Abstract

Objective:

To assess the total sugar content, endogenous pH, total soluble solids content (TSSC) and titratable acidity of the commonly prescribed long-term and short-term liquid oral medicines (LOM) for children and to compare the erosive potential with the total sugar content and total soluble solids of the LOM.

Material and Methods:

Twenty-three most commonly prescribed pediatric LOM were evaluated in-vitro for the cariogenic and erosive potential. Manufacturers' information on labels, endogenous pH, titratable acidity, TSSC, and the total sugar content was determined. Descriptive statistics and the Mann-Whitney U test were applied.

Results:

Overall, 22 LOM contained sugar. Only 3 LOM revealed the sugar content of the formulation but did not disclose the quantity (Cheston, Ventorlin and Eptoin). None of the samples revealed the sugar content as well as endogenous pH in their labels. The overall mean total sugar content was 6.92 ± 3.49 g/100ml, ranging from 3.40 ± 0.00 (corticosteroids) to 9.67 ± 0.61 (antitussive/expectorant). The mean endogenous pH for the total sample of medicines was 5.91 ± 1.51 (range of 3.5 to 10.3). Eptoin (0.013%) presented the lowest titratable acidity and Imol (1.171%) presented the highest titratable acidity with an overall mean of 0.40 ± 0.73. Omnacortil and Epilex presented the highest TSS content (19.3%), and Ventorlin presented the lowest TSS content (18.7%) with an overall mean of 18.97 ± 0.19. Over twelve medicines were identified to have the potential to cause dental erosion. No significant differences were seen in the total sugar content, total soluble solids, titratable acidity, and the endogenous pH between the short-term and long-term LOMs (p=0.145, p=0.263, p=0.067 and p=0.107), respectively.

Conclusion:

The pediatric LOMs showed the presence of the sugar, low endogenous pH, high titratable acidity and high total soluble solids.

Keywords:
Child; Dental Caries; Tooth Erosion; Sucrose

Introduction

Dental caries is the common oral disease and the most prevalent infectious disease in the oral cavity. Among the theories that explain caries onset, the action of acids produced by bacterial fermentation of carbohydrates (sugars) from the diet is universally accepted [¹[1] Cavalcanti AL, De Sousa RI, Clementino MA, Vieira FF, Cavalcanti CL, Xavier AFC. In vitro analysis of the cariogenic and erosive potential of paediatric antitussive liquid oral medications. Tanzan J Health Res 2012; 14(2):139-45.]. Various studies have pointed out the possible relationship between dental caries and frequent intake of liquid oral medicines (LOM) [²[2] Marquezan M, Marquezan M, Pozzobon RT, Oliveira MDM. Medicines used by pediatric dentistry patients and its cariogenic potential. RPG Rev Pós-Grad 2006; 13(4):334-9.

[3] Durward C, Thou T. Dental caries and sugar-containing liquid medicines for children in New Zealand. N Z Dent J 1997; 93(414):124-9.

[4] Feigal RJ, Jensen ME, Mensing CA. Dental caries potential of liquid medications. Pediatrics 1981; 68(3):416-9.^-5[5] Babu KLG, Doddamani GM, Naik LRK, Jagadeesh KN. Pediatric liquid medicaments - are they cariogenic? an in vitro study. J Int Soc Prev Community Dent 2014; 4(2):108-12. https://doi.org/10.4103/2231-0762.137637
https://doi.org/10.4103/2231-0762.137637... ]. Sugar has been widely added to pediatric liquid oral medicines to improve their palatability. Moreover, chronic illness may predispose the children for caries and an additional source of sugar can have an additive effect on the prevalence and severity of caries among children [⁶[6] Maguire A, Rugg-Gunn AJ, Butler TJ. Dental health of children taking antimicrobial and non-antimicrobial liquid oral medication long-term. Caries Res 1996; 30(1):16-21. https://doi.org/10.1159/000262131
https://doi.org/10.1159/000262131... ].

Dental erosion is defined as the “irreversible loss of tooth structure due to chemical dissolution by acids without the involvement of bacteria” [⁷[7] Bahal P, Djemal S. Dental erosion from an excess of vitamin C. Case Rep Dent 2014; 2014:485387. https://doi.org/10.1155/2014/485387
https://doi.org/10.1155/2014/485387... ], besides mechanical activities such as abrasion and attrition [⁸[8] Bartlett D, Dugmore C. Pathological or physiological erosion - is there a relationship to age? Clin Oral Investig 2008; 12(Suppl 1):S27-31. https://doi.org/10.1007/s00784-007-0177-1
https://doi.org/10.1007/s00784-007-0177-... ]. If left untreated, erosion proceeds from the enamel surfaces to the underlying dentine [⁹[9] Lussi A, Schlueter N, Rakhmatullina E, Ganss C. Dental erosion - an overview with emphasis on chemical and histopathological aspects. Caries Res 2011; 45(Suppl 1):2-12. https://doi.org/10.1159/00032591
https://doi.org/10.1159/00032591... ]. Low endogenous pH and high titratable acidity of liquid oral medicines may favor dental erosion [¹⁰[10] Maguire A, Baqir W, Nunn JH. Are sugars-free medicines more erosive than sugars-containing medicines? An in vitro study of paediatric medicines with prolonged oral clearance used regularly and long-term by children. Int J Paediatr Dent 2007; 17(4):231-8. https://doi.org/10.1111/j.1365-263X.2007.00826.x
https://doi.org/10.1111/j.1365-263X.2007... ], especially when the contact of the medicine with the tooth surface remains for a very long time [¹¹[11] Moss SJ. Dental erosion. Int Dent J 1998; 48(6):529-39. https://doi.org/10.1111/j.1875-595x.1998.tb00488.x
https://doi.org/10.1111/j.1875-595x.1998... ].

Evidence from in-vitro studies have established that acidic medicines reduced enamel hardness in deciduous teeth [¹²[12] da Costa CC, Almeida IC, da Costa Filho LC, Oshima HM. Morphology evaluation of primary enamel exposed to antihistamine and fluoride dentifrice - an in vitro study. Gen Dent 54(1):21-7.] with morphological surface alterations of enamel [¹³[13] Babu KL, Rai K, Hedge AM. Pediatric liquid medicaments - do they erode the teeth surface? An in vitro study: part I. J Clin Pediatr Dent 2008; 32(3):189-94. https://doi.org/10.17796/jcpd.32.3.j22m7t8163739820
https://doi.org/10.17796/jcpd.32.3.j22m7... ] and restorative materials [¹⁴[14] Valinoti AC, Neves BG, da Silva EM, Maia LC. Surface degradation of composite resins by acidic medicines and pH-cycling. J Appl Oral Sci 16(4):257-65. https://doi.org/10.1590/s1678-77572008000400006
https://doi.org/10.1590/s1678-7757200800... ]. Other concerning factors with regard to dental caries and dental erosion are the high viscosity of liquid oral medication [³[3] Durward C, Thou T. Dental caries and sugar-containing liquid medicines for children in New Zealand. N Z Dent J 1997; 93(414):124-9.^,4[4] Feigal RJ, Jensen ME, Mensing CA. Dental caries potential of liquid medications. Pediatrics 1981; 68(3):416-9.], lack of oral hygiene practices after intake of LOM [⁴[4] Feigal RJ, Jensen ME, Mensing CA. Dental caries potential of liquid medications. Pediatrics 1981; 68(3):416-9.] and its frequency [¹⁵[15] Bigeard L. The role of medication and sugars in pediatric dental patients. Dent Clin North Am 2000; 44(3):443-56.].

One of the major challenges in administering pediatric LOM is the bitter taste. In order to make it acceptable, pediatric LOM are usually colored, flavored and sweetened with several excipients other than the main active ingredients [¹⁶[16] Mennella JA, Spector AC, Reed DR, Coldwell SE. The bad taste of medicines: overview of basic research on bitter taste. Clin Ther 2013; 35(8):1225-46. https://doi.org/10.1016/j.clinthera.2013.06.007
https://doi.org/10.1016/j.clinthera.2013... ]. The flavor improvement in LOM is related to the frequent use of acids [¹⁶[16] Mennella JA, Spector AC, Reed DR, Coldwell SE. The bad taste of medicines: overview of basic research on bitter taste. Clin Ther 2013; 35(8):1225-46. https://doi.org/10.1016/j.clinthera.2013.06.007
https://doi.org/10.1016/j.clinthera.2013... ^,17[17] Liem DG, Mennella JA. Heightened sour preferences during childhood. Chem Senses 2003; 28(2):173-80. https://doi.org/10.1093/chemse/28.2.173
https://doi.org/10.1093/chemse/28.2.173... ]. For both a chemically stable and sufficient solubility of a drug, a suitable pH is required. Hence, the addition of acidic contents into the drug formulations as buffering agents are responsible for tonicity, physiological compatibility [¹⁰[10] Maguire A, Baqir W, Nunn JH. Are sugars-free medicines more erosive than sugars-containing medicines? An in vitro study of paediatric medicines with prolonged oral clearance used regularly and long-term by children. Int J Paediatr Dent 2007; 17(4):231-8. https://doi.org/10.1111/j.1365-263X.2007.00826.x
https://doi.org/10.1111/j.1365-263X.2007... ] and shelf-life [¹⁸[18] Afifi NA. Pharmaceutical solutions for oral administration. Available at: https://pt.slideshare.net/drnehalalyaffifi/pharm-sol-oral-admin. [Accessed on Apr 15, 2019]
https://pt.slideshare.net/drnehalalyaffi... ].

It has been established that about half of the regularly-used pediatric LOM can damage tooth enamel as they have an endogenous pH below 5.5 [¹⁰[10] Maguire A, Baqir W, Nunn JH. Are sugars-free medicines more erosive than sugars-containing medicines? An in vitro study of paediatric medicines with prolonged oral clearance used regularly and long-term by children. Int J Paediatr Dent 2007; 17(4):231-8. https://doi.org/10.1111/j.1365-263X.2007.00826.x
https://doi.org/10.1111/j.1365-263X.2007... ]. Moreover, the intake of such drugs at night could augment diseases like dental caries and dental erosion, as there is reduced salivary flow rate and increased time of elimination from the oral cavity during this period [¹⁹[19] Cavalcanti A, de Oliveira KF, Xavier AC, Pinto DS, Vieira FF. Evaluation of total soluble solids content (TSSC) and endogenous pH in antimicrobials of pediatric use. Indian J Dent Res 2013; 24(4):498-501. https://doi.org/10.4103/0970-9290.118386
https://doi.org/10.4103/0970-9290.118386... ].

Even though numerous solid forms of oral medication like pills or capsules include a coating to conceal their bitter tastes, children may still not readily accept such methods due to difficulty in swallowing [¹⁶[16] Mennella JA, Spector AC, Reed DR, Coldwell SE. The bad taste of medicines: overview of basic research on bitter taste. Clin Ther 2013; 35(8):1225-46. https://doi.org/10.1016/j.clinthera.2013.06.007
https://doi.org/10.1016/j.clinthera.2013... ]. Therefore, the most commonly chosen formulations for children are in LOM.

A review demonstrated several functions of the excipients in pediatric drug formulation [²⁰[20] Strickley RG, Iwata Q, Wu S, Dahl TC. Pediatric drugs - a review of commercially available oral formulations. J Pharm Sci 2008; 97(5):1731-74. https://doi.org/10.1002/jps.21101
https://doi.org/10.1002/jps.21101... ]; meanwhile, a recent report has addressed issues regarding sugar or carbohydrates of drugs inducing caries and their ill effects on the oral health of children [²¹[21] Donaldson M, Goodchild JH, Epstein JB. Sugar content, cariogenicity, and dental concerns with commonly used medications. J Am Dent Assoc 2015; 146(2):129-33. https://doi.org/10.1016/j.adaj.2014.10.009
https://doi.org/10.1016/j.adaj.2014.10.0... ].

Brazilian authors reported that the antibacterials frequently prescribed to HIV infected paediatric patients contained the highest sucrose concentration, ranging from 40% to 54%. Glucose was found in one of the ten, sucrose was present in seven of them, and none showed lactose [²²[22] Pomarico L1, Czauski G, Portela MB, de Souza IP, Kneipp L, de Araújo Soares RM, et al. Cariogenic and erosive potential of the medication used by HIV-infected children: pH and sugar concentration. Community Dent Health 2008; 25(3):170-2.]. Antitussives are reported to be potentially cariogenic and erosive as well, if used frequently, because of the high titratable acidity and high sugar concentration, especially when adequate oral clearance is not performed after administration of each dose [¹[1] Cavalcanti AL, De Sousa RI, Clementino MA, Vieira FF, Cavalcanti CL, Xavier AFC. In vitro analysis of the cariogenic and erosive potential of paediatric antitussive liquid oral medications. Tanzan J Health Res 2012; 14(2):139-45.].

Many studies have been done in the US [⁴[4] Feigal RJ, Jensen ME, Mensing CA. Dental caries potential of liquid medications. Pediatrics 1981; 68(3):416-9.], Brazil [²[2] Marquezan M, Marquezan M, Pozzobon RT, Oliveira MDM. Medicines used by pediatric dentistry patients and its cariogenic potential. RPG Rev Pós-Grad 2006; 13(4):334-9.], New Zealand [³[3] Durward C, Thou T. Dental caries and sugar-containing liquid medicines for children in New Zealand. N Z Dent J 1997; 93(414):124-9.], and Saudi Arabia [²³[23] Gupta M, Panda S. Cariogenic potential of the commonly prescribed pediatric liquid medicaments in Kingdom of Saudi Arabia: an in vitro study. J Contemp Dent Pract 2017; 18(4):307-11. https://doi.org/10.5005/jp-journals-10024-2036
https://doi.org/10.5005/jp-journals-1002... ] linking frequent use of sweetened LOM and the development of dental caries. Other authors studied the pH and concentration of sugars of pediatric liquid medicaments and suggested that these medications can pose as a threat to dental health [⁵[5] Babu KLG, Doddamani GM, Naik LRK, Jagadeesh KN. Pediatric liquid medicaments - are they cariogenic? an in vitro study. J Int Soc Prev Community Dent 2014; 4(2):108-12. https://doi.org/10.4103/2231-0762.137637
https://doi.org/10.4103/2231-0762.137637... ^,13[13] Babu KL, Rai K, Hedge AM. Pediatric liquid medicaments - do they erode the teeth surface? An in vitro study: part I. J Clin Pediatr Dent 2008; 32(3):189-94. https://doi.org/10.17796/jcpd.32.3.j22m7t8163739820
https://doi.org/10.17796/jcpd.32.3.j22m7... ]. However, only half of the overall medicines that showed sugar in their ingredients presented this information in their directions [²⁴[24] Peres KG, Oliveira CT, Peres MA, Raymundo MS, Fett R. Sugar content in liquid oral medicines for children. Rev Saude Publica 2005; 39(3):486-9. https://doi.org/10.1590/s0034-89102005000300022
https://doi.org/10.1590/s0034-8910200500... ]. Moreover, data about erosive potential and solid content of commonly used pediatric liquid oral medication is lacking. Hence, we aimed to assess the sugar content and erosive potential of the commonly prescribed long-term and short-term LOM for children.

The objectives of this study were to assess the total sugar content, endogenous pH, total soluble solids and titratable acidity of the commonly prescribed long-term and short-term liquid oral medicines for children and to compare the erosive potential with the total sugar content and total soluble solids of the LOM.

Material and Methods

Twenty-three most commonly prescribed pediatric LOM were selected for the study (Table 1). This selection was done after a brief interview with pediatricians (n = 4) and pharmacies (n = 10) in Udupi taluk, Karnataka, India. The list of LOM was prepared, and duplicates were removed and categorized broadly as per the drug classification (Table 1). They included long-term (anti-epileptics, antihistamines, anti-asthmatics, corticosteroids) and short-term medications (antibiotics, analgesics, antitussives/expectorants). The labels of each medicine were examined to capture information on sugar, flavor, and acid contents, as reported by the manufacturer.

Determination of Total Sugars (Phenol Sulfuric Acid Method) [²⁵[25] Dubois M, Gilles KA, Hamilton JK, Rebers PA, Smith F. Colorimetric method for determination of sugars and related substances. Anal Chem 1956; 28(3):350-6. https://doi.org/10.1021/ac60111a017
https://doi.org/10.1021/ac60111a017... ^,26[26] Krishnaveni S, Balasubramanian T, Sadasivam S. Sugar distribution in sweet stalk sorghum. Food Chem 1984; 15(3):229-32. https://doi.org/10.1016/0308-8146(84)90007-4
https://doi.org/10.1016/0308-8146(84)900... ]

Reagents required: Concentrated Sulfuric acid (Reagent grade: specific gravity 1.84); Phenol 80% (80% by weight, 20 gms of distilled water is added to 80 gms of reagent grade phenol); Standard sugar solution (Standard Glucose: Stock - 100 mg in 100 mL of water); Working standard -1gm of glucose in 10ml of distilled water; Test solution (Samples diluted by 1000 times).

Procedure

In to a series of test tubes, working standard solutions ranging from 0.2 ml - 1.2 ml (S1 - S6) of concentration of 20-120 µg were taken. A sample of 0.5 ml was taken in two test tubes and marked T1 and T2 (test solution). The volume of all tubes was made up to 2ml using distilled water. A blank of 2 ml distilled water was also run simultaneously. To each test tube, 0.05 ml of 80% phenol was added, followed by 5ml of concentrated sulfuric acid rapidly added to the solution using a dispenser. The solution was incubated for 30 minutes at room temperature for color development. Orange red colored solution was read at 485nm using an auto colorimeter (BioBee Auto Colorimeter, LT-114, Labtronics, ISO 9001: 2008 certified). The sugar content of the samples was obtained using the formula:

Where, OD is the optical density, OD of standard taken is 80 µg per 0.05 ml of the diluted sample, and the dilution factor is 1000 times (10 µg of drug made up to 10 ml of distilled water).

Endogenous pH Measurement

The endogenous pH of each medication was measured using digital pH meter (Eutec pH 700, Eutech Instruments Pte Ltd, Thermo Fisher Scientific India Inc, India). The pH meter accurate to 0.1 was first calibrated according to the manufacturer’s instructions, using buffer standards of pH 7 and pH 4. The pH meter was set to pH mode and the temperature was adjusted to 25°C. The electrode was placed in the sample to be tested. The pH of the solution appeared on display. The display was allowed to be stabilized before the reading was taken. The pH electrode was rinsed and placed back in the storage solution. As much as 10 mL of each medication was poured into a beaker, the pH meter was immersed into the syrup, and the value was recorded [²⁷[27] Cavalcanti AL, Fernandes LV, Barbosa AS, Vieira FF. pH, titratable acidity and total soluble solid content of pediatric antitussive medicines. Acta Stomatol Croatica 2008; 42(2):164-70.].

Titratable Acidity [²⁸[28] Titratable Acidity. Available at: https://www.uoguelph.ca/foodscience/book-page/titratable-acidity. [Accessed on Novemeber 28, 2019].
https://www.uoguelph.ca/foodscience/book... ]

Dilution used for samples: 10 µl made up to 10ml of distilled water (1:1000). A test solution of 10 ml (1:10) was pipetted in a 100 ml conical flask. Four drops of phenolphthalein indicator were added and titrated against 0.01 N NaOH until a pale pink color was obtained. The titration was repeated thrice for each sample. Burette readings were tabulated, and the titre values were compared.

Titratable acidity was measured in triplicate for each drug by using the same pH meter and increments of 0.1N sodium hydroxide (NaOH) were titrated until neutrality (pH 7.0) was reached.

A primary standard, potassium biphthalate along with factorization of 0.1 N NaOH solution was used to obtain a correction factor of 0.87. The total volume of 0.1 N NaOH solution required to neutralize medicines multiplied to a correction factor of 0.88 corresponded to the titratable acidity value [²⁹[29] Neves BG, Farah A, Lucas E, de Sousa VP, Maia LC. Are paediatric medicines risk factors for dental caries and dental erosion? Community Dent Health 2010; 27(1):46-51.]. Percentage titrable acidity is calculated using the formula as follows [³⁰[30] Sadler GD, Murphy PA. pH and Titratable Acidity. In: Nielsen SS. (Ed). Food Analysis. 5th ed. Cham, Switzerland: Springer; 2017. Pp. 389-406.]:

Determination of Total Solids Content using Specific Gravity [³¹[31] Food Safety and Standards Authority of India. Ministry of Health and Family Welfare. Manual of Methods of Analysis of Foods. Milk and Milk Products. New Delhi: 2016. 195p.]

The total soluble solids content is a measure of the total content of soluble solids (proteins, lipids, glucides, mineral salts, vitamins, organic acids, pigments and other substances) in a sample [³²[32] Ball DW. Concentration scales for sugar solutions. J Chem Educ 2006; 83:1489. https://doi.org/10.1021/ed083p1489
https://doi.org/10.1021/ed083p1489... ]. A concentrated syrup contains 85% w/v or 65% w/w sucrose in purified water with a specific gravity of 1.30. The higher sugar content gives syrups a moderately high viscosity and has a high specific gravity [³³[33] Ansel HC. Pharmaceutics Calculation. 13th. New York: Wolters Kluwer Health; 2010.].

Measurement of specific gravity or density by a lactometer is based on the Archimedes principle. The total solids content is related to its fat percentage and specific gravity by Richmond’s formula. The diluted samples were used in the ratio 1:10 after standardization (10 ml of the sample made up to 100 ml). The observed lactometer reading was calculated to the corrected lactometer reading (CLR) at 27°C as per the fat percentage and temperature. The total solids in solution was then calculated using the following formula:

Statistical Analysis

The samples were analyzed in duplicates, and the average of the two was used for analysis. The samples were dichotomized into potentially erosive and non-erosive LOM based on the pH of LOM (pH values ≤ 5.5 were considered to be potentially erosive). The data were analyzed with the aid of the computer program SPSS (Statistical Package for the Social Sciences, SPSS Inc., Chicago, Illinois, United States of America, version 20.0). Descriptive statistics and Mann-Whitney U test were applied when appropriate. A p-value of <0.05 was considered statistically significant.

Results

Twenty-three most commonly prescribed liquid oral medicines were selected for our study. Overall, twenty-two LOM in our study contained sugar. Only three LOM revealed the sugar content of the formulation, but did not disclose the quantity (Cheston, Ventorlin and Eptoin). None of the samples revealed the sugar content as well as endogenous pH in their labels. All the LOMs had a flavored base, but has not disclosed it on the label (DoloTM, Augmentin, Eptoin and Epilex).

Since the medicines can present different densities, the sugar content was calculated, taking into consideration the volume of the solution. Thus, for sugar content as g/100 mL the total mean ± SD value observed was 6.92 ± 3.49 g/100ml, ranging from 3.40 ± 0.00 (corticosteroids) to 9.67 ± 0.61 (antitussive/expectorant). An almost similar amount of total sugar content was found in antibiotic (8.44 ± 3.51) and antiepileptic (8.20 ± 3.02) LOM. The total sugars present in analgesics and anti-asthmatic LOM were 4.93 ± 1.63 and 4.10 ± 3.70, respectively (Table 2). Antihistamines contained about 5.35 ± 4.62 g/100ml of total sugars. Overall, Short-term LOM presented with higher sugar content (7.92 ± 3.14) than long-term LOM (5.64 ± 3.66). However, the difference was not statistically significant (p=0.145) (Table 3).

The mean ± SD value of endogenous pH for the total sample of medicines was 5.91 ± 1.51 (range of 3.5 to 10.3). Lowest mean pH values were presented by Antitussives/ Expectorants (4.77 ± 1.19) and the highest by Corticosteroids (7.22 ± 0.00) (Table 2). Overall, the endogenous pH was lower in the long-term (5.64 ± 3.66) than in short-term (7.92 ± 3.14) LOM. However, the difference was not statistically significant (p=0.107) (Table 3).

Eptoin (0.013%) presented the lowest titratable acidity and Imol (1.171%) exhibited the highest titratable acidity with an overall mean of 0.40 ± 0.73. The highest mean titratable acidity was seen in antihistamines (1.21 ± 1.90), whereas the lowest mean titratable acidity was seen in corticosteroids (0.04 ± 0.00) (Table 2). Overall, mean titratable acidity was higher in the long-term (0.41 ± 1.05) than in short-term (0.40 ± 0.39) LOM. However, the difference was not statistically significant (p=0.067) (Table 3).

Omnacortil and Epilex presented the highest TSS content (19.3%) and Ventorlin presented the lowest TSS content (18.7%) with an overall mean of 18.97 ± 0.19. The highest mean total soluble solids was seen in corticosteroids (19.30 ± 0.00), whereas the lowest mean total soluble solids was seen in antihistamines (18.87 ± 0.12) (Table 2). Overall, mean total soluble solids was higher in long-term (19.03 ± 0.22) than in short-term (18.93 ± 0.15) LOM. However, the difference was not statistically significant (p=0.263) (Table 3).

No significant differences were seen in the total sugar content, total soluble solids, titratable acidity and the endogenous pH between the short-term and long-term LOMs (p=0.145, p=0.263, p=0.067 and p=0.107) respectively (Table 3).

Over twelve medicines were identified to have the potential to cause dental erosion (pH values ≤ 5.5, the critical pH for demineralization of tooth enamel in a low-calcium environment). The mean ± SD of the sugar content observed for LOM with erosive potential was 6.50 ± 4.19, whereas, for LOM with no erosive potential, the sugar content was 7.39 ± 2.65 (p=0.689). The total soluble content was significantly lower in potentially erosive LOM (18.87 ± 0.14) than in non-erosive LOM (19.09 ± 0.16) (p=0.005) (Table 4).

Discussion

Several pediatric LOM contained inactive ingredients in the form of sugars and acids. However, the majority of the samples did not reveal the sugar content as well as endogenous pH in their labels. We found three out of the 23 LOM included revealed the presence of sugar content, but did not disclose the quantity (Cheston, Ventorlin, and Eptoin). It was reported that only half of the total medicines that presented sugar in their ingredients disclosed this information [²⁴[24] Peres KG, Oliveira CT, Peres MA, Raymundo MS, Fett R. Sugar content in liquid oral medicines for children. Rev Saude Publica 2005; 39(3):486-9. https://doi.org/10.1590/s0034-89102005000300022
https://doi.org/10.1590/s0034-8910200500... ].

We found that 22 of the LOMs contained sugar, which was in line with previous studies [²⁴[24] Peres KG, Oliveira CT, Peres MA, Raymundo MS, Fett R. Sugar content in liquid oral medicines for children. Rev Saude Publica 2005; 39(3):486-9. https://doi.org/10.1590/s0034-89102005000300022
https://doi.org/10.1590/s0034-8910200500... ^,35[35] Cavalcanti AL, Ramos IA, Leite RB, da Costa Oliveira M, de Melo Menezes K, Fernandes LV, et al. Endogenous pH, titratable acidity and total soluble solid content of mouthwashes available in the Brazilian market. Eur J Dent 2010; 4(2):156-9.^,36[36] Pierro VS, Abdelnur JP, Maia LC, Trugo LC. Free sugar concentration and pH of paediatric medicines in Brazil. Community Dent Health 2005; 22(3):180-3.]. The amount of sucrose is usually high (above 35%), as indicated in many reports previously [²⁴[24] Peres KG, Oliveira CT, Peres MA, Raymundo MS, Fett R. Sugar content in liquid oral medicines for children. Rev Saude Publica 2005; 39(3):486-9. https://doi.org/10.1590/s0034-89102005000300022
https://doi.org/10.1590/s0034-8910200500... ^,35[35] Cavalcanti AL, Ramos IA, Leite RB, da Costa Oliveira M, de Melo Menezes K, Fernandes LV, et al. Endogenous pH, titratable acidity and total soluble solid content of mouthwashes available in the Brazilian market. Eur J Dent 2010; 4(2):156-9.^,37[37] Carvalho MF, Pascom AR, Souza-Júnior PR, Damacena GN, Szwarcwald CL. Utilization of medicines by the Brazilian population, 2003. Cad Saude Publica 2005; 21:S100-8. https://doi.org/10.1590/s0102-311x2005000700011
https://doi.org/10.1590/s0102-311x200500... ]. The highest total sugar values were among antitussive and antibiotic medications, similar to those reported previously [³⁸[38] Passos IA, Sampaio FC, Martínez CR, Freitas CH. Sucrose concentration and pH in liquid oral pediatric medicines of long-term use for children. Rev Panam Salud Publica 2010; 27(2):132-7. https://doi.org/10.1590/s1020-49892010000200007
https://doi.org/10.1590/s1020-4989201000... ]. The majority of the pediatric LOMs may contain components named excipients or “inactive ingredients” (fermentable sugars and acids), which can be deleterious to the dental structures [²[2] Marquezan M, Marquezan M, Pozzobon RT, Oliveira MDM. Medicines used by pediatric dentistry patients and its cariogenic potential. RPG Rev Pós-Grad 2006; 13(4):334-9.]. Because of the bitter taste of most medications, sugar is combined with other ingredients to increase acceptance and treatment compliance of children [³⁹[39] Hobson P, Fuller S. Sugar-based medicines and dental disease - progress report. Community Dent Health 1987; 4(2):169-76.]. Although there are artificial substitutes, such as sodium saccharin, sodium cyclamate, aspartame [⁴⁰[40] Sasaki YF, Kawaguchi S, Kamaya A, Ohshita M, Kabasawa K, Iwama K, et al. The comet assay with 8 mouse organs: results with 39 currently used food additives. Mutat Res 2002; 519(1-2):103-19. https://doi.org/10.1016/s1383-5718(02)00128-6
https://doi.org/10.1016/s1383-5718(02)00... ] and sorbitol [⁴¹[41] Kumar A, Rawlings RD, Beaman DC. The mystery ingredients: sweeteners, flavorings, dyes, and preservatives in analgesic/antipyretic, antihistamine/decongestant, cough and cold, antidiarrheal, and liquid theophylline preparations. Pediatrics 1993; 91(5):927-33.], sucrose is most widely used by the pharmaceutical industry because it has a lower cost, has antioxidant properties, preserves the formulation, and has easy processing [¹⁵[15] Bigeard L. The role of medication and sugars in pediatric dental patients. Dent Clin North Am 2000; 44(3):443-56.^,42[42] Chu F, Siu A, Yip H. Rampant caries secondary to cough syrup addiction. Quintessence Int 2001; 32(1):78-9.].

The analysis of endogenous pH revealed that 12 medications presented pH values lower than the pH value that is considered critical for enamel demineralization, which was in accordance with previous studies [²[2] Marquezan M, Marquezan M, Pozzobon RT, Oliveira MDM. Medicines used by pediatric dentistry patients and its cariogenic potential. RPG Rev Pós-Grad 2006; 13(4):334-9.^,10[10] Maguire A, Baqir W, Nunn JH. Are sugars-free medicines more erosive than sugars-containing medicines? An in vitro study of paediatric medicines with prolonged oral clearance used regularly and long-term by children. Int J Paediatr Dent 2007; 17(4):231-8. https://doi.org/10.1111/j.1365-263X.2007.00826.x
https://doi.org/10.1111/j.1365-263X.2007... ^,27[27] Cavalcanti AL, Fernandes LV, Barbosa AS, Vieira FF. pH, titratable acidity and total soluble solid content of pediatric antitussive medicines. Acta Stomatol Croatica 2008; 42(2):164-70.^,43[43] Sunitha S, Prashanth GM; Shanmukhappa, Chandu GN, Subba Reddy VV. An analysis of concentration of sucrose, endogenous pH, and alteration in the plaque pH on consumption of commonly used liquid pediatric medicines. J Indian Soc Pedod Prev Dent 2009; 27(1):44-8. https://doi.org/10.4103/0970-4388.50817
https://doi.org/10.4103/0970-4388.50817... ^,44[44] Greenwood M, Feigal R, Messer H. Cariogenic potential of liquid medications in rats. Caries Res 1984; 18(5):447-9. https://doi.org/10.1159/000260801
https://doi.org/10.1159/000260801... ].

Titratable acidity indicates the erosive potential of the LOMs [⁴⁵[45] Shaw L, Smith AJ. Dental erosion - the problem and some practical solutions. Br Dent J 1999; 186(3):115-8.]. Titratable acidity was shown to be the highest in analgesics. A previous study also revealed higher titratable acidity in sugar-containing medications than sugar-free medications [¹⁰[10] Maguire A, Baqir W, Nunn JH. Are sugars-free medicines more erosive than sugars-containing medicines? An in vitro study of paediatric medicines with prolonged oral clearance used regularly and long-term by children. Int J Paediatr Dent 2007; 17(4):231-8. https://doi.org/10.1111/j.1365-263X.2007.00826.x
https://doi.org/10.1111/j.1365-263X.2007... ], confirming their erosive nature.

The total soluble solids content has a direct relationship with the viscosity of the ingested foods, possibly facilitating the retention on the tooth surfaces. The total soluble solids ranged from 18.7% to 19.3%. Amongst the pediatric antitussive LOMs, total soluble solids content varied from 3.25% to 62.26% [¹[1] Cavalcanti AL, De Sousa RI, Clementino MA, Vieira FF, Cavalcanti CL, Xavier AFC. In vitro analysis of the cariogenic and erosive potential of paediatric antitussive liquid oral medications. Tanzan J Health Res 2012; 14(2):139-45.].

In a previous study, 82% of the syrup formulations evaluated contained sugar, which contraindicates their use by diabetic children and may increase the risk for caries in case of regular use [⁴⁶[46] Kulkarni ML, Sureshkumar C, Venkataramana V. Colourings, flavourings, and sugars in children's medicines in India. BMJ 1993; 307(6907):773. https://doi.org/10.1136/bmj.307.6907.773
https://doi.org/10.1136/bmj.307.6907.773... ]. Our study presented with higher sugar content in short-term LOM than in long-term. However, there was no standard definition of long-term and short-term LOM. Despite no significant difference, the sugars present in the medications can cause dental caries and aggravates in case of poor oral hygiene and other comorbidities [¹⁰[10] Maguire A, Baqir W, Nunn JH. Are sugars-free medicines more erosive than sugars-containing medicines? An in vitro study of paediatric medicines with prolonged oral clearance used regularly and long-term by children. Int J Paediatr Dent 2007; 17(4):231-8. https://doi.org/10.1111/j.1365-263X.2007.00826.x
https://doi.org/10.1111/j.1365-263X.2007... ].

Despite the success of preventive dentistry, there are a growing number of reports of a decline in the quality of young children’s teeth [⁴⁷[47] Ali YA, Chandranee NJ, Khan A, Khan ZH. Prevalence of dental caries in nursery school children of Akola city. J Indian Soc Pedod Prev Dent 1998; 16(1):21-5.]. Since caries and dental erosion have multifactorial etiology, there will be a complex interaction of factors. Frequent intake of sugar-containing acidic medications can be one such potential risk factor for severe dental erosion and dental caries [⁴⁸[48] Naik LRK, Babu KLG, Doddamani GM. Changes in the dental plaque pH due to pediatric liquid medicaments. J Int Oral Health 2017; 9(2):60-4. https://doi.org/10.4103/jioh.jioh_12_16
https://doi.org/10.4103/jioh.jioh_12_16... ^,49[49] Nunn JH, Ng SKF, Sharkey I, Coulthard M. The dental implications of chronic use of acidic medicines in medically compromised children. Pharm World Sci 2001; 23(3):118-9.].

The main limitation of this study is that only the commonly prescribed LOMs of this geographical locality has been evaluated for the presence of sugars. Although similar medicines are available in all countries, new formulations are released annually in many countries, and distribution can vary within the country as well. Therefore, a local system of drug surveillance is necessary.

As the use of pediatric medicines containing sucrose is increasing in many countries [⁵⁰[50] Manikandan K, Sujatha G, Priya RS, Prasad TS, Kumar SS, Shamsudeen SM. Practices and awareness of the paediatricians regarding syrups and sugar free medicines in Chennai City. J Pierre Fauchard Acad 2017; 31(2-4):109-14. https://doi.org/10.1016/j.jpfa.2017.03.003
https://doi.org/10.1016/j.jpfa.2017.03.0... ], it is important that health professionals be aware of the risk of oral health imbalance during the continuous use of pediatric medicines. Simple oral hygiene measures like gargling with water, use of fluoridated dentifrices, twice-daily brushing with or without supervision can be suggested for all children under such medications. Pediatricians and child health care providers should be encouraged to prescribe sugar-free medicines when feasible. However, medications with polyols over long-term usage may have laxative-effects [⁵¹[51] Lenhart A, Chey WD. A systematic review of the effects of polyols on gastrointestinal health and irritable bowel syndrome. Adv Nutr 2017; 8(4):587-96. https://doi.org/10.3945/an.117.015560
https://doi.org/10.3945/an.117.015560... ]. Due to their smaller body size, children might be more sensitive to potential GI effects. Therefore, care should be taken to ensure that children are consuming polyols in smaller amounts [⁵²[52] Kroger M, Meister K, Kava R. Low-calorie sweeteners and other sugar substitutes: a review of the safety issues. Compr Rev Food Sci Food Saf 2006; 5(2):35-47. https://doi.org/10.1111/j.1541-4337.2006.tb00081.x
https://doi.org/10.1111/j.1541-4337.2006... ].

Conclusion

The pediatric LOMs showed the presence of the sugar, low endogenous pH, high titratable acidity, and high total soluble solids. In addition, it would appear that the frequency of sugar intake is more important than the total amount consumed. Clinical studies evaluating the frequency of ingestion of LOMs would be an area to focus for future research

Acknowledgements

Authors would like to thank the local pharmacies for providing the samples for the study.

References

Edited by

Publication Dates

History