ATHEROSCLEROTIC RISK AMONG EPILEPTIC PATIENTS TAKING CARBAMAZEPINE, PHENYTOIN TREATMENT: BRIEF REVIEW

ATHEROSCLEROTIC RISK AMONG EPILEPTIC PATIENTS TAKING CARBAMAZEPINE, PHENYTOIN TREATMENT: BRIEF REVIEW

S. S. Khot*, Md. Hanif Shaikh and Lalitkumar Gupta

Vadu Rural Health Program, K.E.M. Hospital Research Centre, Sardar Moodliar Rd, Rasta Peth, Pune 411011, Maharashtra, India

ABSTRACT: Epilepsy is a common chronic neurological disorder that requires long-term or sometimes lifetime therapy. Anticonvulsant drugs are used in large quantities during long-term antiepileptic therapy and the treatment may be associated with various metabolic abnormalities in connective tissues, endocrine system and the liver. Recent evidence indicates that prolonged use of antiepileptic drugs (AEDs) particularly carbamazepine (CBZ), phenytoin (PHT) might modify some vascular risk factors; however, the influence of AED therapy on the development of atherosclerosis has been the subject of controversy and pretty unclear. Some epidemiological studies have reported a higher prevalence of ischemic vascular disease among epileptic patients on AEDs, while in other studies the mortality due to atherosclerosis-related cardiovascular disease in treated epileptics has been observed to be lower than in the general population. The etiology of atherosclerosis-related vascular diseases in epileptic patients has not been fully clarified. Atherosclerotic vascular alterations may start early in life, this review focuses on major atherogenic risk, including disordered lipid profiles, and increased lipoprotein (a) serum levels among epileptic patients

Antiepileptic Drugs, Atherosclerosis, Lipids, Epileptic Children, Carbamazepine, Phenytoin

INTRODUCTION: Epilepsy is the most common serious neurological condition and approximately 50 million people worldwide have it. This neurological disease account 1% of global burden of disease (WHO). This equals lung cancer in men and breast cancer in women. In India it is estimated to have 60-80 lakhs of people with epilepsy ^{1, 2}.

In the US, about 100,000 new cases of epilepsy are diagnosed ^{3, 4}. In the UK, between 1 in 140 and 1 in 200 people (at least 300,000 people) are currently being treated for epilepsy ⁵. Epidemiological studies suggest that between 70 and 80% of people developing epilepsy will go into remission, while the remaining patients continue to have seizures and are refractory to treatment with the currently available therapies ^{6, 7}.

The most common risk factors for epilepsy are cerebrovascular disease, brain tumours, alcohol, traumatic head injuries, malformations of cortical development, genetic inheritance, and infections of the central nervous system. In resource-poor countries, endemic infections, such as malaria and neurocysticercosis, seem to be major risk factors ⁸.

Multiple epidemiologic studies have shown positive correlations between epilepsy and comorbid vascular disease. Patients with epilepsy suffer mildly increased mortality from ischemic heart disease, with standardized mortality ratios (SMRs) between 1.2 and 2.5 in several studies in developed countries ^{9, 10}. One Chinese study demonstrated an SMR of 10.7 for myocardial infarction ¹¹ and comorbid myocardial ischemia as reported on death certificates was positively correlated with epilepsy with an odds ratio of 16 ¹². Nonfatal ischemic heart disease is also significantly elevated 34% to 63% above controls ¹³. Stronger correlations between epilepsy and cerebrovascular disease are seen, with mortality ratios 3.7 to 5.3 ¹⁴ and morbidity close to 7 in one study. The latter correlation is to be expected, as stroke is a known causative factor for epilepsy. Whether having epilepsy increases subsequent cerebrovascular risk is more difficult to demonstrate in the literature, as the crosssectional nature of most studies makes it difficult to infer causation.

Very little data exist regarding the effects of specific AEDs on the incidence of vascular events. One Finnish study found a lower prevalence of ischemic heart disease in epilepsy patients, and furthermore found that patients who were on enzyme-inducing AEDs had 29% lower mortality due to heart disease ¹⁵. When a Norwegian group performed a survey of coronary risk profiles on patients with epilepsy and controls, however, they found no significant differences ¹⁶.

It is possible that the Finnish study reflects genetic variants in the isolated, homogeneous Finnish population, as Finnish studies of serologic risk factors also yield different results than those in other populations. This review focuses on risk of atherogenic metabolic alterations, disordered lipid profiles, and increased lipoprotein (a) serum levels among epileptic patients on  phenytoin, carbamazepine treatment.

Mechanism of Enzyme induction effects on Serum Cholesterol: The enzyme-inducing AEDs phenytoin  (PHT), carbamazepine (CBZ), increase the activity of the hepatic cytochrome P450 system, which is involved in synthesis of serum cholesterol. Animal data show that a particular enzyme, CYP51A1, catalyzes the conversion of lanosterol into cholesterol intermediates ¹⁷. When these intermediates build up through inhibition of the enzyme, they in turn inhibit the rate-limiting step of cholesterol synthesis, 3-hydroxy-3-methylglutaryl-coenzyme A  reductase, and slow the synthesis of cholesterol ¹⁸.

It follows that induction of CYP51A1 should therefore increase cholesterol production through metabolism of these intermediates and reduced feedback inhibition. While the pathway has not been explicitly studied in humans to our knowledge, this mechanism engenders some predictions regarding the effects of certain AEDs in patients. For example, an enzyme-inducing AED such as PHT , CBZ should increase serum cholesterol.

On the other hand, valproic acid (VPA), an enzyme-inhibiting medication, should decrease metabolism of inter- mediates and increase feedback inhibition, thereby decreasing production of cholesterol. One might also conjecture that pharmacogenetic heterogeneity of these effects could result in varying effects of a given AED on lipids in different patients ¹⁹.

AED and Atherosclerosis risk: Atherosclerosis is the leading cause of death in the developed world, although the true frequency is difficult to accurately determine because it is a predominantly asymptomatic condition ²⁰.  It is a disease of  large and medium-sized arteries, and is characterized by endothelial dys-function, vascular inflammation, and the presence of buildup (fatty streaks) consisting of lipids, calcium, and cellular debris within the intima of the vessel wall.

Some epidemiological studies have indicated that the prevalence and death rates from atherosclerosis related cardiovascular disease (CVD) are slightly elevated in adult epileptic patients taking antiepileptic drugs (AEDs) ²¹. However, other studies have come to the contrasting conclusion that mortality due to ischemic heart disease appears to be lower in treated epileptics than in the general population ²².

Epidemiological studies in adults with epilepsy have found that the risk for ischemic heart disease is  increased  by 34%, and the risk for fetal CVD is increased by 68% . In a cohort of   9000 patients, once hospitalized for epilepsy, a cause-specific mortality assessment found a standardized mortality ratio of 2.5 for ischemic heart disease and 3.5 for stroke. However, in a study of 30–50 year old males, no difference was found in the total coronary risk profile between those with epilepsy and controls.

Thus, the influence of AED therapy on the development of atherosclerosis has been the subject of controversy, although recent evidence indicates that prolonged antiepileptic treatment might modify some vascular risk factors ²³.

It has been well documented that atherosclerotic vascular alterations may start early in life and progress with age. The first signs of hyperlipidemia can be detected in childhood ²⁴ and  fatty  streaks, which are the earliest pathologic lesions of the  atherogenic process, can be observed in the aorta and coronary arteries of individuals by the age of  20. Thus, recent studies have focused on the incidence of vascular risk factors  and  a higher risk of atherosclerosis development among children with epilepsy; however, this link has not yet been firmly established and remains controversial ^{25, 26, 27, 28}.

Epilepsy is a relatively frequent chronic disorder in childhood and often requires lifelong therapy. It is widely suggested that either epilepsy itself or the prolonged administration of some AEDs is associated with the undesirable metabolic side effects implicated in dysfunction of the vessel wall.

This dysfunction can promote atherogenesis and ultimately result in occlusive vascular diseases such as stroke, myocardial infarction, and peripheral arterial disease ^{29, 30, 31}. The study conducted by Dechadarevian et al. demonstrated the presence of atherosclerotic changes at autopsy of an 11-year-old child who died following a status epilepticus who had been treated with carbamazepine (CBZ) for long-standing epilepsy. The child had hypercholesterolemia and an over 40% reduction in the vessel lumen diameter due to marked intimal proliferation and  accumulation of foam cells in the coronary arteries ³² .

1. Carbamazepine: Carbamazepine (CBZ) is widely used as an anticonvulsant drug in adults and children. The drug is known to cause multiple metabolic alterations, among them changes in serum lipoprotein concentrations. The precise frequency and nature of these changes are unclear as are the underlying  mechanisms of  action. In many studies increased total and/or low-density lipoprotein cholesterol (LDL-C) concentrations were found, and elevated high-density lipoprotein cholesterol (HDL-C) is also frequently reported ^33-43. The interpretation of most studies is limited due to unsatisfactory study designs; there are very few  prospective studies ^{44, 45, 46} whereas all other studies were cross-sectional and a variety of different control groups were used for comparison. In many studies there were antiepileptic comedications. Studies in children are difficult to interpret because lipoprotein profiles change with increasing age. In addition, it cannot be completely ruled out that epilepsy itself can lead to changes in lipoprotein profiles.

Cholesterol concentrations and especially the ratio of LDL-C to HDL-C are relevant determinants for the incidence and mortality from coronary heart disease ^{47, 48}. There is some evidence that coronary heart disease is less common in patients with epilepsy ⁴⁹ although these data are still uncertain. CBZ is known to be a powerful inducing agent of cytochrome P-450 enzymes ^{50, 51} and its effects on lipoproteins have been largely attributed to its enzyme-inducing action. Overall, however, there is very little information about the metabolic changes that are responsible for the effects of CBZ on lipids and no study controlled for confounding factors such as diet.

CBZ also induces liver microsomal enzymes, thereby altering the metabolism of lipids, bile acids and bilirubin ⁵². This leads to alteration in serum lipid levels and thus affects the development  of  atherosclerosis. Some serum lipids and apoproteins are atherogenic while others seem to have an anti-atherogenic effect. Subjects with high serum HDL-C levels have a low risk of coronary heart disease, whereas those with high serum TC and LDL-C have increased risk. However the ratio between the cholesterol fractions (TC/HDL-C; HDL-C/ LDL-C) is a better predictor for the development of atherosclerosis. Increased HDL-C/ TC and HDL-C/LDL-C is a powerful protective factor against atherosclerosis while the reverse increases the risk.

There are contradictory reports on the relationship of antiepileptic drugs to serum lipids. CBZ therapy leads to increased serum HDL-C levels, and HDL-C/TC ratio also tends to be increased. Muuronen, et al. reported that the mortality related to atherosclerotic heart disease was lower among patients treated with antiepileptic drugs than in the general population. They related this finding to the increased levels of HDL-C in these patients.

Some studies have failed to demonstrate a significant change in serum lipids in patients receiving CBZ monotherapy⁵³.  However most workers have shown significant increase in TC and other lipid fractions in epileptic children receiving CBZ ^{54, 55, 56}   Franzoni, et al. showed that rise in TC was a result of increased   LDL-C levels only. Others have suggested that the increase in TC is due to increase in both LDL-C and HDL-C ⁵⁷. Similarly, there are contradictory reports on the effects of anticonvulsants on atherogenic ratio (TC/HDL and LDL/HDL ratio). Increased TC/HDL and LDL/HDL ratio indicate a higher risk of atherosclerosis.

It is suggested that an increase in this ratio, following CBZ therapy might increase the risk of atherosclerosis. Aggarwal et al., does not show a significant alteration in TC/HDL and LDL/HDL ratio. This result matches with the results of others ³⁸ showing no significant difference in TC/HDL-C and LDL-C/HDL-C ratio in children receiving CBZ. LDL-C levels were 33.3% higher in cases compared to controls whereas HDL-C levels were 53.3% higher. Since HDL-C levels are supposed to be protective, significance of these changes needs to be studied further ³³.

Some investigators reported a significant decrease in TC/HDL ratios during the CBZ treatment ¹⁹ and some reported a slight increase during the first year of treatment followed by an insignificant decrease ⁴⁶. This ratio was reported to be increased 18 and 6 months after the onset of CBZ treatment in two studies performed in adult and pediatric patients, respectively ^{35, 43}  Similarly, there are contradictory reports on the LDL/HDL ratio in the studies performed in adults⁴⁵. However, the results of the studies performed in the children revealed an increase in this ratio, similar to the results in our CBZ group. In the CBZ group, TC/HDL and LDL/HDL ratios greater than the upper limit of normal were more frequent in the second and sixth months, respectively, as were the levels of TC and LDL.

In conclusion, these studies demonstrated that TC, LDL, and the atherogenic ratios increase during treatment with CBZ. In addition, the increase in the level of GGT is thought to be related to the inductive effect of CBZ. The National Child Education Program in the United States dictates that some preventive measures should be taken in childhood to prevent premature atherosclerosis.

Furthermore, some investigators have recommended avoiding a diet with high cholesterol levels in children treated with CBZ ^{36, 39}. The published data related to the alterations of serum lipids resulting from antiepileptic treatment inducing microsomal enzyme activation, suggest that the changes in the serum lipids beyond 3 months of treatment could be more significant.

However, larger populations are needed to assess the relative risk of atherosclerosis caused by the alterations observed during treatment with CBZ. Further studies are required to examine the implication of these changes and the need for preventive measures. Long term prospective studies are required to evaluate the risk of atherosclerosis caused by alteration in serum lipid levels in epileptic patients receiving therapy with CBZ.

2. Phenytoin: Phenytoin (PHT) is used as an anticonvulsant drug in adults and children. The drug is known to cause multiple metabolic alterations, among them changes in serum lipoprotein concentrations. The precise frequency and nature of these changes are unclear as are the underlying  mechanisms of  action. In many studies increased total and/or low-density lipoprotein cholesterol (LDL-C) concentrations were found, and elevated high-density lipoprotein cholesterol (HDL-C) is also frequently reported ^{58, 59}.

In particular growing evidence suggests that the older generation AEDs that are commonly used for treatment of epilepsy including phenytoin exert prominent effects on the hepatic enzyme system and may alter metabolic pathways that are related to increased vascular risk. Recent studies ^{60, 61} indicated that PHT is the potent inducer of the cytochrome P450 (CYP450) system, which exerts strong effects on serum lipid profile. It follows that this enzyme inducing drug may substantially increase the risk of atherosclerosis.

Emerging evidence further showed that treatment with PHT is significantly associated with increased blood levels of total cholesterol, atherogenic (non HDL) cholesterol and    triglycerides ⁶². Chaung et al., showed that the increase in thickness of CCA IMT in monotherapy with PHT may be related to total cholesterol and  LDL-C ⁶³. Close monitoring of serum lipid levels and and long-term follow up of patients receiving phenytoin to observe the incidence of ischemic heart disease  is needed to obtained clinically significant results.

Effects of AEDs on Carotid Intima-media thickness: Although enzyme-inducing medications appear to increase lipids and other serologic markers of vascular risk, the question remains as to whether these changes in risk markers actually increase the incidence of ischemic events in treated patients. Ischemic vascular disease can have many causes, but if inducer-treated epilepsy patients were truly subject to higher rates of myocardial infarction and stroke from the aforementioned serologic alterations, one would expect that vascular disease in these patients would have an atherosclerotic etiology.

Carotid intima-media thickness (CA-IMT) as assessed by ultrasound is considered to be a surrogate measure of atherogenesis and has been strongly correlated with risk of both stroke and myocardial infarction in several prospective studies ^{64, 65, 66}. One study of patients treated mainly with enzyme-inducing drugs showed higher CA-IMT relative to controls ⁶⁷.

Chaung et al., also demonstrated that the duration of monotherapy with CBZ & PHT is significantly associated with acceleration of atherosclerosis in patients with epilepsy, via different underlying mechanism. Dyslipidemia has long long been known to be important risk factors for atherosclerosis.

LDL-C plays an important role in the atherosclerotic process by increasing endothelial permeability, retention of lipoproteins within the intima of blood vessel, recruitment of inflammatory cells and formation of foam cells. Emerging evidence further showed that treatment with enzyme inducing AED’s such as CBZ and PHT, is significantly associated with increased blood levels of total cholesterol, atherogenic cholesterol, triglyceride and tHCY.

It is therefore of interest that increase in thickness of CCA IMT   in monotherapy with PHT and CBZ may be related to total cholesterol and LDL-C ⁶³.

Another investigation found that CBZ-treated patients had higher CA-IMT than VPA-treated patients, who in turn had higher CA-IMT than untreated patients with epilepsy. When carotid thickness was studied in children treated with VPA alone, treated patients had significantly higher CA-IMT without a difference in serum lipids ⁶⁸. CA-IMT in epilepsy patients appears to be positively correlated with duration of AED therapy ⁶⁹ though these investigators did not separate their findings according to different groups of AEDs.

These data confirm that enzyme-inducing AEDs may be associated with increased vascular risk over time, consistent with their effects on serologsic markers. However, they also suggest that VPA might increase vascular risk through mechanisms unknown. It is possible that epilepsy itself might increase vascular risk, which might then be further exacerbated by enzymatically active AEDs.

Future studies are needed to compare CA-IMT between those treated with newer-generation non-enzyme-inducing agents such as levetiracetam, lamotrigine, and topiramate.

CONCLUSION: The risk of vascular complications from AED therapy is an area of legitimate concern in need of further study. Enzyme-inducing AEDs in particular may pose a risk by increasing atherogenic serum cholesterol fractions. AED may also have adverse long-term metabolic consequences, including obesity, insulin resistance, and the metabolic syndrome.

Pharmacoepidemiologic studies are needed to determine the long-term vascular effects of carbamazepine and phenytoin. Because patients with epilepsy require medication for years, and often for life, it is difficult to justify the long-term use of these agents when there are capable alternatives. Many of the adverse effects of the older drugs appear to be rapidly reversible, prompting consideration of whether patients who are currently treated with these agents should be switched to alternative therapies, even in the absence of obvious side effects.

Newer medications without effects on hepatic enzymes likely do not have these chronic metabolic consequences, and we recommend their use over older-generation drugs whenever possible.

REFERENCES:

1. Srinivas HV. Epilepsy: the future scenario. Ann Indian Acad Neurol 2010; 31:2-5.
2. Sander JW. The epidemiology of epilepsy revisited. Curr Opin Neurol 2003; 16:165-170.
3. Begley CE, Annegers JF, Lairson LB, Reynolds TF. Epilepsy incidence, prognosis, and use of medical care in Houston, Texas, and Rochester,Minnesota. Epilepsia 1998; 39(6):222.
4. Annegers JF. Epidemiology of epilepsy. In: Wyllie E, editor. The treatment of epilepsy: principles and practice. 2nd ed. Baltimore: Williams & Wilkins 1997; 165-172.
5. Yuen AW, Sander JW. Is omega-3 fatty acid deficiency a factor contributing to refractory seizures and SUDEP? A hypothesis. Seizure 2004; 13:104-107.
6. Kwan P, Sander JW. The natural history of epilepsy: an epidemiological view. J Neurol Neurosurg Psychiatry 2004; 75:1376-1381.
7. Halatchev VN. Epidemiology of epilepsy--recent achievements and future. Folia Medica (Plovdiv) 2000; 42:17-22.
8. Duncan JS, Sander JW, Sisodiya SM, Walker MC. Adult epilepsy. Lancet 2006; 367:1087-1100.
9. Annegers JF, Hauser WA, Shirts  SB. Heart disease mortality and morbidity in patients with epilepsy. Epilepsia 1984; 25:699-704.
10. Nilsson L, Tomson T, Farahmand BY, Diwan V, Persson PG. Cause-specific mortality in epilepsy: a cohort study of more than 9,000 patients once hospitalized for epilepsy. Epilepsia 1997; 38:1062-1068.
11. Ding D, Wang W, Wu J, Ma G, Dai X, Yang B, et al. Premature mortality in people with epilepsy in rural China: a prospective study. Lancet Neurol 2006; 5:823–827.
12. Satishchandra P, Chandra V, Schoenberg BS. Case-control study of associated conditions at the time of death in patients with epilepsy. Neuroepidemiology 1988; 7:109-114.
13. Gaitatzis A, Carroll  K, Majeed  AW, Sander J. The epidemiology of the comorbidity of epilepsy in the general population. Epilepsia 2004; 45:1613-1622.
14. Cockerell OC, Johnson AL, Sander JW, Hart YM, Goodridge DM, Shorvon SD. Mortality from epilepsy: results from a prospective population-based study. Lancet 1994; 344:918–921.
15. Muuronen A, Kaste M, Nikkila EA, Tolppanen EM. Mortality from ischaemic heart disease among patients using anticonvulsive drugs: a case-control study. Br Med J.1985; 23:1481-1483.
16. Nakken KO, Kornstad S. Do males 30–50 years of age with chronic epilepsy and on long-term anticonvulsant medication have lower-than-expected risk of developing coronary heart disease? Epilepsia 1988; 39:326-330.
17. Gibbons GF. The role of cytochrome P450 in the regulation of cholesterol biosynthesis. Lipids 2002; 37:1163–1170.
18. Kandutsch AA, Chen HW. Inhibition of cholesterol synthesis by oxygenated sterols. Lipids 1978; 13:704–707.
19. Khoury LP, Mintzer S. Antiepileptic Drugs and Markers Of Vascular Risk. Current Treat Option Neurol 2011; 12(4):300-308.
20. Berenson GS, Srinivasan SR, Bao W, Newman WP, Tracy RE, Wattigney WA. Association between multiple cardiovascular risk factors and atherosclerosis in children and young adults. The Bogalusa Heart Study. N Engl J Med 1998; 338:1650-1656.
21. Elliott JO, Jacobson MP, Haneef Z. Cardiovascular  risk factors and homocysteine in epilepsy. Epilepsy Res 2007; 76:113-123.
22. Kaste M, Muuronen A, Nikkila EA, Neuvonen PJ. Increase of low serum concentrations of high-density lipoprotein (HDL) cholesterol in TIA-patients treated with phenytoin. Stroke 1983; 14:525-530.
23. Tumer L, Serdaroglu  A, Hasanoglu  A, Biberoglu G, Aksoy  E. Plasma homocysteine and lipoprotein (a) levels as risk factors for atherosclerotic vascular disease in epileptic children taking anticonvulsants. Acta Paediatr 2002; 91:923-926.
24. Strong  JP, Zieske AW, Malcom GT. Lipoproteins and atherosclerosis in children: an early marriage? Nutr Metab Cardiovasc Dis 2001; 11:16-22.
25. Demircioglu S, Soylu A, Diric  E. Carbamazepine and valproic acid: effects on the serum lipids and liver functions in children. Pediatr Neurol 2000; 23:142-146.
26. Huemer M, Ausserer B, Graninger G, Hubmann M, Huemer C, Schlachter K, Tscharre A. Hyperhomocysteinemia in children treated with antiepileptic drugs is normalized by folic acid supplementation. Epilepsia 2005; 46:1677-1683.
27. Reddy MN. Effect of anticonvulsant drugs on plasma total cholesterol, high-density lipoprotein cholesterol, and apolipoproteins A and B in children with epilepsy. Proc Soc Exp Biol Med 1985; 180:359–363.
28. Verrotti A, Pascarella R, Trotta D, Giuva T, Morgese G, Chiarelli F. Hyperhomocysteinemia in children treated with sodium valproate and carbamazepine. Epilepsy Res 2000; 41:253–257.
29. Dasheiff  RM, Sudden unexpected death in epilepsy: a series from an epilepsy surgery program and speculation on the relationship to sudden cardiac death. J Clin Neurophysiol 1991; 8:216–222.
30. Hamed S, Hamed E, Hamdy R, Nabeshima T. Vascular risk factors and oxidative stress as independent  predictors of asymptomatic atherosclerosis in adult patients with epilepsy. Epilepsy Research 2007; 74:183-192.
31. Hamed SA, Nabeshima T. The high atherosclerotic risk among epileptics: the atheroprotective role of multivitamins. J Pharmacol Sci 2005; 98:340-353.
32. Dechadarevian  J, Legido  A, Miles D, Katsetos, C. Epilepsy, atherosclerosis, myocardial infarction, and carbamazepine. J Child Neurol 2003; 18:150-151.
33. Aggarwal A, Kumar M, Faridi MMA. Effect of carbamazepine on serum lipids and liver function tests. Indian Pediatrics 2005; 42:913-918
34. Sudhop T, Bauer J, Elger CE, Von BK. Increased high-density lipoprotein cholesterol in patients with epilepsy treated with carbamazepine: a gender-related study. Epilepsia 1999; 40:480-484.
35. Sozuer DT, Atakil D, Dogu O, Baybas S, Arpaci B. Serum lipids in epileptic children treated with carbamazepine and valproate. Eur J Pediatr 1997; 156:565–567.
36. Verrotti A, Domizio S, Angelozzi B, Sabatino G, Morgese G, Chiarelli F. Changes in serum lipids and lipoproteins in epileptic children treated with anticonvulsants. J Pediatr Child Health 1997; 33:242-245.
37. Yalcin E, Hassanzadeh A, Mawlud K. The effects of long-term anticonvulsive treatment on serum lipid profile. Acta Paediatr Jpn 1997; 39:342–345.
38. Eiris JM, Lojo S, Del Rio MC. Effects of long-term treatment with antiepileptic drugs on serum lipid levels in children with epilepsy. Neurology 1995; 45:1155–1157.
39. Franzoni E, Govoni MD, Addato S, Gualandi S, Sangiorgi Z, Descovich GC. Total cholesterol, high density lipoprotein cholesterol and triglycerides in children receiving antiepileptic drugs. Epilepsia 1992; 33:932-935.
40. Luoma PV, Myllyla VV, Sotaniemi EA, Lehtinen IA, Hokkanen EJ. Plasma high-density lipoprotein cholesterol in epileptics treated with various anticonvulsants. Eur Neurol 1980;19: 67–72
41. Luoma PV, Sontaniemi EA, Pelkonen RO, Ehnholm C. High-density lipoproteins and hepatic microsomal enzyme induction in alcohol consumers. Res Commun Chem Pathol Pharmacol 1982; 37:91-96.
42. Reddy MN. Effect of anticonvulsant drugs on plasma total cholesterol, high-density lipoprotein cholesterol, and apolipoproteins A and B in children with epilepsy. Proc Soc Exp Biol Med.1985; 180:359–363.
43. Zeilthofer S, Doppelbauer A, Tribl G, Leitha T, Deecke L. Changes in serum lipid pattern during long term anticonvulsant treatment. Clin Invest 1993; 71:574-578.
44. Brown DW, Ketter TA, Crumlish J, Post RM.Carbamazepine-induced increases in total serum cholesterol: clinical and theoretical implications. J Clin Psychopharmacol 1992; 12:431-437.
45. Heldenberg D, Harel S, Holtzman M, Levtow O, Tamir I. The effect of chronic anticonvulsant therapy on serum lipids and lipoproteins in epileptic children. Neurology 1983; 33:510–513.
46. Isojarvi JI, Pakarinen AJ, Myllyla VV.Serum lipid levels during carbamazepine medication: a prospective study. Arch Neurol 1993; 50:590–593.
47. Assmann, G, Funke H. HDL metabolism and atherosclerosis. J Cardiovasc Pharmacol 1990; 16(9): S15–S20.
48. Castelli WP, Garrison RJ,Wilson PW,Abbott RD, Kalousdian S, Kannel WB.Incidence of coronary heart disease and lipoprotein levels. JAMA 1986; 256:2835-2838.
49. Livingston  S. Phenytoin and serum cholesterol. Br Med J 1976; 586–586.
50. Isojarvi JI, Pakarinen AJ, Rautio A, Pelkonen O, Myllyla VV.Liver enzyme induction and serum lipid levels after replacement of carbamazepine with oxacarbazepine. Epilepsia 1994; 35:1217-1220.
51. Pirmohamed M, Kitteringham NR, Breckenridge AM, Park BK. The effect of enzyme induction on the cytochrome P450-mediated bioactivation of carbamazepine by mouse liver microsomes. Biochem Pharmacol 1992; 44:2307-2314.
52. Havel RJ, Kane JP. Structure and metabolism of plasma lipoproteins.In: Secriver CR, Beaudet, A.L., Sly W.S., Valle, D., (eds). The Metabolic and Molecular Basis of Inherited Disease, 7th edn, vol II. New York, McGraw-Hill, 1995; 1841-1851.
53. Deda G, Caksen H, Icagasioglu D. Effect of long term carbamazepine therepy on serum lipids, vitamin B12 and folic acid level in children. J Pediatr Endocrinol Metab 2003; 16:193-196.
54. Yilmaz E, Dosan Y, Gurgoze MK, Gungor S. Serum lipid changes during anticonvulsive treatment in epileptic children. Acta Neurol Belg. 2001; 101:217-220.
55. Nikolaos T, Stylianos G, Chryssoula N, Irini P, Christos M, Dimitrios T, 2004. The effect of long-term antiepileptic treatment on serum cholesterol (TC, HDL, LDL) and triglyceride levels in adult epileptic patients on monotherepy. Med Sci Monit 2004; 10:MT50-MT52.
56. Bramswig S, Sudhop T, Luers C, Von-Bergman K, Berthhold HK. Lipoprotein A concentration increases during treatment with carbamazepine. Epilepsia 2003; 44:457-460.
57. Eiris JM, Rodriguez IN, Rio MD, Mesegaer P, Rio MC, Gago MC. The effects on lipid and apolipoprotein serum levels of long-term carbamazepine, valproic acid and phenobarbital therapy in children with epilepsy. Epilepsy Res 2000; 41:1-7.
58. Dewan P, Aggarwal A, Afaridi MM. Effect of phenytoin and valproic acid therapy on serum lipid level and liver function tests. Indian Pediatrics 2008; 45:855-858.
59. Kaste M, Muuronen A, Nikkila EA, Neuvonen PJ. 1983. Increase of low serum concentrations of high-density lipoprotein (HDL) cholesterol in TIA-patients treated with phenytoin. Stroke 1983; 14:525–530.
60. Mintzer S, Mattson RT. Should enzyme-inducing antiepileptic drugs be considered first-line agents? Epilepsia 2009; 50(8):42–50.
61. Belcastro V, Striano P, Gorgone G, Costa C, et al., Hyperhomocysteinemia in epileptic patients on new antiepileptic drugs. Epilepsia 2010; 5(1):274–279.
62. Svalheim S, Luef G, Rauchenzauner M, Morkrid L, Gjerstad L, Tauboll E, Cardiovascular risk factors in epilepsy patients taking levetiracetam, carbamazepine or lamotrigine. Acta Neurol Scand 2010; 122(190):30–33.
63. Chaung, Y.C., Chaung, H.Y., et al., 2012. Effects of long term antiepileptic drug monotherapy on vascular risk factors and atherosclerosis. Epilepsia 53 (1), 120-128.
64. O’Leary DH, Polak JF, Kronmal RA, et al. Cardiovascular Health Study Collaborative Research Group. Carotidartery intima and media thickness as a risk factor for myocardial infarction and stroke in older adults. N Engl J Med 1999; 340:14–22.
65. Lorenz MW, Kegler S, Steinmetz H. Carotid intima-media thickening indicates a higher vascular risk across a wide age range: prospective data from the Carotid Atherosclerosis Progression Study (CAPS). Stroke 2006; 37:87–92.
66. Silvestrini M, Cagnetti C, Pasqualetti P, et al. Carotid wall thickness and stroke risk in patients with asymptomatic internal carotid stenosis. Atherosclerosis. 2010; 210(2):452-457.
67. Schwaninger M, Ringleb P, Annecke A, et al. Elevated plasma concentrations of lipoprotein(a) in medicated epileptic patients. J Neurol 2000; 247:687–690.
68. Erdemir A, Cullu N, Yis U, et al. Evaluation of serum lipids and carotid artery intima media thickness in epileptic children treated with valproic acid. Brain Dev 2009; 31:713–716.
69. Tan TY, Lu CH, Chaung HY, Lin TK, Liou CW, Chang WN et al., Long term antiepileptic drug therapy contributes to the acceleration of atherosclerosis. Epilepsia 2009; 50(6):1579-1586.
    

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    How to cite this article:

    Khot SS, Shaikh H and G. Lalitkumar: Atherosclerotic risk among Epileptic patients taking Carbamazepine, Phenytoin treatment: A Brief Review. Int J Pharm Sci Res. 2013; 4(3); 900-906.

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