--These results suggest the A1 allele of the DRD2 gene is associated with a number of behavior disorders in which it may act as a modifying gene rather than as the primary etiological agent.

BackgroundBevacizumab is an exogenous inhibitor which inhibits the biological activity of human VEGF. Several studies have investigated the effectiveness of bevacizumab therapy according to different cancer types but these days there is an intense debate on its utility. We have investigated different methods to find the best tumor volume estimation since it creates the possibility for precise and effective drug administration with a much lower dose than in the protocol.Materials and MethodsWe have examined C38 mouse colon adenocarcinoma and HT-29 human colorectal adenocarcinoma. In both cases, three groups were compared in the experiments. The first group did not receive therapy, the second group received one 200 μg bevacizumab dose for a treatment period (protocol-based therapy), and the third group received 1.1 μg bevacizumab every day (quasi-continuous therapy). Tumor volume measurement was performed by digital caliper and small animal MRI. The mathematical relationship between MRI-measured tumor volume and mass was investigated to estimate accurate tumor volume using caliper-measured data. A two-dimensional mathematical model was applied for tumor volume evaluation, and tumor- and therapy-specific constants were calculated for the three different groups. The effectiveness of bevacizumab administration was examined by statistical analysis.ResultsIn the case of C38 adenocarcinoma, protocol-based treatment did not result in significantly smaller tumor volume compared to the no treatment group; however, there was a significant difference between untreated mice and mice who received quasi-continuous therapy (p = 0.002). In the case of HT-29 adenocarcinoma, the daily treatment with one-twelfth total dose resulted in significantly smaller tumors than the protocol-based treatment (p = 0.038). When the tumor has a symmetrical, solid closed shape (typically without treatment), volume can be evaluated accurately from caliper-measured data with the applied two-dimensional mathematical model.ConclusionOur results provide a theoretical background for a much more effective bevacizumab treatment using optimized administration.

Voltage gated sodium channels play important roles both in vital physiological functions and several pathological processes of the central nervous system. Epilepsy, chronic pain, neurodegenerative diseases, and spasticity are all characterized by an over-excited state of specific groups of central neurons that is accompanied by an abnormally increased activity of sodium channels. An efficient strategy of controlling such diseases is to use blockers that preferentially act on these over-excited cells. State dependently acting agents, such as phenytoin, or lamotrigine, leave normal physiological functions relatively intact, resulting in a favorable therapeutic window. Nine isoforms of the channel forming alpha subunit are known, which show distinct expression patterns in different tissues. Another possible way to decrease the chance of adverse effects is to develop agents selectively inhibiting the channel subtype involved in the pathomechanism of the disease to be treated. Many recent patents claim sodium channel blockers with improved characteristics regarding state dependency or subtype selectivity. Such agents may offer a breakthrough in the treatment of a variety of central nervous system diseases. This review focuses on the current trends in sodium channel research, surveying the traditional and newly emerging therapeutic fields, and the diverse medicinal chemistry of sodium channel blockers.

The spinal reflex depressant mechanism of tolperisone and some of its structural analogs with central muscle relaxant action was investigated. Tolperisone (50 -400 M), eperisone, lanperisone, inaperisone, and silperisone (25-200 M) dose dependently depressed the ventral root potential of isolated hemisected spinal cord of 6-day-old rats. The local anesthetic lidocaine (100 -800 M) produced qualitatively similar depression of spinal functions in the hemicord preparation, whereas its blocking effect on afferent nerve conduction was clearly stronger. In vivo, tolperisone and silperisone as well as lidocaine (10 mg/kg intravenously) depressed ventral root reflexes and excitability of motoneurons. However, in contrast with lidocaine, the muscle relaxant drugs seemed to have a more pronounced action on the synaptic responses than on the excitability of motoneurons. Whole-cell measurements in dorsal root ganglion cells revealed that tolperisone and silperisone depressed voltage-gated sodium channel conductance at concentrations that inhibited spinal reflexes. Results obtained with tolperisone and its analogs in the [3 H]batrachotoxinin A 20-␣-benzoate binding in cortical neurons and in a fluorimetric membrane potential assay in cerebellar neurons further supported the view that blockade of sodium channels may be a major component of the action of tolperisone-type centrally acting muscle relaxant drugs. Furthermore, tolperisone, eperisone, and especially silperisone had a marked effect on voltagegated calcium channels, whereas calcium currents were hardly influenced by lidocaine. These data suggest that tolperisonetype muscle relaxants exert their spinal reflex inhibitory action predominantly via a presynaptic inhibition of the transmitter release from the primary afferent endings via a combined action on voltage-gated sodium and calcium channels.2-Methyl-1-(4-methylphenyl)-3-(1-piperidinyl)-1-propanone hydrochloride (tolperisone) is an old, centrally acting muscle relaxant drug that is mainly used for treating muscle spasticities of neurological origin and painful muscle spasms due to rheumatologic conditions. Besides being an effective antispastic agent (Pratzel et al., 1996;Dulin et al., 1998), tolperisone also has analgesic activity in rodents (Sakaue et al., 2004) and in humans (Svensson et al., 2003). It possesses relatively few side effects in humans (Dulin et al., 1998). Other propiophenone muscle relaxants include 1-(4-ethylphenyl)-2-methyl-3-(1-piperidinyl)-1-propanone hydrochloride (eperisone), which is also a registered drug (Bose, 1999), and (Ϫ)-2-(R)-methyl-3-(1-pyrrolidinyl)-1-[4-(trifluoromethyl)phenyl]-propanone hydrochloride (lanperisone; Sakitama et al., 1997) and 1-(4-ethylphenyl)-2-methyl-3-(1-pyrrolidinyl)-1-propanone hydrochloride (inaperisone; Morikawa et al., 1992), two agents that had been tested in human phase III studies but not introduced into the clinical practice. 1-[(4-Fluorobenzyl)dimethylsilylmethyl]piperidine hydrochloride (silperisone), a sila analog of tolperisone (Farkas et ...

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