academic purposes. The procedures of this preliminary study were approved by the Institutional Animal Care and Use Committee of Seoul National University (SNU‐230608‐3). This manuscript has not been published or presented elsewhere in part or in entirety and is not under consideration by another journal.

Supporting information

Figure S1 Frontal view of bilateral maxillary canines of the patient of in this case. The left maxillary canine was observed to be noticeably smaller than the right.

Kim, S. E. (2024). Dental erosion following clopidogrel administration in a dog: A case‐based study. Veterinary Medicine and Science, 10, e31384. 10.1002/vms3.1384

DATA AVAILABILITY STATEMENT

The data that support the findings of this study are available from the corresponding author upon reasonable request.