Acting on the Central Nervous System CNS

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 of neurotransmission. Therefore, antidepressants 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]. 

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

An HPLC-ESI-MS method simultaneously quantifies midazolam (MDZ) and its major metabolite T-hydroxymi-dazolam (T-OHM) in a small volume (200 p,l) of human plasma. Midazolam, T-OHM, and T-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 (r 0.99) from 15 to 600 ng/ml (MDZ) and 5 to 200 ng/ml (T-OHM). Limits of detection and quantification 2 and 5 ng/ml, respectively, for both MDZ and T-OHM. Mean relative recoveries at 40 and 600 ng/ml (MDZ) 79.4 and 84.2, respectively for T-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 T-OHM less than 13%. 

There was no interference from other commonly used anti-malarials, 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 mUd-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 ehmination presumably help in reducing motor problems in patients with Parkinson s disease. 

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Pirsidomine 135 has antiischaemic and antianginal properties, and is similar in action to molsidomine, undergoing bioactivation in vivo to compound 136 <1996MI4937>. Sydnocarb (mesocarb) 59 acts on the central nervous system (CNS) and has been used as a psychotropic drug and antidepressant <2004CHE507>. 

Lindane in 1) cream, lotion and shampoo formulations is also used as a parasiticide and ovacide (Kwell) in the treatment of lice (ref. 92, p. 1446). Lindane has a local irritant action and can be absorbed dermally. Acute toxicity in humans may occur by all exposure routes ingestion, inhalation or dermal (ref. 97). All isomers of BHC act on the central nervous system (CNS), but not identically the gamma and... 

This complex barrier has to be crossed by drag molecules via passive diffusion or active transport in order to reach the brain compartment This is required for all drags acting on the central nervous system (CNS). The degree of uptake into the CNS or CSF can be quite different despite the similar mechanism involved in diffusion. This can be explained by the much greater surface of the blood-brain membrane compared to the surface of CSF and/or the existence of specific carrier proteins in the CNS. 

Drugs and chemicals are known to cause activated interaction. The depressant action of opioid drugs is enhanced by drugs acting on the central nervous system (CNS) such as alcohol, anesthetics, anxiolytics, hypnotics, tricyclic antidepressants, and antipsychotics. Concomitant administration of opioid analgesics and monoamine oxidase inhibitors (MAOIs) should be avoided, or extra care should be taken if such a therapy is inevitable. Fatal reactions are reported when treated along with selegiline. Interactions also are reported with cyclizine, cimetidine, mexiletine, cisapride, metoclopramide, or domperidone. 

Dextromethorphan is the methylated dextro-isomer of levorphanol. Unlike the L-isomer, it has no analgesic properties. Dextromethorphan acts on the central nervous system (CNS) to elevate the cough threshold. It retains only the antitussive activity of other morphine derivatives. Administration of dextromethorphan may be associated with histamine release. Dextromethorphan is often present in multisymptom products with a combination of ingredients. Toxic effects of concurrent agents such as antihistamines, decongestants, analgesics, and/or alcohol may be exhibited. 

Three major areas of drug research and development which have undergone considerable changes in recent years include cardiovascular agents, drugs acting on the central nervous system (CNS) and antimicrobial agents. 

The therapy class of a drug can play a role in determining its physical properties, especially where there are specific permeability requirements. Thus drugs that act on the central nervous system (CNS) have to cross the blood-brain barrier and have lower and mol. wt than their non-CNS... 

Mode of action. Amfetamine acts by releasing noradrenaline (norepinephrine) stored in nerve endings in both the CNS and the periphery. As with all drugs acting on the central nervous system, the psychological effects vary with mood, personality and environment, as well as with dose. 

L. inflata L. is a traditional medicinal plant native to North America. It contains several piperidine alkaloids. The main alkaloid is lobeline which has a stimulatory effect on the respiratory center and it is applied in the cases of asthma, gas- and narcotic-poisoning. Thus, lobeiine is currently the subject of renewed interest for the treatment of drug abuse and neurological disorders, like Alzheimer s or Parkinson s disease, which pose an important public health problem in industrial countries. As lobeiine can act as a competitive nicotinic receptor antagonist, it is frequently used in antismoking preparations. Interest in Lobelia alkaloids, and in particular (-)-lobeline, the most active of them, has increased in recent years due to their activity on the central nervous system (CNS). 

Other channel and receptor systems in neuronal tissues have been proposed to play a role in the generation of compound-specific clinical symptoms in mammals. The complex nature of the effects of pyrethroids on the central nervous system (CNS) has led various workers to suggest that they also act via modulation of nicotinic cholinergic transmission, reduce peripheral presynaptic adrenoceptor sensitivity [23] which leads to an enhancement of noradrenaline release [24], and affect the serotonin neurotransmission [25]. However, because neurotransmitter-specific pharmacological agents offer only poor or partial protection against poisoning, it is unlikely that any one of these effects represents an alternative primary mechanism of action of the pyrethroids. 

Analgesics are divided into two groups opioids (morphine-like substances), which predominantly influence the central nervous system (CNS) and nonopioids (nonsteroidal antiinflammatory or fever-reducing drugs—NSAID), which act predominantly on the peripheral nervous system. 

Synthetic drugs of comparable selectivity and affinity to the 1,4-dihydropyridines do not yet exist for the other channel types, T, N, P/Q, and R these remain characterized by complex polypeptide toxins of the aga- and conotoxin classes. Neuronal pharmacology, including that of the central nervous system (CNS), is dominated by the N, P/Q, and R channels. This underscores the normally weak effect of L-channel antagonists on CNS function. Drugs that act at the N, P, and R channels with comparable selectivity and affinity to the 1,4-dihydropyridines may be expected to offer major potential for a variety of CNS disorders, including neuronal damage and death from ischemic insults. 

CNS agents of the 1,4 benzodiazepine class presumably exert their effects by binding at stereo specific receptors at several sites within the central nervous system (CNS). Alprazolam like other benzodiazepines exerts its anxiolytic action by potentiating GABA activity. GABA is a neurotransmitter which inhibits the CNS activity. Alprazolam acts preferentially in midbrain, ascending reticular formation (which maintains wakefulness) and on limbic system (thought and mental functions). 

Since the first description of glial cells, Camillo Golgi (1843-1926) and Santiago Ramon y Cajal (1852-1934) recognized that astrocytes are located in strategic positions between neurons and capillaries to act as a conduit for signals between different cells types in the central nervous system (CNS Ramon y Cajal, 1899). Later on, examination of the nervous system at the ultrastructural level has shown that astrocytes can be intimately associated with synapses, literally enwrapping many pre- and postsynaptic terminals. For instance, in the hippocampus, 57% of the axon-spine interfaces are associated with astrocytes (Ventura and Harris, 1999). It is likely that this close physical relationship provides an opportunity for many functional interactions between astrocytes and neurons. 

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