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Abstract
Summary
Epilepsy is a common neurological disease and the prevalence of epilepsy is generally taken as between 5 and 10 cases per 1000 persons, and the overall incidence as about 50 cases per 100.000 persons. The figures are higher in the developing countries. The prevalence of epilepsy in a rural area in Turkey was 10.2 per 1000 while in Saudi Arabia it was 6.6/1000 population. The overall prevalence rate of recurrent non-febrile active epilepsy was 8.85/1000 population in Ismailia governorate.
As a sizeable population is affected by epilepsy, so, its effective management is a matter of concern and patients with epilepsy usually need to take drugs continuously for many years, so avoidance of side-effects is particularly important. Phenytoin is the oldest non sedative antiepileptic drug and is the most effective drug against partial seizures and the generalized tonic-clonic seizures.
A marked amount of clinical observations indicates the existence of an association between the use of antiepileptic drugs and immunological disturbances and/or immunotoxic reactions based on the available evidence the highest risk is associated with the use of phenytoin and carbamazepine
This study was designed to:
Evaluate the probable toxic effect (s) of phenytoin as an antiepileptic drug on some immunologic parameters as indicators to the immune system in patients under the treatment by that drug and to correlate between the drug concentration in hair by hair analysis and its effect (s) on the immune system.
This study was conducted over a period of 12 months on 69 patients (group 1) and 23 healthy persons served as controls (group 2) in Ismailia governorate. The groups of patients were the epileptic patients receiving phenytoin as a treatment for epilepsy in psychiatric and neurological outpatient clinic in Suez Canal University Hospital in Ismailia governorate in a period from 3/2004 to 2/2005.
The first group (1-A): It included 23 epileptic patients who were treated for duration ranged from 6 to 12 months by phenytoin.
The second group (1-B): It included 23 epileptic patients who were treated for duration ranged from 13 to 24 months by phenytoin
The third group (1-C): It included 23 epileptic patients who were treated for duration more than 24 months by phenytoin.
Then the patients inside the groups sub-grouped into patients receiving less than 200 mg/day and equal or more than 200 mg /day of phenytoin.
The control group:
This group included 23 persons ranged of age between 20-45 years and they did not take any drug for chronic use at all, and they were free from any chronic diseases
Evaluation the toxic effects of phenytoin according to three parameters:
1- Evaluation of the natural immunity.
2- Evaluation of the cellular immunity.
3- Evaluated of the humoral mediated immunity.
Evaluation the natural immunity according to:
-Counting of total and differential leucocytic count on blood film.
Evaluation the cellular immunity according to:
-Identification and counting of T-lymphocytes subsets (CD4+ and CD8+) with monoclonal antibodies directed against relevant CD markers by using flow cytometry.
Evaluation the humoral mediated immunity according to:
-Measurement of concentration of serum immunoglobulins (IgG and IgM) by single radial immunodiffusion.
Detection of the phenytoin in hair:
Hair analysis for detection of the drugs has become important in providing evidence of drug use and monitoring over a longer period than conventional testing in blood and urine which reflect the drug use in acute cases so, groups of patients were subjected to:
Detection of the phenytoin in their hair by using colour tests and thin layer chromatography (T.L.C.) and quantification of the phenytoin concentration in hair by using High Performance Liquid Chromatography (H.P.L.C.)
In the present study, the results revealed that patients of (group 1-A) showed a decrease in the mean of total leucocytic count when compared to control group but that decrease remains within the normal values and with increasing the period of administration in groups and 1-B and 1-C there was a significant decrease in mean total leucocytic count when compared to control group and group 1-A of patients. These results meaning that the decrease in total leucocytic count is time dependent in epileptic patients under phenytoin treatment. Also the decrease in total leucocytic count was dose dependent as it was highly significant in group of patients receiving equal or more than 200 mg/day of phenytoin when compared to control group.
The results concluded that the phenytoin administration has a suppressor effect on the differential leucocytic count where it cause a significant decrease in the mean lymphocytic count in groups 1-A, -1-B and group 1-C of patients when compared to control group . and it cause a significant decrease in the mean neutrophils count in groups 1-B and group 1-C of patients when compared to control group .The reduction of the differential leucocytic count was affected only in high dose of phenytoin (≥ 200mg of phenytoin daily) as the total number of the neutrophils, lymphocytes and monocytes were decreased and it was statistically significant when compared to control group
The results revealed that the mean serum concentration of the IgM titer was decreased in all groups of patients, the groups 1-A and 1-B of patients showed a significant decrease when compared to control group while the group 1-C of patients showed a significant decrease in the IgM titer in comparison to control group and groups 1-A and group 1-B.
The present study showed that IgG titer was decreased in all groups of patients, The decrease in the group 1-A and 1-B was little with no significance while in group 1-C, the IgG titer was significantly decrease when compared to control group or groups 1-A and 1-B of patients , this reduction was more significant in patients receiving more than 200 mg/day of phenytoin when compared to control group. The results indicated that the effect of phenytoin administration on Igs is not only time dependent but also dose dependent, while in the group of patients who receiving equal or more than 200 mg/day showed a more significant decrease in IgM and IgG titer.
In the present study the results revealed that there were a significant decrease in mean of CD4+ percentage in all group of patients in comparison to control group and both groups 1-B and 1-C showed a significant decrease in its percentage in comparison to group 1-A, these meaning that the decrease is time dependent and demonstrating the pronounced effect of the drug, this reduction was more significant in patients receiving equal or more than 200 mg/day of phenytoin when compared to control group.
The study revealed that the mean of the percentage of CD8+ showing a significant increase in all groups of patients in comparison to control group while the figure in both group 1-B and 1-C are apparently the same both group 1-B and 1-C showed a significant decrease in comparison to group 1-A.
The mean of CD4+/CD8+ ratio was significantly decreased in group 1-A and 1-B and 1-C in comparison to control, this reduction was significant in patients receiving equal or more than 200 mg/day of phenytoin when compared to control group.
The results indicated that the decrease in the CD4+ percentage and mean of CD4+/CD8+ percentage was dose dependent especially in group of patients who had been received equal or more than 200 mg of phenytoin daily who showed highly significant decrease in CD4+ percentage and CD4+/CD8+ ratio compared to control group.
The results of detection of phenytoin in human hair revealed that, by T.L.C. phenytoin was present in all hair samples. Zwikker’s reagent and the dithiazone reagent were used to spray the plates. It gave obvious and stable colours (blue violet and yellow to orange respectively), stand for a very long time for phenytoin when the eluent was methanol to chloroform 1:9. By HPLC, phentoin was present in all hair samples at concentrations ranged from 4.3 to 9.5 ng /mg in hair samples with a retention time 6.16 min when the mobile phase was acetonitrile 70% to methanol 30%.
In this study the results revealed that the phenytoin has been detected at mean concentrations of 4.3 to 9.5 ng /mg after administration of 100-300 mg/day of phenytoin respectively for months. These concentrations correlated with different daily doses. The results show an excellent linear correlation between the drug concentrations in human hair and increasing daily doses.
The results indicated that the reduction of total leucocytic count was concentration dependent (according to HPLC readings) as it was statistically significant with concentrations 6.5, 7 and 9.5 ng/mg of phenytoin in hair.
The results indicated that the reduction of serum IgM titer was concentration dependent (according to HPLC readings) as it was significantly decrease with concentrations 6.5, 7 and 9.5 ng/mg than IgG titer which significantly decreased with concentration of 9.5 ng /mg phenytoin only .
The results indicated that the reduction of mean of CD4+ and CD4+/CD8+ ratio was concentration dependent (according to HPLC readings) in phenytoin treated patients as it was significant with concentrations 6.5, 7 and 9.5 ng/mg of phenytoin when compared to control group. The mean of CD8+ was significantly increased with concentrations 7 and 9.5ng/mg of phenytoin when compared to control group.
The present results recommended that Patients with immunosuppression under the effect of phenytoin must change the prescribed dose or shift to another antiepileptic drug under the supervision of their physicians especially when the duration of treatment is long with a high dose. While all of immunotoxic test are expensive, the measurement of concentration of immunoglobulins considered economic, simple and sensitive so, we recommend doing that evaluation periodically for the epileptic patients.