Therapeutically relevant concentration

Recent studies have demonstrated that lithium (and to a lesser extent VPA) produces, at therapeutically relevant concentrations, complex alterations in basal and/or stimulated DNA-binding of 12-o-tetradecanoyl-phorbol 13-acetate (TPA) response element (TRE) to AP-1 transcription factors. These alterations are produced not only in human SH-SY5Y cells in vitro, but also in rodent brain following chronic, in vivo administration [5, 7, 15-21]. Corresponding to an increase in basal AP-1 DNA-binding activity, lithium and VPA have been shown to increase the expression of a luciferase reporter gene driven by an SV40 promoter that contains TREs in a time- and concentration-dependent fashion. Mutations in the TRE... 

In view of bcl-2 s major neuroprotective and neurotrophic roles, a study was undertaken to determine if lithium, administered at therapeutically relevant concentrations, affects neurogenesis in the adult rodent brain. To investigate the effects of chronic lithium on neurogenesis, mice were treated with therapeutic lithium (plasma levels 0.97 0.20 mM), for 4 weeks. After treatment with lithium for 14 days, the mice were administered single doses of BrdU (bromodeoxyuridine, a thymidine analog which is incorporated into the DNA of dividing cells) for 12 consecutive days. Lithium treatment continued throughout the duration of the... 

Evidence accumulating from various laboratories has clearly demonstrated that lithium, at therapeutically relevant concentrations, exerts significant effects on the PKC signaling cascade. Current data suggest that chronic lithium attenuates PKC activity, and down-regulates the expression of PKC isozymes V in the frontal cortex and hippocampus [79, 80], Chronic lithium has also been demonstrated to dramatically reduce the hippocampal levels of a major PKC substrate, myristoylated-alanine-rich C kinase substrate (MARCKS), which has been implicated in regulating long-term neuroplastic events. 

Li+, at therapeutically relevant concentrations, is a potent inhibitor of norepinephrine-stimulated adenylate cyclase activity ex vivo in both rat [133] and human brain [134], and it inhibits norepinephrine-stimulated cAMP accumulation in Li+-treated patients. Li+ also inhibits dopamine-stimulated cAMP accumulation in rat brain [135]. These inhibitory effects of Li+ have been shown to be region specific within rat brain, a fact that has obvious significance for a therapeutic mechanism of action. It is interesting that other antimanic drugs may also have dampening effects on dopaminergic neurotransmission. 

The anticonvulsant properties of the drug would appear to be due to its ability to inhibit fast sodium channels, which may be unrelated to its psychotropic effects. Like lithium, it has been shown to decrease the release of noradrenaline and reduce noradrenaline-induced adenylate cyclase activity unlike lithium, it seems to have little effect on tryptophan or 5-HT levels in patients at therapeutically relevant concentrations. It also reduces dopamine turnover in manic patients and increases acetylcholine... 

M) for plasma proteins than for their specific binding sites (receptors). In the range of therapeutically relevant concentrations, protein binding of most drugs increases linearly with concentration (exceptions salicylate and certain sulfonamides). 

As with several other AEDs, it is difficult to ascribe a single mechanism of action to valproic acid. This compound has broad anticonvulsant activity, both in experimental studies and in the therapeutic management of human epilepsy. Valproic acid has been shown to block voltage-dependent sodium channels at therapeutically relevant concentrations. In several experimental studies, valproate caused an increase in brain GABA the mechanism was unclear. There is evidence that valproate... 

In recent years, research on the molecular mechanisms underlying lithium s therapeutic effects has focused on intracellular second messenger generating systems and, in particular, receptor-coupled hydrolysis of phosphoinositide 4,5-biphosphate (PIP2) (Baraban et al. 1989). Lithium, at therapeutically relevant concentrations in the brain, is a potent inhibitor of the intracellular enzyme, inositol monophosphatase [Kj = 0.8 mM), which plays a major role in... 

Ethosuximide has an important effect on Ca2+ currents, reducing the low-threshold (T-type) current. This effect is seen at therapeutically relevant concentrations in thalamic neurons. The T-type calcium currents are thought to provide a pacemaker current in thalamic neurons responsible for generating the rhythmic cortical discharge of an absence attack. Inhibition of this current could therefore account for the specific therapeutic action of ethosuximide. 

In cell culture preparations, diphenylhydantoin, carbamazepine and valproate have been shown to reduce membrane excitability at therapeutically relevant concentrations. This membrane-stabilizing effect is probably due to a block in the sodium channels. High concentrations of diazepam also have similar effects, and the membrane-stabilizing action correlates with the action of these anticonvulsants in inhibiting maximal electroshock seizures. Intracellular studies have shown that, in synaptosomes, most anticonvulsants inhibit calcium-dependent calmodulin protein kinase, an effect which would contribute to a reduction in neurotransmitter release. This action of anticonvulsants would appear to correlate with the potency of the drugs in inhibiting electroshock seizures. The result of all these disparate actions of anticonvulsants would be to diminish synaptic efficacy and thereby reduce seizure spread from an epileptic focus. 

Chemical PEs have recently been studied for increasing transdermal delivery of ASOs or other polar macromolecules [35]. Chemically induced transdermal penetration results from a transient reduction in the barrier properties of the stratum corneum. The reduction may be attributed to a variety of factors such as the opening of intercellular junctions due to hydration [36], solubilization of the stratum corneum [37, 38], or increased lipid bilayer fluidization [39, 40]. Combining various surfactants and co-solvents can be used to achieve skin penetration, purportedly resulting in therapeutically relevant concentrations of ASO in the viable epidermis and dermis [41]. In summary, it appears feasible to deliver ASO to the skin using a number of different delivery techniques and formulations. 

Other compounds producing some inhibition of ZDV conjugation were oxazepam, salicylic acid, and acetylsalicyclic acid. More recently, Trapnell et al. examined the inhibition of ZDV at a more relevant concentration of 20 pM in bovine serum albumin (BSA)-activated microsomes by atovaquone, methadone, fluconazole, and valproic acid at therapeutically relevant concentrations (127). Both fluconazole and valproic acid inhibited ZDV glucuronidation by more than 50% at therapeutic concentrations. Clinical interaction studies have been conducted with methadone, fluconazole, naproxen, probenecid, rifampicin, and valproic acid (see Table 10). 

Dopamin and phenazopyridine in therapeutically relevant concentrations can produce elevated bilirubin levels. Toxical concentration of indomethacin, oxytetracylin and pyritinol may cause an increase of bilirubin values. 

Effect is indicated by +. ++, effective , inconsistent data NE, not effectivein therapeutically relevant concentrations , no data available (or found). Data are from Refs. 76, 77. 

Like ethosuximide, dimethadione inhibits T-type Ca + currents in dissociated thalamic neurons in therapeutically relevant concentrations. This provides a plausible explanation of the anti-absence seizure effects of trimethadione. 

The clinical efficacy of lithium in the prophylaxis of recurrent affective episodes in bipolar disorder is characterized by a lag in onset and remains for weeks to months after discontinuation. Thus, the long-term therapeutic effect of lithium likely requires reprogramming of gene expression. Protein kinase C and GSK-3 signal transduction pathways are perturbed by chronic lithium at therapeutically relevant concentrations and have been implicated in modulating synaptic function in nerve terminals (84). 

D. Dobrev and U. Ravens, Therapeutically relevant concentrations of neomycin selectively inhibit P-type Ca2+ channels in rat striatum, Eur. J. Pharmacol, 461 (2003) 105-111. 

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