Metoclopramide and homicidal ideation: a case report and literature review.

BACKGROUND: Metoclopramide is an anti-emetic and gastrointestinal pro-motility agent associated with well-known neuropsychiatric adverse effects, such as dyskinesia, akathisia, and depression. It has never been reported to be associated with homicidal ideation. OBJECTIVE: The authors review the literature on metoclopramide-induced adverse neuropsychiatric reactions and the mechanisms by which these may occur. METHODS: The authors present a case report of a patient who developed anxiety, agitation, suicidal and homicidal ideation following brief exposure to metoclopramide. RESULTS: The adverse effects of agitation and homicidal ideation were temporally related to the starting and stopping of metoclopramide. The patient subsequently developed agitation without homicidal ideation when given a serotonergic antidepressant a week later, suggesting that serotonin handling may have played a significant role in causing the patient's symptoms. CONCLUSIONS: Although metoclopramide is well-known for its side effects related to dopamine blockade, its action at 5-HT3 and 5-HT4 receptors may also be clinically significant in the genesis of neuropsychiatric side effects, especially related to mood and behavior.

Polar 3-alkylidene-5-pivaloyloxymethyl-5'-hydroxymethyl-gamma-lactones as protein kinase C ligands and antitumor agents.

A series of DAG-lactones with polar 3-alkylidene substituents have been investigated as PKC-alpha ligands and antitumor agents. Extensive analysis of structure-activity relationships for the 3-alkylidene chain revealed that polar groups such as ether, hydroxyl, aldehyde, ester, acyloxy, and amido were tolerated with similar binding affinities and reduced lipophilicities compared to the corresponding unsubstituted alkylidene chain. Among the derivatives, compounds 5, 6 and 8 with an ether type of side chain showed high binding affinities in range of K(i)= 3-5 nM and excellent antitumor profiles, particularly against the colo205 colon cancer and the K562 leukemia cell lines.

Conformationally constrained analogues of diacylglycerol. 29. Cells sort diacylglycerol-lactone chemical zip codes to produce diverse and selective biological activities.

Diacylglycerol-lactone (DAG-lactone) libraries generated by a solid-phase approach using IRORI technology produced a variety of unique biological activities. Subtle differences in chemical diversity in two areas of the molecule, the combination of which generates what we have termed "chemical zip codes", are able to transform a relatively small chemical space into a larger universe of biological activities, as membrane-containing organelles within the cell appear to be able to decode these "chemical zip codes". It is postulated that after binding to protein kinase C (PKC) isozymes or other nonkinase target proteins that contain diacylglycerol responsive, membrane interacting domains (C1 domains), the resulting complexes are directed to diverse intracellular sites where different sets of substrates are accessed. Multiple cellular bioassays show that DAG-lactones, which bind in vitro to PKCalpha to varying degrees, expand their biological repertoire into a larger domain, eliciting distinct cellular responses.

Conformationally constrained analogues of diacylglycerol (DAG). 27. Modulation of membrane translocation of protein kinase C (PKC) isozymes alpha and delta by diacylglycerol lactones (DAG-lactones) containing rigid-rod acyl groups.

Highly rigid and geometrically well-defined rods composed of ethynylene-substituted aromatic spacers [oligo(p-phenyleneethynylene), OPE] were incorporated as acyl moieties on diacylglycerol lactones (DAG-lactones) and investigated for their ability to bind to protein kinase C (PKC) and translocate PKC alpha and delta isoforms to plasma and internal membranes. The kinetics of PKC translocation were correlated with biological responses, viz. ERK phosphorylation, induction of IL-6 secretion, inhibition of cell proliferation, and induction of cellular attachment, that display very different time courses. Because OPE rods assemble through noncovalent forces and form stable films, they may influence the microdomain environment around the DAG-lactone membrane-binding site. A comparison of two DAG-lactones (1 and 10), one with two PE units (1) and the other with an equivalent flexible acyl chain (10) of matching lipophilicity, clearly demonstrated the effect of the rigid OPE chain in substantially prolonging the translocated state of both PKC alpha and delta.

Tumor-directed radiation and the immunotoxin SS1P in the treatment of mesothelin-expressing tumor xenografts.

PURPOSE: Mesothelin is a cell surface protein overexpressed in mesotheliomas and pancreatic and ovarian cancers. The goal of this study was to determine if radiation therapy in combination with the antimesothelin immunotoxin SS1(dsFv)PE38 (SS1P) would result in enhanced antitumor activity against mesothelin-expressing xenografts in nude mice. EXPERIMENTAL DESIGN: Female athymic nude mice bearing s.c. mesothelin-expressing xenografts were treated with SS1P alone, tumor-focused radiation alone, or the combination of the two. Two different regimens of the combination therapy were tested. In the low-dose combination schedule, mice were treated with either 5 Gy radiation alone, 0.2 mg/kg SS1P alone, or the same doses of radiation and SS1P in combination. In the high-dose combination experiments, mice were treated with either 15 Gy radiation alone, 0.3 mg/kg SS1P alone, or the combination of radiation and SS1P. RESULTS: In the low-dose radiation and SS1P combination studies, mice treated with the combination of radiation and SS1P had a statistically significant prolongation in time to tumor doubling or tripling compared with control, SS1P, or radiation alone. A similar increase in time to tumor doubling or tripling was seen in mice treated with high-dose radiation and SS1P combination. CONCLUSIONS: Combination of SS1P with tumor-directed radiation results in enhanced antitumor activity against mesothelin-expressing tumor xenografts. This effect was seen when either low or high doses of radiation were used.