Drug intake during Ramadan
http://www.100md.com
《英国医生杂志》
1 Laboratory of Pharmacology and Toxicology, Faculty of Medicine and Pharmacy, 19 Rue Tarik Bnou Ziad, Casablanca 20000, Morocco
Correspondence to: N Aadil aadil_nadia@yahoo.fr
Introduction
To build up this review, we used our own knowledge, experience, and previous publications on the subject of drug intake during Ramadan. We also searched Medline and consulted several websites.
Route of administration
Dosing schedules have to be altered during Ramadan. In fact, drug doses can be taken only between sunset and dawn, and the time span between them is shorter than outside Ramadan. Two different types of dosage schedule are commonly used during Ramadan.
Single daily dose
The easiest situation is that of patients who have a usual evening dose. Their therapeutic scheme remains unchanged during Ramadan, as it does not interfere with fasting. When the usual intake is in the morning or during the day, the doctor must be careful when delaying the intake to the evening that this will not alter the efficacy of treatment or the tolerance of the drug.
The efficacy and toxicity of many drugs can vary depending on the time of administration in relation to the circadian rhythms of biochemical, physiological, and behavioural processes. Thus, circadian time has to be taken into account as an important factor influencing a drug's pharmacokinetics or its effects or side effects. Table 1 summarises the results of some chronopharmacokinetic and pharmacodynamic studies for selected drugs.w1-w12
Table 1 Selected drugs with circadian variation in pharmacokinetics and pharmacodynamics
Few studies have investigated this subject in relation to Ramadan. A comparative study of the pharmacokinetics of theophylline before and during Ramadan in healthy volunteers showed a significant decrease in the amount of drug absorbed for the 8 pm intake (two hours after Iftar) compared with the 4 am intake (immediately after Sohour).6 This result was mainly explained by the changes in the circadian variations of the gastric pH and by the modifications of rhythms and quality of meals during Ramadan.7
A similar study on the pharmacokinetics of valproic acid in healthy volunteers showed a significant influence of the alterations to life rhythm and administration schedule on the pharmacokinetic parameters of this drug. In addition to the delayed absorption phase for the 8 pm intake during Ramadan, the main impairment was a significant decrease in the plasma elimination half life for the 5 am intake compared with the same intake time outside Ramadan.8 As this parameter determines the administration schedule, it would be relevant to monitor the use of this antiepileptic drug during Ramadan.
Studies on antihypertensive drugs have not shown any significant effect on their efficacy from either the Ramadan life rhythm or the changes in administration schedule.9 10 These studies were done in patients with high blood pressure and treated by once daily preparations, before and during Ramadan. All patients in these studies continued their drugs during Ramadan. The results of ambulatory blood pressure monitoring in the first study did not show any significant differences between the periods before Ramadan and during Ramadan in systolic pressure, diastolic pressure, 24 hour pressure, diurnal pressure, or nocturnal pressure.9 However, the authors observed that during the month of Ramadan the peak of the awakening is delayed by two hours and the nocturnal trough is delayed by one hour. The administration schedules in this study were not the same in the two time periods. The patients took their drugs at 8 am outside Ramadan and at the break of fasting (7-8 pm) during Ramadan. Perk et al reported similar results of 24 hour blood pressure monitoring before Ramadan and during the last week of Ramadan in 70 hypertensive patients, all of whom continued their once daily antihypertensive drugs during Ramadan.10 No significant differences were found between mean blood pressure or blood pressure load before and during Ramadan. The authors of both studies concluded that in patients with essential hypertension without complications, fasting during the month of Ramadan can be safely undertaken with continuation of previous drug treatment.
Fasting from dawn to dusk during Ramadan could cause problems with drug dosage regimens for Muslim patients
Saour et al evaluated, over a period of five years, the efficacy and tolerance of a long acting oral anticoagulant in two groups of patients.11 During this period, the 106 patients in the first group made the Ramadan fast, whereas the 183 patients in the second group did not fast. All the patients in the first group took their drugs at night rather than during the day. The incidence of thromboembolic events and haemorrhagic complications did not differ significantly between the two groups. The authors concluded that Ramadan fasting has no adverse effects on the efficacy and safety of long term oral anticoagulant treatment.
Two or more daily doses
During Ramadan, accurate distribution of drugs prescribed twice a day is difficult to achieve between the break from fasting and the beginning of fasting. Refraining from fasting according to the Islamic rules could be a wiser prescription. Nonetheless, patients with two doses could take the first one at the break of fasting and the second one before the beginning of fasting, in which case the dosing time and the time span between the doses are both altered. These alterations could affect the drug's plasma concentration profile and, therefore, its efficacy and tolerance. This is even more relevant for drugs with a narrow therapeutic index as the risk of toxicity is higher.
In fact, Daghfous et al reported an influence of fasting on the pharmacokinetics and side effects of a sustained release preparation of theophylline taken twice a day.12 The study included 12 patients with current stable asthma and was done in two stages—the first stage was during Ramadan, and the second stage was four weeks after the end of Ramadan. In both periods, the patients received two oral doses of theophylline, one just before dawn (3 am) and the second at sunset (7 pm) for five days. Outside Ramadan, only four out of 12 patients reported adverse events of minor nausea. During the fast of Ramadan, eight out of 12 patients reported adverse effects of abdominal pain and nausea. Six of them had also vomiting; fasting was then interrupted. In these patients, the blood theophylline concentrations were moderately, but not significantly, higher than in the patients without marked gastrointestinal problems. The authors concluded that a longer acting preparation taken in a single daily dose, preferably at the end of the night, would be a solution for asthmatic patients during Ramadan.
In the event of therapeutic problems during Ramadan, the number of doses should be reduced by using, when available, slow release formulations or chronotherapeutic formulations. Verapamil hydrochloride (Verelan PM, Covera-HS),13 propranolol CR (Innopran XL),14 diltiazem hydrochloride (graded release diltiazem),15 and tulobuterol (tulobuterol transdermal therapeutic system),16 are some of the new chronotherapeutic formulations available. Otherwise, a drug with a longer elimination half life should be used. Such drugs will have a longer duration of action and can therefore be taken at longer intervals, such as once a day. This is the case with non-steroidal anti-inflammatory drugs that are used for joint disease such as arthritis: ibuprofen (half life 2-3 hours), flurbiprofen (3-4 hours), naproxen (12-15 hours), and piroxicam (26-38 hours) are some examples. Patients who are prescribed drugs such as ibuprofen or flurbiprofen need to take doses three or four times a day to maintain a concentration of the drug in the body tissues sufficient to provide adequate pain relief. These drugs could be replaced by a single daily dose of piroxicam, which is more suitable for the fasting patient.17
Interaction with food intake
Extensive misuse of prescribed drugs during Ramadan may lead to therapeutic failures. The lack of survey data on this subject impairs effective evaluation of the problem. This lack of information is a problem for doctors, as they cannot give unbiased advise. Further studies should be carried out to provide more guidelines about the ways in which the administration of drugs should be modified. In the meantime, doctors and scientists in the Muslim world should be encouraged to follow up their patients with chronic diseases during Ramadan, in order to establish optimal dosage regimens.
According to the data that are available, patients arbitrarily modify the times of doses, the number of doses, the time span between doses, and even the total daily dosage of drugs during the month of Ramadan, often without seeking any medical advice. Recommendations are not easy to make as the reliability of the available results remains questionable. In fact, most of the studies carried out during Ramadan were retrospective, and small samples were often used. Other methodological errors were also seen, such as incomplete descriptions of the therapeutic schemes observed before and during Ramadan. In order to make an objective comparison of the results obtained before and during the month of Ramadan, the administered doses, the number of daily doses, and the administration times need to be shown for the two periods studied. For patients with chronic diseases, the new dosage regimen to be used during Ramadan needs to be established beforehand. Patients must also be informed about when they should take their drugs (before, during, or after food intake), particularly when they are treated with drugs of which the absorption could be impaired by food intake.
The best reference period for comparison with Ramadan would be the period before Ramadan rather than that immediately afterwards. Ramadan is characterised by repeated fasting and altered life habits that last four weeks, and its influence on chronobiological parameters can last beyond the end of the month of Ramadan.
The choice of drugs to be studied during Ramadan could be determined by surveys evaluating the therapeutic problems encountered during this month of fasting. Focus should be on drugs for chronic diseases, and especially on those with a narrow therapeutic index. Wide dissemination of research results, as well as achievement of consensus on relevant clinical and therapeutic issues, would allow health professionals throughout the Muslim world, and in countries with an important Muslim population, to provide accurate and standardised advice on the appropriate use of drugs during the holy month of Ramadan.
Additional educational resource
Islam Set (www.islamset.com)—Includes responses to questions on a variety of Islam related science subjects
Extra references are on bmj.com
Contributors: NA had the original idea for the article. All three authors contributed to the literature search. NA and IEH wrote the review. NA is the guarantor.
Funding: None.
Competing interests: None declared.
References
Aslam M, Healy MA. Compliance and drug therapy in fasting Moslem patients. J Clin Hosp Pharm 1986;11: 321-5.
Aslam M, Assad A. Drug regimens and fasting during Ramadan: a survey in Kuwait. Public Health 1986;100: 49-53.
Wheatly RS, Shelly MP. Stopping bronchodilator treatment is dangerous. BMJ 1993;307: 801.
Etemadyfar M. Effect of Ramadan on frequency of seizures. Abstract book, Congress on Health and Ramadan, October 2001. Tehran: Iranian Journal of Endocrinology and Metabolism, 2001: 32.
Recommendations of the 9th Fiqh-Medical seminar "An Islamic View of Certain Contemporary Medical Issues," Casablanca, Morocco, 14-17 June 1997 (www.islamset.com/search/index.html).
Gay JP, Cherrah Y, Aadil N, Hassar M, Brazier JL, Ollagnier M. Influence of Ramadan on the pharmacokinetics of a SR preparation of theophylline and cortisol cycle. J Interdiscipl Cycle Res 1990;21: 190-2.
Iraki L, Bogdan A, Hakkou F, Amrani N, Abkari A, Touitou Y. Ramadan diet restrictions modify the circadian time structure in humans: a study on plasma gastrin, insulin, glucose, and calcium and on gastric pH. J Clin Endocrinol Metab 1997;82: 1261-73.
Aadil N, Fassi-Fihri A, Houti I, Benaji B, Ouhakki M, Kotbi S, et al. Influence of Ramadan on the pharmacokinetics of a single oral dose of valproic acid administered at two different times. Methods Find Exp Clin Pharmacol 2000;22: 109-14.
Habbal R, Azzouzi L, Adnan K, Tahiri A, Chraibi N. Variations of blood pressure during the month of Ramadan. Arch Mal Coeur Vaiss 1998;91: 995-8.
Perk G, Ghanem J, Aamar S, Ben-Ishay D, Bursztyn M. The effect of the fast of Ramadan on ambulatory blood pressure in treated hypertensives. J Hum Hypertens 2001;15: 723-5.
Saour JN, Sick JO, Khan M, Mamo I. Does Ramadan fasting complicate anticoagulant therapy? Ann Saudi Med 1989;9: 538-40.
Daghfous J, Beji M, Louzir B, Loueslati H, Lakhal M, Belkahia C. Fasting in Ramadan, the asthmatics and sustained release theophylline. Ann Saudi Med 1994;14: 523.
Smith DH. Pharmacology of cardiovascular chronotherapeutic agents. Am J Hypertens 2001;14: 296-301s.
Sica D, Frishman WH, Manowitz N. Pharmacokinetics of propranolol after single and multiple dosing with sustained release propranolol or propranolol CR (innopran XL), a new chronotherapeutic formulation. Heart Dis 2003;5: 176-81.
Glasser SP, Neutel JM, Gana TJ, Albert KS. Efficacy and safety of once daily graded-release diltiazem formulation in essential hypertension. Am J Hypertens 2003;16: 51-8.
Horiguchi T, Kondo R, Myazaki J, Torigoe H, Tachikawa S. Clinical evaluation of tulobuterol patch in patients with mild or moderate persistent bronchial asthma—effects of long-term treatment on airway inflammation and hypersensitivity. Nihon Kokyuki Gakkai Zasshi 2004;42: 132-7.
Aslam M, Wilson JV. Medicines, health and the fast of Ramadan. J R Soc Health 1992;112: 135-6.
Hamaguchi T, Shinkuma D, Irie T, Yamanaka Y, Morita Y, Ivanoto B, et al. Effect of high-fat meal on the bioavailability of phenytoin in a commercial powder with a large particle size. Int J Clin Pharmacol Ther Toxicol 1993;31: 326-30.
Wilder BJ, Leppik I, Hietpas TJ, Cloyd JC, Randinitis EJ, Cook J. Effect of food on absorption of Dilantin Kapseals and Mylan extended-release phenytoin sodium capsules. Neurology 2001;57: 571-3.(N Aadil, assistant profes)
Correspondence to: N Aadil aadil_nadia@yahoo.fr
Introduction
To build up this review, we used our own knowledge, experience, and previous publications on the subject of drug intake during Ramadan. We also searched Medline and consulted several websites.
Route of administration
Dosing schedules have to be altered during Ramadan. In fact, drug doses can be taken only between sunset and dawn, and the time span between them is shorter than outside Ramadan. Two different types of dosage schedule are commonly used during Ramadan.
Single daily dose
The easiest situation is that of patients who have a usual evening dose. Their therapeutic scheme remains unchanged during Ramadan, as it does not interfere with fasting. When the usual intake is in the morning or during the day, the doctor must be careful when delaying the intake to the evening that this will not alter the efficacy of treatment or the tolerance of the drug.
The efficacy and toxicity of many drugs can vary depending on the time of administration in relation to the circadian rhythms of biochemical, physiological, and behavioural processes. Thus, circadian time has to be taken into account as an important factor influencing a drug's pharmacokinetics or its effects or side effects. Table 1 summarises the results of some chronopharmacokinetic and pharmacodynamic studies for selected drugs.w1-w12
Table 1 Selected drugs with circadian variation in pharmacokinetics and pharmacodynamics
Few studies have investigated this subject in relation to Ramadan. A comparative study of the pharmacokinetics of theophylline before and during Ramadan in healthy volunteers showed a significant decrease in the amount of drug absorbed for the 8 pm intake (two hours after Iftar) compared with the 4 am intake (immediately after Sohour).6 This result was mainly explained by the changes in the circadian variations of the gastric pH and by the modifications of rhythms and quality of meals during Ramadan.7
A similar study on the pharmacokinetics of valproic acid in healthy volunteers showed a significant influence of the alterations to life rhythm and administration schedule on the pharmacokinetic parameters of this drug. In addition to the delayed absorption phase for the 8 pm intake during Ramadan, the main impairment was a significant decrease in the plasma elimination half life for the 5 am intake compared with the same intake time outside Ramadan.8 As this parameter determines the administration schedule, it would be relevant to monitor the use of this antiepileptic drug during Ramadan.
Studies on antihypertensive drugs have not shown any significant effect on their efficacy from either the Ramadan life rhythm or the changes in administration schedule.9 10 These studies were done in patients with high blood pressure and treated by once daily preparations, before and during Ramadan. All patients in these studies continued their drugs during Ramadan. The results of ambulatory blood pressure monitoring in the first study did not show any significant differences between the periods before Ramadan and during Ramadan in systolic pressure, diastolic pressure, 24 hour pressure, diurnal pressure, or nocturnal pressure.9 However, the authors observed that during the month of Ramadan the peak of the awakening is delayed by two hours and the nocturnal trough is delayed by one hour. The administration schedules in this study were not the same in the two time periods. The patients took their drugs at 8 am outside Ramadan and at the break of fasting (7-8 pm) during Ramadan. Perk et al reported similar results of 24 hour blood pressure monitoring before Ramadan and during the last week of Ramadan in 70 hypertensive patients, all of whom continued their once daily antihypertensive drugs during Ramadan.10 No significant differences were found between mean blood pressure or blood pressure load before and during Ramadan. The authors of both studies concluded that in patients with essential hypertension without complications, fasting during the month of Ramadan can be safely undertaken with continuation of previous drug treatment.
Fasting from dawn to dusk during Ramadan could cause problems with drug dosage regimens for Muslim patients
Saour et al evaluated, over a period of five years, the efficacy and tolerance of a long acting oral anticoagulant in two groups of patients.11 During this period, the 106 patients in the first group made the Ramadan fast, whereas the 183 patients in the second group did not fast. All the patients in the first group took their drugs at night rather than during the day. The incidence of thromboembolic events and haemorrhagic complications did not differ significantly between the two groups. The authors concluded that Ramadan fasting has no adverse effects on the efficacy and safety of long term oral anticoagulant treatment.
Two or more daily doses
During Ramadan, accurate distribution of drugs prescribed twice a day is difficult to achieve between the break from fasting and the beginning of fasting. Refraining from fasting according to the Islamic rules could be a wiser prescription. Nonetheless, patients with two doses could take the first one at the break of fasting and the second one before the beginning of fasting, in which case the dosing time and the time span between the doses are both altered. These alterations could affect the drug's plasma concentration profile and, therefore, its efficacy and tolerance. This is even more relevant for drugs with a narrow therapeutic index as the risk of toxicity is higher.
In fact, Daghfous et al reported an influence of fasting on the pharmacokinetics and side effects of a sustained release preparation of theophylline taken twice a day.12 The study included 12 patients with current stable asthma and was done in two stages—the first stage was during Ramadan, and the second stage was four weeks after the end of Ramadan. In both periods, the patients received two oral doses of theophylline, one just before dawn (3 am) and the second at sunset (7 pm) for five days. Outside Ramadan, only four out of 12 patients reported adverse events of minor nausea. During the fast of Ramadan, eight out of 12 patients reported adverse effects of abdominal pain and nausea. Six of them had also vomiting; fasting was then interrupted. In these patients, the blood theophylline concentrations were moderately, but not significantly, higher than in the patients without marked gastrointestinal problems. The authors concluded that a longer acting preparation taken in a single daily dose, preferably at the end of the night, would be a solution for asthmatic patients during Ramadan.
In the event of therapeutic problems during Ramadan, the number of doses should be reduced by using, when available, slow release formulations or chronotherapeutic formulations. Verapamil hydrochloride (Verelan PM, Covera-HS),13 propranolol CR (Innopran XL),14 diltiazem hydrochloride (graded release diltiazem),15 and tulobuterol (tulobuterol transdermal therapeutic system),16 are some of the new chronotherapeutic formulations available. Otherwise, a drug with a longer elimination half life should be used. Such drugs will have a longer duration of action and can therefore be taken at longer intervals, such as once a day. This is the case with non-steroidal anti-inflammatory drugs that are used for joint disease such as arthritis: ibuprofen (half life 2-3 hours), flurbiprofen (3-4 hours), naproxen (12-15 hours), and piroxicam (26-38 hours) are some examples. Patients who are prescribed drugs such as ibuprofen or flurbiprofen need to take doses three or four times a day to maintain a concentration of the drug in the body tissues sufficient to provide adequate pain relief. These drugs could be replaced by a single daily dose of piroxicam, which is more suitable for the fasting patient.17
Interaction with food intake
Extensive misuse of prescribed drugs during Ramadan may lead to therapeutic failures. The lack of survey data on this subject impairs effective evaluation of the problem. This lack of information is a problem for doctors, as they cannot give unbiased advise. Further studies should be carried out to provide more guidelines about the ways in which the administration of drugs should be modified. In the meantime, doctors and scientists in the Muslim world should be encouraged to follow up their patients with chronic diseases during Ramadan, in order to establish optimal dosage regimens.
According to the data that are available, patients arbitrarily modify the times of doses, the number of doses, the time span between doses, and even the total daily dosage of drugs during the month of Ramadan, often without seeking any medical advice. Recommendations are not easy to make as the reliability of the available results remains questionable. In fact, most of the studies carried out during Ramadan were retrospective, and small samples were often used. Other methodological errors were also seen, such as incomplete descriptions of the therapeutic schemes observed before and during Ramadan. In order to make an objective comparison of the results obtained before and during the month of Ramadan, the administered doses, the number of daily doses, and the administration times need to be shown for the two periods studied. For patients with chronic diseases, the new dosage regimen to be used during Ramadan needs to be established beforehand. Patients must also be informed about when they should take their drugs (before, during, or after food intake), particularly when they are treated with drugs of which the absorption could be impaired by food intake.
The best reference period for comparison with Ramadan would be the period before Ramadan rather than that immediately afterwards. Ramadan is characterised by repeated fasting and altered life habits that last four weeks, and its influence on chronobiological parameters can last beyond the end of the month of Ramadan.
The choice of drugs to be studied during Ramadan could be determined by surveys evaluating the therapeutic problems encountered during this month of fasting. Focus should be on drugs for chronic diseases, and especially on those with a narrow therapeutic index. Wide dissemination of research results, as well as achievement of consensus on relevant clinical and therapeutic issues, would allow health professionals throughout the Muslim world, and in countries with an important Muslim population, to provide accurate and standardised advice on the appropriate use of drugs during the holy month of Ramadan.
Additional educational resource
Islam Set (www.islamset.com)—Includes responses to questions on a variety of Islam related science subjects
Extra references are on bmj.com
Contributors: NA had the original idea for the article. All three authors contributed to the literature search. NA and IEH wrote the review. NA is the guarantor.
Funding: None.
Competing interests: None declared.
References
Aslam M, Healy MA. Compliance and drug therapy in fasting Moslem patients. J Clin Hosp Pharm 1986;11: 321-5.
Aslam M, Assad A. Drug regimens and fasting during Ramadan: a survey in Kuwait. Public Health 1986;100: 49-53.
Wheatly RS, Shelly MP. Stopping bronchodilator treatment is dangerous. BMJ 1993;307: 801.
Etemadyfar M. Effect of Ramadan on frequency of seizures. Abstract book, Congress on Health and Ramadan, October 2001. Tehran: Iranian Journal of Endocrinology and Metabolism, 2001: 32.
Recommendations of the 9th Fiqh-Medical seminar "An Islamic View of Certain Contemporary Medical Issues," Casablanca, Morocco, 14-17 June 1997 (www.islamset.com/search/index.html).
Gay JP, Cherrah Y, Aadil N, Hassar M, Brazier JL, Ollagnier M. Influence of Ramadan on the pharmacokinetics of a SR preparation of theophylline and cortisol cycle. J Interdiscipl Cycle Res 1990;21: 190-2.
Iraki L, Bogdan A, Hakkou F, Amrani N, Abkari A, Touitou Y. Ramadan diet restrictions modify the circadian time structure in humans: a study on plasma gastrin, insulin, glucose, and calcium and on gastric pH. J Clin Endocrinol Metab 1997;82: 1261-73.
Aadil N, Fassi-Fihri A, Houti I, Benaji B, Ouhakki M, Kotbi S, et al. Influence of Ramadan on the pharmacokinetics of a single oral dose of valproic acid administered at two different times. Methods Find Exp Clin Pharmacol 2000;22: 109-14.
Habbal R, Azzouzi L, Adnan K, Tahiri A, Chraibi N. Variations of blood pressure during the month of Ramadan. Arch Mal Coeur Vaiss 1998;91: 995-8.
Perk G, Ghanem J, Aamar S, Ben-Ishay D, Bursztyn M. The effect of the fast of Ramadan on ambulatory blood pressure in treated hypertensives. J Hum Hypertens 2001;15: 723-5.
Saour JN, Sick JO, Khan M, Mamo I. Does Ramadan fasting complicate anticoagulant therapy? Ann Saudi Med 1989;9: 538-40.
Daghfous J, Beji M, Louzir B, Loueslati H, Lakhal M, Belkahia C. Fasting in Ramadan, the asthmatics and sustained release theophylline. Ann Saudi Med 1994;14: 523.
Smith DH. Pharmacology of cardiovascular chronotherapeutic agents. Am J Hypertens 2001;14: 296-301s.
Sica D, Frishman WH, Manowitz N. Pharmacokinetics of propranolol after single and multiple dosing with sustained release propranolol or propranolol CR (innopran XL), a new chronotherapeutic formulation. Heart Dis 2003;5: 176-81.
Glasser SP, Neutel JM, Gana TJ, Albert KS. Efficacy and safety of once daily graded-release diltiazem formulation in essential hypertension. Am J Hypertens 2003;16: 51-8.
Horiguchi T, Kondo R, Myazaki J, Torigoe H, Tachikawa S. Clinical evaluation of tulobuterol patch in patients with mild or moderate persistent bronchial asthma—effects of long-term treatment on airway inflammation and hypersensitivity. Nihon Kokyuki Gakkai Zasshi 2004;42: 132-7.
Aslam M, Wilson JV. Medicines, health and the fast of Ramadan. J R Soc Health 1992;112: 135-6.
Hamaguchi T, Shinkuma D, Irie T, Yamanaka Y, Morita Y, Ivanoto B, et al. Effect of high-fat meal on the bioavailability of phenytoin in a commercial powder with a large particle size. Int J Clin Pharmacol Ther Toxicol 1993;31: 326-30.
Wilder BJ, Leppik I, Hietpas TJ, Cloyd JC, Randinitis EJ, Cook J. Effect of food on absorption of Dilantin Kapseals and Mylan extended-release phenytoin sodium capsules. Neurology 2001;57: 571-3.(N Aadil, assistant profes)