Drugs acting on the central nervous system CNS

The Parkinson's-Reversing Breakthrough

Is There A Cure for Parkinson Disease

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Epilepsy can be explained as communication disorder among nerve cells. The disintegration of the balance of the excitatory and inhibitory stimuli leads to the predominance of excitatory impulses; thus, epileptic fit could occur. In the brain the most important excitatory neurotransmitter is glutamate, while the major inhibitory neurotransmitter is GABA. Thus, increasing GABA or decreasing glutamate can suppress the incidence of fits. TDM is indicated in the treatment of epilepsy since the symptoms of inefficacy (uncontrolled disease) and toxicity can be similar. This is further complicated by the fact that compliance of epileptic patients is not always appropriate [26]. Moreover, epilepsy is one of the most frequently occurring neurological disorder affecting millions of patients worldwide.

Depression is beyond any doubt the major psychiatric disorder that could affect every fifth individual at least once during their lifetime. There are several theories to explain development of depression including the role of noradrenaline, serotonine, acetylcholine, and dysregulation ofneurotransmission. Therefore, anti-depressants have many different and well-defined mechanisms of action such as enhancement of neurotransmitter synthesis, inhibition of neurotransmitter reuptake, monoamino oxidase (MAO) inhibition, antagonism of the activity of presynaptic inhibitory receptors, or increase in the activity of postsynaptic receptors. The reason for TDM in this class of drugs is that the metabolism and elimination show wide interindividual variability; thus, when standard doses are applied the serum concentration is often out of the therapeutic range [27].

The most frequent movement disorders are Parkinson's disease and Huntington chorea. The characteristic features of the former are hypokinetic movements and rigor of the muscles, while of the latter are hyperkinetic movements and hypotension of the muscles. In case of Parkinson's disease, the dopaminerg tracts are damaged in nigrostriatal system, while in Huntington chorea GABAerg neurons are insufficiently functioning, acetylcholine synthesis decreased, dopamine level increased, and the activity of NMDA receptors are enhanced. Thus, influencing dopamine synthesis and/or metabolism is beneficial in Parkinson's disease, while substituting acetylcholine, increasing GABA, antagonizing dopamine, and blocking the activity of NMDA receptors are all therapeutic targets in Huntington chorea. Measuring the correlation of drug concentration and efficacy may improve the benefit from all of these therapies or help to individualize dosing (e.g., in elderly).

MS-based methodology used in the measurement of CNS-acting drugs are shown in Table 4.

Table 4

Applications of MS in the measurement of drugs acting on CNS

Ref. Drug

Comment

[28] Amoxapine, amitriptyline, Citalopram, clomipramine, dothiepin, doxepin, fluoxetine, imipramine, maprotiline, mianserin, paroxetine, sertraline, trimipramine (and some of their respective active metabolites: nortriptyline, monodesmethyl citalopram, desmethylclomipramine, desipramine, norfluoxetine, desmethyl mianserin, N-desmethyl sertraline)

[29] Citalopram (CIT), desmethylcitalo-pram (DCIT)

[30] Midazolam

A special turbulent-flow liquid chromatographic (TFC) technology, coupled with MS-MS to monitor 13 antidepressants and some of their active metabolites in human serum. Such tests are necessary if the drug either is toxic in high concentration or appears ineffective in therapy. Owing to their different chromatographic behavior, the antidepressants are divided into two separate groups (two parallels should be injected to cover the whole range of compounds). Calibration curves have been established for the concentration range of 10-500 ng/ml. No memory effect was observed even after the highest concentration samples. Intraassay and interassay precisions: 0.4-12 and 1-16%, respectively.

A GC-MS technique to elucidate the effect of aging on the steady-state plasma concentrations of citalopram (CIT) and desmethylcitalopram (DCIT). One hundred and twenty-eight depressive patients were treated with 10-80 mg/ day CIT. Patients were divided into three age groups (<64 years, 65-79 years, and >80 years). Despite comparable body mass indices (BMI) and renal and hepatic functions, plasma levels of CIT and DCIT exhibited large variations (16-fold and 12-fold, respectively). When compared to adults, mean plasma concentration of CIT and DCIT was 48% in the oldest age group and 33% higher in the elderly group, which has to be taken into account in their treatment, the dose should be reduced. An HPLC-ESI-MS method simultaneously quantifies midazolam (MDZ) and its major metabolite 1'-hydroxymi-dazolam (1'-OHM) in a small volume (200 p!) of human plasma. Midazolam, 1'-OHM, and 1'-chlordiazepoxide (internal standard) are extracted from plasma samples using liquid-liquid extraction with 1-chlorobutane. The chromatographic separation is performed on a C18 column using as mobile phase water-acetonitrile, 75:25% (v/v), containing formic acid (0.1%, v/v). Protonated molecular ions were detected in the positive-ion mode. Calibration curves are linear (r2 > 0.99) from 15 to 600 ng/ml (MDZ) and 5 to 200 ng/ml (1'-OHM). Limits of detection and quantification: 2 and 5 ng/ml, respectively, for both MDZ and 1'-OHM. Mean relative recoveries at 40 and 600 ng/ml (MDZ): 79.4 and 84.2, respectively; for 1'-OHM at 30 and 200 ng/ml the values were 89.9 and 86.9, respectively. The intraassay and interassay coefficients of variation (CVs) for MDZ were less than 8%, and for 1'-OHM less than 13%.

Table 4 Continued

Ref. Drug Comment

There was no interference from other commonly used antimalarials, antipyretic drugs, and antibiotics. The method was successfully applied in a pharmacokinetic study. An LC-MS-MS technique for pharmacokinetic purposes to monitor drug levels in patients with mild-to-moderate Parkinson's disease treated orally by pergolide. Plasma levels were correlated with the efficacy of the treatment. Steady-state pharmacokinetic profiles and motor score were determined on 14 patients in this dose-escalating study. Typical absorption times: 2-3 h, elimination half-life: ±21 h. The fast absorption and slow elimination presumably help in reducing motor problems in patients with Parkinson's disease.

Chromatographic (LC-MS) and solid-phase extraction (SPE) conditions have been optimized for Clozapine, with cycle times of 2.2 min. Depending on the ionization modes detection limits varied between 0.15 and 0.3 mg/ml. A quadratic calibration curve was found for clozapine and its N-oxide and a linear one for the desmethyl metabolite (R > 0.99 in all cases). Accuracy is better than 10% in the whole therapeutic concentration range. Interassay precision: 5-20% of the standard deviation from the highest to the lowest therapeutic concentrations. Quantitative measurements are possible down to 350 ng/ml.

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