Neurological agents

Lithium, like alcohol, can influence mood. This was discovered nearly 50 years ago by Cade (468), who was investigating the effects of lithium urate merely because it is a soluble urate salt. Lithium and not urate turned out to be the effective agent. Simple salts such as Li2C03 are widely used (by as many as 1 in every 1000 of the popula- 

Lithium(I) ions are small but strongly hydrated and could interfere with Mg(II) biochemistry. However, the favored mode of action is interference with Ca(II) metabolism via inhibition of enzymes in the inositol phosphate pathways (470-472). Inositol phosphates are responsible for mobilizing Ca(II) inside cells in response to external stimnlii. Lithium also stimulates glutamate release presumably via activation of the AT-methyl-D-asparate receptor and leads to Ca(II) entry (473). The increased influx of intracellular Ca(II) may activate phospholipase C and stimulate accumulation of inositol 1,4,5-triphosphate (473). 

Lithium can selectively inhibit the activity of glycogen synthase kinase-3 6 (GSK-3 ji), an enzyme which regulates cell fate determina- 

Metallothionein was first discovered in 1957 as a cadmium-binding cysteine-rich protein (481). Since then the metallothionein proteins (MTs) have become a superfamily characterized as low molecular weight (6-7 kDa) and cysteine rich (20 residues) polypeptides. Mammalian MTs can be divided into three subgroups, MT-I, MT-II, and MT-III (482, 483, 491). The biological functions of MTs include the sequestration and dispersal of metal ions, primarily in zinc and copper homeostasis, and regulation of the biosynthesis and activity of zinc metalloproteins. 

The recently identified brain-specific isoform of metallothionein, MT-III (neuronal growth inhibitory factor, GIF), has been linked with its potential role in neurophysiological and neuromodulatory functions (484). The human form of MT-III contains 68 amino acids with a 70% sequence (Fig. 23) similarity to other mammalian MTs and a 

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Patients receiving monoamine oxidase inhibitors (MAOI) as antidepressant therapy have been especially subject to the hypertensive effects of vasoactive amines (52). These dietary amines have also been impHcated as causative agents ia migraine. Other aaturaHy occurring alkaloids (qv) have been recognized for centuries as possessing neurological stimulant and depressant properties. 

Another condition involving ceruloplasmin is aceru-loplasminemia. in this genetic disorder, levels of ceruloplasmin are very low and consequently its ferroxidase activity is markedly deficient. This leads to failure of release of iron from cells, and iron accumulates in certain brain cells, hepatocytes, and pancreatic islet cells. Affected individuals show severe neurologic signs and have diabetes mellitus. Use of a chelating agent or administration of plasma or ceruloplasmin concentrate may be beneficial. 

This section will review the phase III clinical trials of IV thrombolytic agents for acute ischemic stroke, organized by the type of agent and the time window from stroke onset to study drug delivery (Table 3.1). The 1995 National Institute of Neurological Disorders and Stroke (NINDS) rt-PA trial is presented first because it showed that IV rt-PA, given within 3 hours of stroke onset, reduced stroke-related disability. This trial was the basis for the United States Food and Drug Administration (FDA) approval for rt-PA for use in acute ischemic stroke. 

Elkind MS, Flint AC, Sciacca RR, Sacco RL. Lipid-lowering agent use at ischemic stroke onset is associated with decreased mortality. Neurology 2005 65 253-258. 

The proposal that NO or its reactant products mediate toxicity in the brain remains controversial in part because of the use of non-selective agents such as those listed above that block NO formation in neuronal, glial, and vascular compartments. Nevertheless, a major area of research has been into the potential role of NO in neuronal excitotoxicity. Functional deficits following cerebral ischaemia are consistently reduced by blockers of NOS and in mutant mice deficient in NOS activity, infarct volumes were significantly smaller one to three days after cerebral artery occlusion, and the neurological deficits were less than those in normal mice. Changes in blood flow or vascular anatomy did not account for these differences. By contrast, infarct size in the mutant became larger... 

A number of azetidine-based compounds have been disclosed in patent applications from Aventis Pharma for CBi-modulated treatment of diseases such as obesity, Parkinson s disease, schizophrenia, respiratory and neurological diseases [330-334]. Compound (556) was specifically claimed for use in two formulation patent applications [330, 331] for a stable semi-solid composition and oral emulsion composition, respectively. The optional coadministration of an agent that activates norepinephrinergic and se-rotoninergic neurotransmission (for example, sibutramine) or dopaminergic neurotransmission was also claimed for the treatment of obesity. The optional use of a dopamine agonist (for example, levodopa) was claimed... 

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