C A R I O G E N I C P O T E N T I A L O F H I V M E D I C AT I O N S

ARTICLE ABSTRACT In children infected with human immunodeficiency virus (HIV), initiation of antiretroviral therapy (ART) commences at a very young age. These drugs are administered over a prolonged period and could be a possible risk factor for dental caries in these children. Objectives: To assess endogenous pH, titratable acidity and type and concentration of sugars present in drugs used in treatment of HIV-infected children. Study design: Eleven drugs that are regularly prescribed to treat HIV infection in children (antiretrovirals, antibacterial, antifungal) were selected. The endogenous pH and titratable acidity of each drug was assessed. Type and concentration of sugars present in these medications was estimated using thin layer chromatography. Results: Medications were mostly in syrup form and their pH ranged from 2.27 to 7.98. Titratable acidity varied between 0.01 to 0.37 mmol. Sucrose was present in all medications, and more than 60 g% of sucrose was present in anti-acterial and antifungal preparations. Conclusion: The physical properties and sugar content of medications used in ART pose a risk to dental health of ­children.

KEY WORDS: HIV, antiretroviral therapy, pediatric medications, syrups, sucrose, pH

Cariogenic potential of medications used in treatment of children with HIV infection Priya Subramaniam, MDS;1* Krishna Kumar, MDS2 1Professor

and Head; 2Senior Resident, Department of Pedodontics and Preventive Dentistry, The Oxford Dental College and Hospital, Bommanahalli, Hosur Road, Bangalore, 560068, India. *Corresponding author e-mail: [email protected] Spec Care Dentist 34(3): 127-130, 2014

Introd uct ion

Globally an estimated 2.5 million children are living with HIV/AIDS, with 10,000 becoming infected daily.1 In 2009, it was estimated that there are 2.39 million people living with HIV in India and children constitute 4.4%.2 Of the 1,05,000 children in India, 77,044 children were registered at 285 antiretroviral therapy (ART) centers.2

ART is the mainstay in treatment of individuals with human immunodeficiency virus (HIV). Intervening early may prevent damage to the immune system and potentially retard dissemination of infection. Treatment with ART improves immune function and decreases mortality, morbidity, and opportunistic infections in HIV-infected persons. Combination ART is recommended for all infants, children, and adolescents who meet treatment criteria. The treatment regimen often contain three or more agents.3 The preferred first-line regimen for infants and children is two nucleoside reverse transcriptase inhibitors (NRTIs) and one nonnucleoside reverse transcriptase inhibitor (NNRTI).3 In addition, other drugs are required to manage numerous infectious and systemic consequences of HIV infection.3–5 Patients are given multiple doses of several antiretroviral drugs every day, as well as prophylactic antibiotics and supplemental vitamins. In cases of infection, multiple therapy, with two or more antiretroviral drugs, along with an ­antibacterial and/or antifungal may be

© 2013 Special Care Dentistry Association and Wiley Periodicals, Inc. DOI: 10.1111/scd.12041

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administered. These drugs are available as suspensions, solutions, syrups and tablets for oral administration. A problem with liquid formulations is the taste. When liquid formulations are developed, the taste is often so unpleasant that they may be practically unusable. Drug administration to ­children is more complex than it is to adults. Bad-tasting drugs are a well-­ recognized factor in treatment failures in children and lead practitioners to try many approaches to improve palatability of drugs for children.6 High concentrations of sugars are added to them, in order to make them palatable and appropriate for administration.6 Medications are often mixed with ­chocolate milk, sweetened juices, or pudding. But, this can be detrimental to dental health, a particular problem for children with HIV, many of whom have severely decayed teeth.6 Attention should be paid to the possible adverse effects of these antiretroviral medications on oral health. It is important to assess the cariogenic potential of ­medications used in ART.

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Table 1. Properties of drugs prescribed for HIV-infected children. Sl. no.

Pharmacological ingredient

Trade name

Available form

Mode of action

pH

Titratable acidity (mmol)

1.

Zidovudin

Retrovir

Syrup

Antiretroviral

2.27

0.01

2.

Stavudine

Stadine

3.

Lamivudine

Epivir

Syrup

Antiretroviral

6.28

0.14

Solution

Antiretroviral

5.21

0.21

4.

Nevirapine

Nevir

Syrup

Antiretroviral

4.39

0.12

5.

Didanosine

Didanosine

Solution

Antiretroviral

7.98

0.34

6.

Amprenavir

Agenerase

Solution

Antiretroviral

5.56

0.21

7.

Abacavir

Ziagen

Solution

Antiretroviral

3.24

0.11

8.

Ritonavir

Norvir

Solution

Antiretroviral

4.54

0.18

9.

Amoxicillin

Mox

Syrup

Antibacterial

6.24

0.27

10.

Azitromycine

Azinkya

Syrup

Antibacterial

7.87

0.37

11.

Ketoconazole

Cygnus

Suspension

Antifungal

5.78

0.28

Hence, the purpose of this study was to assess the endogenous pH of antiretroviral, antibacterial, and ­antifungal drugs used in HIV-infected children, their titratable acidity, and the type and concentration of sugars present in them.

Methodology

Eleven drugs (antiretrovirals, antibacterial, antifungal) that are regularly prescribed in India for the treatment of children with HIV were selected. These medications were selected based on the treatment regimen followed by Asha Kirana Hospital, a HIV center in Mysore, India. Eight of them were antiretroviral products used to control HIV infection by viral load reduction, two drugs were antibacterial products used to prevent opportunistic infection and one was an antifungal agent. They were in the form of syrups, suspensions, and solutions (Table 1). These drugs were administered to HIV-infected children at the center and the patients did not have a choice to select the formulations. Two samples of each drug, from the same pharmaceutical batch or lot were taken for analysis. The endogeneous pH of each medicament was determined by a previously calibrated digital pH meter (Model PE-133, Elico Private Limited).

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Analysis of type and ­concentration of sugars7 Analysis for four sugars was performed using thin layer chromatography (TLC) on silica-coated plates, with the following solvent mixture: butanol/ethanol/H2O (2:1:1, by volume). Two grams of each drug was diluted in 100 ml of distilled water in a volumetric flask. Then, one aliquot (500 μl) of each solution was centrifuged and 2 μl of the supernatant were analyzed. The samples were deposited as a spot on the stationary phase. The constituents of a sample can be identified by simultaneously running standards with the unknown substance. Standards of glucose, sucrose, lactose, and fructose (Merck™) were used at 1 mg/ml. The plates were dried at 100° C. Spots were visualized with Orcinol— H2SO4 reagent.7 Readings were presented as medians of the mean values of free sugar concentration (g%). All samples were prepared in triplicate.

Estimation of titratable acidity The titratable acidity of the drugs was assessed using the method described by Maguire et al.8 Using the manual method of titration, each sample was titrated by adding 0.1 M sodium hydroxide (NaOH) solution until an endpoint pH of 7 was obtained. Endpoint pH and volume of 0.1 M NaOH added was recorded. This measurement was done in triplicate and

a mean value recorded. The mean ­titratable acidity was calculated using the formula:[(a/2) × 5] × 0.1 (mmol) where, volume of 0.1 M NaOH needed to reach pH (7.0) = a (ml); divided by 2 since the sample was 2 ml; multiplied by 5 for standard 5 ml dose; and m ­ ultiplied by 0.1 for titratable acidity expressed in mmol.

R es ul t s The medications comprised of five syrups, five solutions, and one suspension (Table 1) The pH of all the medications ranged from 2.27 to 7.98. Of the 11 medications, zidovudin which is a syrup formulation showed the lowest pH. Among the syrups, only azitromycine, an antibacterial drug had an endogenous pH greater than 7. Almost all antiretroviral preparations, regardless of being either a syrup or a solution had a low endogenous pH.

Values for titratable acidity varied between 0.01 to 0.37 mmol Sucrose was present in all medications, and more than 60 g% of sucrose was ­present in the antibacterial and antifungal preparations. Only zidovudin had glucose in its formulation and a high content of sucrose (Tables 1 and 2).

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Table 2. Concentration of sugars in drugs prescribed for HIV infection. Drug

Glucose (g%)

Sucrose (g%)

Zidovudin

23

36

Stavudine

0

12

Lamivudine

0

27

Nevirapine

0

24

Didanosine

0

8

Amprenavir

0

18

Abacavir

0

17

Ritonavir

0

21

Amoxicillin

0

62

Azitromycine

0

64

Ketoconazole

0

62

D i s cu s s ion

Children with chronic conditions and who are taking medicines may be at higher risk for dental diseases.9–11 Apart from their highly compromised immune status, HIV-infected children present with poor oral health. Lack of access to dental care and neglect by health professionals further aggravates their poor oral condition. Pediatric medications that are available in the form of syrups and suspensions are popular and are easily accepted by children. Liquid and chewable medications are usually very unpleasant to the taste, and sometimes it is necessary to combine different sweeteners in the same product in order to overcome this inconvenience.12 The most used sweetener by the pharmaceutical industry is sucrose12 due to its properties of being a preservative, an antioxidant, a solvent, and a thickening agent. It is also of low cost, and can be easily processed. Pharmaceutical preparations with acidic pH and high sugar content have a potential for increasing dental caries when used several times each day over long periods of time.13 However, it is not just the endogenous pH of the medicament, that is important, but rather the titratable acidity. An in vitro study found pediatric sugar-free medicines to be less erosive than sugar containing medicines; and a

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more significant predictor of erosive potential was their dose form.8 The mean endogenous pH and titratable acidity for 41 sugar containing formulations were 5.26 and 0.139 mmol, respectively, whereas; it was 5.73 and 0.413 mmol, respectively, for 56 sugars-free formulations.8 The greater the buffering capacity of a liquid, the longer it will take for saliva to neutralize the acid.14–16 An earlier study analyzed pH and sugar concentration in seven antiretroviral and three antibacterial medications that are frequently prescribed to HIVinfected children. Two antiretroviral drugs (zidovudin and abacavir sulphate) had pH below critical level (3.55 and 3.93, respectively). Sugar was present in seven of the ten medications analyzed. The antibacterial preparations contained the highest concentration of sucrose, ranging from 40% to 54%.17 Sugars added to medicines can be fermented by oral bacteria, resulting in a fall in the intra-oral pH and leading to the development of dental caries. Some of these preparations can also lead to decrease in salivary flow. Ingestion of antiretroviral medications resulting in low pH levels below the critical level has been related to severe cases of dental ­erosion.18 Oral hygiene measures following intake of medicated syrups in children is known to be unsatisfactory.19,20 It is now

widely accepted that sugar-containing medicines are a cause of dental caries in chronically sick children.20–22 Frequent and prolonged intake of such sweetened medications by HIV-infected children can promote dental caries and dental erosion in this high-risk group. Therefore, it is necessary for pharmaceutical companies to consider reformulation of these preparations, so as to make them less caries promoting. In developing countries, regulatory bodies should address issues concerning drugs and their impact on oral health, especially in chronically ill individuals. In addition to liquid formulations, other forms such as dispersal, chewable tablets, or sprinkle formulations should be produced. It is highly important that pediatric dentists educate other health professionals on the need for good oral hygiene in these children and for regular referrals to the dentist.

C oncl us ion

The medications regularly prescribed for HIV-infected children were mostly in the syrup form and had a high-sucrose content and low-endogenous pH. Although the active ingredient of these preparations is necessary for their treatment, some of the other ingredients and their physical properties pose a risk to dental health.

C onf l ict of Inte r e st

I would like to state that we have no conflict of interest in this study. We did not avail of any financial assistance or funding during the conduct of this study and also during the preparation of the manuscript.

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study of paediatric medicines with prolonged oral clearance used regularly and long-term by children. Int J Pediatr Dent 2007;17(4):231-8. 9. Policy on Caries Assessment Tool (CAT). Oral Health Policies American Academy of Pediatric Dentistry Guidelines. Pediatr Dent 2012;34(6):118-25. 10. Milano M. A cross-sectional study of medication-related factors and caries experience in asthmatic children. Pediatr Dent 2006;28: 415-9. 11. Roberts GJ, Roberts IF. Dental disease in chronically sick children. J Dent Child 1981; 48:346-51. 12. Silva SMB, Santos CF. Pediatric drugs and risk of caries—a review. Rev Fac Odont Bauru 1994;2:15–21. 13. Costa CC, Almeida IC, Costa Filho LC. Erosive effect of an antihistamine-containing syrup on primary enamel and its reduction by fluoride dentifrice. Int J Pediatr Dent 2006;16(3):174-80. 14. Lima KT, Almeida ICS, Senna ETL. Sweeteners and endogenous pH of pediatric medicines [Abstract B-110]. J Dent Res 2000;79:1130. 15. Lussi A, Jaeggi T. Chemical factors. In: Lussi A, ed. Dental erosion. Monographs in oral ­science. Basel: Karger; 2006:20,112-8.

16. Penazzato M, Prendergast A, Tierney J, Cotton M, Gibb D. Effectiveness of antiretroviral therapy in HIV-infected children under 2 years of age. Cochrane Database Syst Rev 2012;11(7):CD004772. 17. Pomarico L, Czauski G, Portela MB, 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. 18. Moss SJ. Dental erosion. Int Dent J 1998; 48(6):529-39. 19. da Silva Pierro VS, Barcelos R, Maia LC, da Silva AN. Pediatricians’ perception about the use of antibiotics and dental caries—a preliminary study. J Public Health Dent 2004; 64(4):244-8. 20. Neves BG, Pierro VS, Maia LC. Pediatricians’ perceptions of the use of sweetened medications related to oral health. J Clin Pediatr Dent 2008;32(2):133-7. 21. Sahgal J, Sood PB, Raju OS. A comparison of oral hygiene status and dental caries in children on long term liquid oral medications to those not administered with such medications. J Indian Soc Pedod Prev Dent 2002;20(4):144-51. 22. Maguire A, Rugg-Gunn AJ. Prevalence of long term use of liquid oral medicines by children in northern region, England. Community Dent Health 1994;11:91-6.

Cariogenic potential of HIV medications

26/03/14 6:11 PM

Cariogenic potential of medications used in treatment of children with HIV infection.

In children infected with human immunodeficiency virus (HIV), initiation of antiretroviral therapy (ART) commences at a very young age. These drugs ar...
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