This work was performed to explore the effect of polymorphism in multidrug resistant genes on plasma phenytoin levels and patient outcome to evaluate its involvement in drug resistance and toxicity, which is usually associated with antiepileptic drugs. Therefore, we genotyped the adenosine triphosphate-binding cassette subfamily B member 1 (ABCB1) in 100 patients suffering from partial or generalized tonic-clonic seizures and receiving phenytoin and 50 healthy control subjects. Steady state plasma phenytoin levels were also determined in the epileptic patients. Patients were evaluated after 3 and 6 months and were classified either as drug resistant patients or responsive patients. Results revealed 37 patients with drug responsive epilepsy and 63 patients with drug resistant epilepsy. Genotyping of our patients and control subjects revealed a genotype distribution of CC, CT, TT: 55.50%, 38.00%, 6.50% for drug resistant patients, CC, CT, TT: 13.50%, 46.00%, 40.50% for drug responsive patients, and CC, CT, TT: 24.00%, 48.00%, 28.00% for the control subjects. Patients with drug-resistant epilepsy were more likely to have the CC than the TT genotype compared with either responsive patients (P < 0.0001) or control subjects (P < 0.0001). The C polymorphism was over-represented among patients with drug-resistant epilepsy as compared with either those with drug-responsive epilepsy (P < 0.001) or control subjects (P < 0.001). Of the total 100 epileptic patients, 13 patients had their plasma phenytoin levels exceeding the maximum safe concentration. These 13 patients were more likely to have TT genotype than the CC genotype compared with the remainder of patients who had their plasma phenytoin levels at 20 microg/mL or less. Responsive patients showed no deviation from the control group regarding the genotype (P > 0.05) or allele frequency (P > 0.05). In conclusion, because most of the antiepileptic drugs are multidrug resistant gene substrates, the ABCB1 is thus an important candidate gene for potentially influencing the response to antiepileptic drugs. Our findings suggest that using genotype data may make it possible to safely reduce the time required to reach an effective dose. Therefore, it is a priority to assess the utility of dose adjustment on the basis of genotype for these medicines that are substrates for this gene.
Background Amigrain®, the market formulation of the ternary mixture of analgin, caffeine, and ergotamine is used for the symptomatic treatment of migraine. Objectives The aim of the work is to develop and validate an HPLC- DAD method and a novel spectrophotometric method for simultaneous determination of analgin, caffeine and ergotamine in their pharmaceutical formulation. Method The HPLC separation of the ternary mixture was carried out using an Inertsil -C8 column and a gradient elution of mobile phase composed of “acetonitrile and ammonium format buffer (pH 4.2)”, the UV detection for analgin and caffeine was carried out at λ = 280, 254 nm and fluorometric detection for ergotamine was carried out at λ exc =310 nm, λ emm =360 nm .The two spectrophotometric methods were double divisor ratio spectra derivative (DDRD) and ratio dual wavelength (RDW) methods. The first method was used for determination of ergotamine at 355 nm and caffeine at 268 nm by the third and first derivative. The second one was based on using amplitude difference for the determination of caffeine and analgin. Results HPLC and spectrophotometric methods were applied over the concentration ranges of 50–400, 25–200, and 0.5–10 μg/mL and 10 –35, 2 –30, and 10 –70 μg/mL for analgin, caffeine and ergotamine for the two methods. Conclusion The proposed methods were successfully applied for the determination of the cited drugs in their pharmaceutical formulation and the obtained results were statistically compared with those of the reported methods without any significant difference. Highlights The developed HPLC-DAD method has a high sensitivity for ergotamine. The spectrophotometric methods offer novelty, green solvent usage, and economic cost.
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