Clinical Toxicology, 43:269–275, 2005 Copyright D Taylor & Francis Inc. ISSN: 0731-3810 print / 1097-9875 online DOI: 10.1081/CLT-200066067
ARTICLE
Comparison of the Adsorption Capacities of an Activated-Charcoal–Yogurt Mixture Versus Activated-Charcoal–Water Slurry In Vivo and In Vitro
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Lotte Christine Groth Hoegberg, Pharm. M.S., Ph.D. Department of Clinical Biochemistry and Department of Clinical Pharmacology, Bispebjerg Hospital, Copenhagen, Denmark
Anne-Bolette Christophersen, M.D. and Hanne Rolighed Christensen, M.D., Ph.D. Department of Clinical Pharmacology, Bispebjerg Hospital, Copenhagen, Denmark
Helle Riis Angelo, Pharm. M.S., Ph.D. Department of Clinical Biochemistry, Bispebjerg Hospital, Copenhagen, Denmark
Background. An activated charcoal – yogurt mixture was evaluated in vivo to determine the effect on the gastrointestinal absorption of paracetamol, as compared to activated-charcoal – water slurry. The potential advantage of the activated-charcoal – yogurt mixture is a better palatability and general acceptance by the patients without loss of efficacy. In addition, paracetamol adsorption studies were carried out in vitro to calculate the maximum adsorption capacity of paracetamol to activatedcharcoal – yogurt mixture. Methods. In vivo: A randomized crossover study on 15 adult volunteers, using paracetamol 50 mg/kg as a simulated overdose. Each study day volunteers were given a standard meal 1 h before paracetamol, then 50 g activated charcoal 1 h later in either of two preparations: standard water slurry or mixed with 400 mL yogurt. Paracetamol serum concentrations were measured using HPLC. The areas under the concentration-time curve (AUC) of the two preparations were compared and used to estimate the efficacy of each preparation. The palatability of both preparations was evaluated using a visual-analogue scale where the volunteers were asked to evaluate the appearance, smell, flavor, texture, ability to swallow, and overall impression of the mixtures. The time spent to consume the activated charcoal was also registered. In vitro: Activated charcoal, simulated gastric (pH 1.2) or intestinal (pH 7.2) fluid, and paracetamol were mixed with yogurt followed by 1 h incubation. The maximum adsorption capacity of paracetamol to activated charcoal was calculated using Langmuir’s adsorption isotherm. Paracetamol concentration was analyzed using HPLC. Results. In vivo there was no significant differ-
Received 25 March 2005; accepted 26 March 2005. Address correspondence to Lotte Christine Groth Hoegberg, Pharm. M.S., Ph.D., Department of International Health, Center for Medical Parasitology, University of Copenhagen, Copenhagen, Denmark. E-mail: lottehoegberg@sol.dk
ence (p > 0.05) in the AUC of paracetamol between the two activated-charcoal preparations. Geometric mean values and 95% CI for the AUCs were (in mg/l min): 6307 (4932 – 8065) for the activated charcoal – water slurry and 6525 (5111 – 8330) for the activated charcoal – yogurt mixture. The palatability study showed significant difference (p < 0.05) only in duration of administration, in favor of the activated charcoal-water slurry. In vitro the maximum adsorption capacity of activated charcoal with added yogurt was 544 mg paracetamol/g activated charcoal (pH 1.2), and 569 mg paracetamol/g activated charcoal (pH 7.2). Conclusion. The two activated-charcoal preparations showed equal (NS) absorption reduction of paracetamol in vivo. Mixing activated charcoal with yogurt rather than water prolonged the ingestion time, but did not improve the palatability in adults. The presence of yogurt reduced the adsorption capacity in vitro by 9 – 13% (p < 0.05) compared to control without yogurt (previous study with the same setup). Keywords
INTRODUCTION Activated charcoal has long been known to be effective in reducing the gastrointestinal absorption of many drugs, making it a potentially useful agent in the management of acute poisonings (1 – 7). However, the black and gritty activated-charcoal –water slurry is rather unpalatable and getting children to drink the suspension might be problematic (8 – 13). Therefore it would be helpful if the activated charcoal could be administered in another preparation than the recommended water slurry. Many additives have been tried, in order to increase the acceptance
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Absorption reduction; Activated charcoal; Adsorption; Gastric decontamination; Intoxication; Paracetamol; Poisoning; Yogurt
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of activated charcoal (1,6,9 –12,14 – 18). The general recommendation though is that activated charcoal should not be mixed with anything but water (19). An activated-charcoal – yogurt mixture is often used with success in treating some pediatric poisonings in our neighboring Nordic countries, but no investigations have been made on the adsorption qualities of such a mixture so far. The potential advantage of an activated-charcoal –yogurt mixture is a better palatability and general acceptance by the patients without loss of efficacy. We therefore wanted to 1) examine the adsorptive capacity of activated charcoal mixed with yogurt in vivo and in vitro (simulating in vivo conditions at pH 1.2 and 7.2) and 2) to evaluate the palatability of the activated charcoal – yogurt mixture. Paracetamol was used as a model drug (1,17,20). METHODS In Vivo Fifteen healthy adult volunteers participated in the in vivo part of the study, eight men and seven women, median age 27 years (range 22– 38 years) and median weight 73 kg (range 50.5 –93 kg). Volunteer characteristics are given in Table 1. They had no history of hepatic, gastrointestinal, or renal disease, no history of alcohol or drug abuse, and no current use of medication. Written informed consent was obtained from each participant prior to enrolment in the study. The study protocol was approved by the Ethics committee and the Danish Medicines Agency. Approval from the National Registry Board was not necessary. Study Design A randomized crossover design was used, consisting of two study days each separated by at least five days wash out. One
of the study days served as a control. The volunteers were randomized at the time of inclusion. Possible dropouts would be replaced. Preceding sessions would be rejected and subsequently repeated in the original sequence. All subjects arrived at 8 AM following an overnight fast, commenced from midnight, and were fed a standardized semisolid breakfast meal composed by the hospital dietician (20). Paracetamol tablets were ingested 1 h after completion of the meal with approximately 150 mL of tap water. On each of the study days the volunteers received activated charcoal as gastrointestinal decontamination 1 h after tablet ingestion. The activated charcoal was given either as water slurry or mixed with yogurt (400 mL). A light snack and water were served not earlier than 3 h after the intervention with activated charcoal. Volunteers were in a sitting position for most of the time during the study day. Paracetamol Paracetamol was chosen to model a drug overdose and given in nontoxic doses of 50 mg/kg bodyweight (21). It was administered as pediatric tablets, in the strength of 125 mg per tablet (Pamol1, Nycomed, Roskilde, Denmark), to mimic the larger number of tablets seen in a nonspecific overdose compared to the number seen in a therapeutic situation. The number of tablets given to each participant during each session ranged from 21– 38. The mean dose of paracetamol administered was 3750 mg (range 2625 –4750 mg). Activated Charcoal The activated charcoal used was Carbomix1 (surface area 2000 m2/g, Norit Cosmara, B.V., Amersfoort, The Netherlands) as a standard granulate mixed with either tap water or yogurt just prior to administration. It contained no laxatives, and only additives necessary for granulation and for the filling
TABLE 1 Volunteer characteristics Volunteer number: 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15
Sex
Bodyweight (kg)
Age at time of study (years)
Dose of paracetamol (mg)
Female Female Female Male Male Female Male Male Male Male Female Female Male Male Female
57 58 63 74 72 50.5 73 85 87.5 93 60 72 88 78 77
30 38 34 26 23 23 23 32 32 29 25 22 27 31 24
2875 3000 3250 3750 3625 2625 3750 4250 4375 4750 3000 3625 4500 3900 3875
CHARCOAL – YOGURT MIXTURE VS. CHARCOAL – WATER SLURRY
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process. In Denmark Carbomix1 is used in emergency care units. On one study day the volunteers were given a standard dose for adults of 50 g activated charcoal freshly mixed with 400 mL of tap water according to the instructions on the container. On the other study day they received 50 g activated charcoal freshly mixed with 400 mL yogurt (Arla Foods, Viby J, Denmark). The yogurt was a commercial brand obtained from a local dealer, and the energy weight distribution was 3.2% from protein, 3% from fat, and 12% from carbohydrates. Paracetamol Assay Blood samples were collected via an indwelling Teflon catheter inserted into a forearm vein. 5 mL blood samples were collected at 0, 15, 30, 45, 60, 75, 90, 120, 180, 240, 300, 360, and 420 min. Plain glass tubes were used, the samples were centrifuged, and serum was stored at minus 22°C until analysis. Paracetamol concentrations were determined using high-pressure liquid chromatography (HPLC). The limit of quantitation was 0.7 mg/l. The coefficients of variation for repeated measures were 2.9 –7.5% (20). Pharmacokinetics The area under the serum drug concentration-time curve after the administration of paracetamol was calculated using the software WinNonlin1 standard version 3.1 (Pharsight, Mountain View, California). A one-compartment model, firstorder kinetics with lag time gave an optimal fit. The total area under the curve from 0 to 1 (AUC(0, 1)) was calculated as well as the second parameters, Tmax, Cmax, and elimination half-lives. Palatability Study The volunteers were asked to evaluate the appearance, smell, flavor, texture, ability to swallow, and overall impression of both the activated charcoal –water slurry and the activated charcoal –yogurt mixture. The palatability of both preparations was evaluated using a visual-analogue scale (100 mm) with markings only at the ends of the line (completely unacceptable at 0 mm and completely acceptable at 100 mm). The time spent to consume the activated charcoal preparations was registered. Statistical Analysis After logarithmic transformation of the values of the AUCs, these were found to have a normal distribution. The secondary parameters were found to follow a normal distribution without transformation. Results were thus expressed as geometric mean for the AUCs and mean for the secondary parameters. Ninety-five percent confidence intervals were given for all means. Statistical analysis was made using ANOVA and post hoc student’s paired t test. P values of < 0.05 were considered to be statistically significant, and all results were adjusted by the Bonferroni method for multiple comparisons (22).
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We calculated our sample size using the minimum relevant difference of our primary end point, the size of the AUC. We wanted to be able to detect a minimum relevant difference of 15% between AUC for the different activated charcoal doses. From a previous study using the same design but different interventions, the standard deviation of the differences in AUC of paracetamol when 50 g of activated charcoal was administered, compared to control with no activated charcoal, was known to be 17.6% (20). With a power of 90% and a 5% two-sided level of significance, the sample size was calculated to minimum 14.5. The difference for each evaluated item between the two activated charcoal preparations evaluated on the visualanalogue scale in the palatability study was calculated using Wilcoxon test for paired differences. In Vitro The effect of yogurt on the adsorption of paracetamol to activated charcoal was also determined in vitro. The method is described in details in a previous study (1). Primary end point was the comparative size of the maximum adsorption capacity of paracetamol to activated charcoal mixed with either water or yogurt. Activated charcoal, simulated gastric or intestinal fluid, and paracetamol were mixed with yogurt as described in procedures. The maximum adsorption capacity of paracetamol to activated charcoal was calculated as milligram paracetamol adsorbed per gram of activated charcoal, using Langmuirs adsorption isotherm (1,6). The concentration of paracetamol in the liquid phase was analyzed using HPLC (1). Apparatus and Materials All devices (shaking incubator, centrifuge, HPLC system), chromatographic conditions (column, mobile phase, flow rate, UV-detector), and standards for calibration curves have been described previously (1). Paracetamol (acetaminophen) was Ph.Eur.2.ed. grade from Rhone-Poulenc (Anthony, France). The activated charcoal was Carbomix1. The pH 7.2 phosphate buffer and the acidic medium, pH 1.2, simulating intestinal and gastric environment, respectively, were prepared as described by Tsitoura et al. 1997 (23). The yogurt was the same as in the in vivo part of this study. Procedures The effects of yogurt on the maximum adsorption capacity of paracetamol to activated charcoal were determined at pH 1.2, and pH 7.2. 250 mg Carbomix1 granules were suspended in 2 mL tap water. An amount of 2.5 mL simulated gastric or intestinal fluid was added to the activated charcoal suspension followed by 2.5 mL of yogurt. Paracetamol was thereafter added as solid material. The suspensions were incubated at 37°C for 1 h, with constant stirring. The liquid phase from the
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TABLE 2 Pharmacokinetic parameters of paracetamol after decontamination with either activated charcoal – water slurry or activated charcoal – yogurt mixture Activated charcoal –water slurry AUC(0- 1) (mg h/l) Tmax (min) Cmax (mg/l) t1/2 (h)
6307 51 35 1.7
(4932 –8065) (45 –57) (29 –41) (1.4 –1.9)
Activated charcoal – yogurt mixture 6525 70 35 1.6
(5111 – 8330) (61 – 80) (29 – 41) (1.3 – 1.8)
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Data are given as geometric mean (95% confidence intervals) for the 15 subjects.
incubated trials was withdrawn and centrifuged. Before the HPLC analysis proteins from the yogurt were precipitated with a 2% zinc sulfate-7-hydrate solution (50% v/v methanol/ water) (1). Estimation of Paracetamol Adsorption Parameters (Data Analysis) The Langmuir adsorption isotherm was used to estimate the adsorption parameter Qm, corresponding to the maximum adsorption capacity (6). Qm was in this trial defined as the maximum quantity of paracetamol (mg) adsorbed per gram activated charcoal. The results with added yogurt were compared to control (previous study with the same setup) (1). The results were calculated as mean of five trials. Confidence intervals for the average values were calculated using students t-distribution with n = 5. P <0.05 was regarded as significant. RESULTS In Vivo The pharmacokinetic parameters for paracetamol after ingestion of the activated charcoal –water slurry and activated
FIG. 1. Serum paracetamol concentration-time curves for the subjects when activated charcoal was given in two different preparations—water slurry (open circles) or mixed with yogurt (closed circles). The values of each concentration making up the curve are median values of all subjects.
charcoal –yogurt mixture are given in Table 2. There were no dropouts. Ingestion of Activated Charcoal – Water Slurry and Activated Charcoal – Yogurt Mixture The areas under the curve of paracetamol of the activated charcoal-water slurry preparation served as control. The median values for the area under the curve, AUC(0- 1), and Tmax, Cmax, and t1/2, for both activated charcoal preparations are summarized in Table 2. Figure 1 shows the serum paracetamol concentration-time curves for the subjects when activated charcoal was given in the two different preparations. There was no significant difference (p > 0.05) in AUC between the activated charcoal – water slurry and the activated charcoal –yogurt mixture. Palatability Study The palatability study results and the time spent to consume the activated charcoal –water slurry and activated charcoal – yogurt mixture are shown in Table 3 as median values, and 95% confidence intervals are in parenthesis. There were no significant differences in the subjects evaluated. There was significant difference (p < 0.05) in the consuming time in favor of the activated charcoal – water slurry. In Vitro The maximum adsorption capacity, Qm, of paracetamol to activated charcoal with added yogurt was 544 mg paracetamol/ g activated charcoal at pH 1.2 and 569 mg paracetamol/g activated charcoal at pH 7.2 (Table 4). When adding yogurt to the activated charcoal, the adsorption capacity was lowered significant by 9 –13% (pH 7.2 –pH 1.2) (p < 0.05) compared to controls without yogurt (1). Figure 2 is adsorption saturation curves and represent the amount of paracetamol adsorbed to activated charcoal, Q (mg paracetamol/g activated charcoal) vs. Cf (mg/l, the paracetamol concentration in liquid phase at equilibrium, calculated as the average of the obtained results in the five trials), at 37°C, pH 1.2 and pH 7.2, with and without yogurt.
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TABLE 3 Palatability evaluated on a visual-analogue scale (100 mm) and time (min) spent consuming the activated charcoal –water slurry and activated charcoal – yogurt mixture Appearance (mm)
Smell (mm)
Flavor (mm)
Texture (mm)
Ability to swallow (mm)
Overall impression (mm)
Duration of administration (min)
(NS)
(NS)
(NS)
(NS)
(NS)
(NS)
(p < 0.05)
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Activated 57 (45 – 73) 95 (91 – 97) 69 (51 – 84) 39 (27 –55) 41 (21 – 60) 57 (47 –69) charcoal – water slurry Activated 47 (25 – 62) 91 (86 – 94) 66 (51 – 77) 34 (20 –43) 35 (24 – 47) 43 (29 –55) charcoal – yogurt mixture
3 (2 – 6) 12 (7 – 19)
Data are given as median values (95% confidence intervals).
TABLE 4 In vitro results Qm, mg Paracetamol adsorbed/g activated charcoal
pH 1.2 pH 7.2
Control
With yogurt
% Reduction compared to control
624 (613 –635) 626 (612 –641)
544 (532 –555) 569 (564 –573)
13% (p < 0.05) 9% (p < 0.05)
Maximum adsorption capacity, Qm (mg paracetamol adsorbed/g activated charcoal), of paracetamol to activated charcoal – water slurry [control (1)] and activated charcoal mixed with yogurt; means of five trials (95% confidence intervals). In the column farthest to the right is the reduction in maximum adsorption capacity of paracetamol to activated charcoal in the presence of yogurt calculated expressed as percent compared to control (1).
The asymptotic approximation to a plateau, corresponding to the maximum adsorption capacity, indicates saturation of the activated charcoal. Langmuir plots (not shown), with and without yogurt, showed good linearity (r = 0.9920 –0.9975) at both pH values. This indicates that data fit well to the Langmuir model.
DISCUSSION An activated charcoal –yogurt mixture is easy to prepare. It seems to be an attractive option, when trying to create a more acceptable activated charcoal formulation. The practice of adding yogurt to activated charcoal to improve palatability was not found to interfere with the
FIG. 2. Adsorption saturation curves of adsorption of paracetamol to activated charcoal at 37°C at pH 1.2 and pH 7.2. Every mark is calculated as a mean of five trials; the approximation to a plateau corresponding to the maximum adsorption capacity indicates saturation of the activated charcoal. Open circle corresponds to paracetamol adsorption to activated charcoal (control), and closed circle is activated charcoal mixed with yogurt.
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antidotal efficacy of the activated charcoal in vivo, though yogurt slightly decreases the ability of the activated charcoal to adsorb paracetamol in vitro. The difference between the in vivo and in vitro results is probably due to the higher degree of variance seen in vivo compared to the in vitro studies. The area under the curve of the 50 g activated charcoal – water slurry dose was found to be in concordance with the 50 g activated charcoal –water slurry dose of a previous study using the exact same design of a model drug overdose (20). There were no adverse reactions seemingly correlated to the activated charcoal. The adult subjects in our study did not find the palatability of the activated charcoal improved when mixed with yogurt compared to the activated charcoal – water slurry. Furthermore the ingestion time was increased four times, from 3 min to 12 min, for ingestion of the activated charcoal –water slurry and the activated charcoal – yogurt mixture, respectively. This increase in ingestion time might be due to the high weight of the activated charcoal – yogurt mixture to be ingested shortly after a relatively large breakfast meal and/or that there was not enough yogurt in the mixture. The activated charcoal almost drained the liquid from the yogurt. The subjects described that the activated charcoal grains made the activated charcoal – yogurt mixture a little gritty, although it did not take away the fruity flavor of the yogurt. A definite drawback was the grayish color of the mixture. Overall, the adult subjects did not rate the activated charcoal – yogurt mixture as more acceptable than the activated charcoal – water slurry. This finding might not necessarily be extrapolated to the paediatric population. Clinical practice in our neighboring Nordic countries shows that children seem to accept the activated charcoal –yogurt mixture rather than the activated charcoal – water slurry. Results from investigations regarding adding dairy products or products containing milk components to improve palatability of activated charcoal are conflicting. The palatability of the activated charcoal is shown to be improved when products like ice cream, milk, chocolate milk, or milk chocolate were added to the charcoal (9,13,17,24). Investigations describe slight decreases in the adsorption of acetylsalicylic acid and paracetamol to the activated charcoal when ice cream, milk, cocoa powder, or milk chocolate (9,15,17,24,25) were added to the activated charcoal, but milk and ice cream are also shown not to reduce the adsorption efficiency of the activated charcoal (16,18). It appears in investigations concerning children that the use of yogurt or ice cream to make ingestion of activated charcoal easier is acceptable (6,9,12). Activated charcoal can successfully be administered with some sweet substance such as yogurt, in which the charcoal granulate is easily mixed (12). M. Shannon recommends ‘‘A slurry consisting of activated charcoal and a flavouring agent should be given to the child’’ (26), and Lamminpa¨a¨ et al. recommended in their investigation an amount of activated charcoal
(1 g/kg) ‘‘to be given with yoghurt, juice or a food that the child likes’’ (12). The recommendation not to mix activated charcoal with anything but water (19) could be loosened as several investigations, including this present study, have not found significantly decreased adsorption of the model drug when the activated charcoal was mixed with a flavoring agent to improve the palatability. CONCLUSION In vitro, yogurt reduced the adsorption capacity of paracetamol to activated charcoal 10– 13% (p < 0.05) compared to controls without yogurt (1). However, the ingestion of an activated charcoal –yogurt mixture or activated charcoal – water slurry showed equal absorption reduction of paracetamol in vivo. Mixing activated charcoal with yogurt rather than water did not improve the palatability in adults and took considerably longer to ingest, but these findings might not necessarily be extrapolated to the pediatric population. ACKNOWLEDGMENTS The manufacturer of Carbomix1, Norit Cosmara B.V., Amersfoort (The Netherlands), contributed to cover half of the cost of the compensation to the volunteers. The distributing agent in Denmark, Aage Christensen A/S, Valby (Denmark) kindly supplied the Carbomix1 used in the study. The study was partly granted from the Danish Health Research Council. Special thanks to Ms. Ulla Abildtrup for helping with the laboratory work, and to Stig Ejdrup Andersen and Erik Christensen for checking the statistics. REFERENCES 1. Hoegberg LCG, Angelo HR, Christophersen AB, Christensen HR. Effect of ethanol and pH on the adsorption of paracetamol to high surface activated charcoal, in vitro studies. J Toxicol, Clin Toxicol 2002; 40:59 – 67. 2. Andersen AH. Experimental studies on the pharmacology of activated charcoal. I. Adsorption power of charcoal in aqueous solutions. Acta Pharm Toxicol 1946; 2:69 – 78. 3. Holt LE, Holz PD. The black bottle. J Pediatr 1963; 63:306 – 314. 4. Piccioni AL. Activated charcoal as an antidote for poisonings. Am J Hosp Pharm 1967; 24:38 – 39. 5. Piccioni AL. Management of acute poisonings with activated charcoal. Am J Hosp Pharm 1971; 28:62 – 64. 6. Cooney DO. Activated Charcoal in Medical Applications. New York, NY: Marcel Dekker, 1995. 7. Bond GR. The role of activated charcoal and gastric emptying in gastrointestinal decontamination: a state-of-the-art review. Ann Emerg Med 2002; 39:273 – 286. 8. Arena JM. Gastric lavage, ipecac, or activated charcoal? JAMA 1970; 212:328. 9. Levy G, Soda DM, Lampman TA. Inhibition by ice cream of the antidotal efficacy of activated charcoal. Am J Hosp Pharm 1975; 32:289 – 291.
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