Olanzapine therapy in treatment-resistant psychotic mood disorders: a long-term follow-up study.

BACKGROUND: Recent studies suggest a role for the atypical antipsychotic olanzapine in the acute treatment of psychotic mood disorders, but long-term data are unavailable. The purpose of this naturalistic study was to determine the long-term effectiveness and tolerability of olanzapine as add-on therapy in psychotic mood disorders. METHOD: Hospital records were reviewed for 125 inpatients at the state psychiatric hospital in Buffalo, N.Y., who received at least 6 weeks of add-on olanzapine treatment for psychotic mood disorders (schizoaffective disorders [bipolar and depressive type], bipolar disorders [I, II, and NOS], and major depressive disorder). A group of schizophrenic patients served as a control group (N = 50). Baseline measures, including age, gender, number of hospitalizations in the 2 years prior to olanzapine treatment, concomitant medications, the Clinical Global Impressions scale (CGI), and the Global Assessment of Functioning-Equivalent (GAF-EQ) and Kennedy Axis V psychological impairment, violence, social skills, and activities of daily living subscale scores, were obtained. Follow-up information was obtained from the patients at least 6 months after initiation of olanzapine or by chart review and discussion with the treating psychiatrist. Patients with a diagnosis of psychotic mood disorders were compared with patients with the non-affective psychotic disorder (schizophrenia) on a variety of outcome measures. RESULTS: Follow-up information was available on 102 patients (82%). Mean follow-up was 15 months; 50 (49%) of the 102 patients remained on olanzapine treatment at follow-up (32 psychotic mood disorder, 18 schizophrenic). The primary reason for discontinuation in both groups was lack of response. Both the psychotic mood disorder and schizophrenic groups had comparable outcomes on the CGI and GAF-EQ. Improvement on the Kennedy Axis V psychological impairment and social skills subscales was seen only in the psychotic mood disorders group (p < .01); both groups showed significant (p < .02) improvement in the violence subscale. Sustained mood-stabilizing effect was evident in only 7/27 (26%) of the psychotic mood disorders patients continuing on add-on olanzapine treatment at follow-up. CONCLUSION: Lack of response was the primary reason for discontinuation of add-on olanzapine in both groups. Mood symptoms predicted a better response to add-on olanzapine in patients with psychotic mood disorders on selective outcome measures. However, only 26% of the patients with psychotic mood disorders sustained a clinically meaningful mood-stabilizing effect with add-on olanzapine treatment at follow-up.

Paclitaxel and radiotherapy: sequence-dependent efficacy--a preclinical model.

The optimal sequence of a paclitaxel-radiation combination was investigated in vitro in two human colon adenocarcinoma cell lines, HT29 and LoVo. Three schedules of combined treatment were tested by clonogenic and flow cytometric assays. Paclitaxel was given 24 h prior to a single radiation shot (first schedule) or 24 h (second schedule) or 48 h (third schedule) before 3 days of concomitant radiation. Dose-response data were fit to a linear quadratic model, and mean inactivation dose and sensitizer enhanced ratio were calculated. In HT29 cells, the first and second schedule resulted in an additive effect, whereas a supraadditive interaction was observed with the third combination schedule. This effect was obtained with amounts of paclitaxel lower than IC50, which did not result in cell cycle perturbation, and with low radiation dose (2 Gy) that may be given in a clinical setting. LoVo cells were less sensitive to combined treatment than HT29 cells, switching from infraadditive (first and second schedule) to additive interaction (third schedule). Posttreatment recovery studies of third schedule showed a loss of cell survival in HT29 cells but not in LoVo cells. In contrast to LoVo cells, the third schedule in HT29 cells was able to induce perturbation of cell cycle kinetics, an effective impairment of DNA repair, and apoptotic cell death. HT29 and LoVo cells showed constitutional different characteristics: HT29 cells were more sensitive to paclitaxel exposure, less radiosensitive, and had a different cell cycle redistribution after radiation exposure than LoVo cells; moreover, HT29 cells showed a major propensity to undergo apoptosis. These results suggest that the radiosensitizing effect of paclitaxel was strictly schedule dependent, and the inhibition of DNA repair, cell cycle redistribution, and apoptosis could be the mechanisms for the induction of radiosensitization by paclitaxel.

Paclitaxel and N-methylformamide: in vitro interactions in human colon cancer cell line.

The combination of differentiation-inducing agents with conventional antineoplastic drugs has been suggested as a potential new cancer therapeutic approach. We have assayed the cytotoxic effect of N-Methylformamide (NMF) as a differentiating agent combined with Paclitaxel, a novel antineoplastic agent, on cell survival of a human adenocarcinoma cell line HT29. The cell killing of this combination was evaluated by clonogenic assay and cell cycle perturbation was analyzed by flow cytometric methods. HT29 cells were exposed to graded doses of Paclitaxel (0.001-0.01-0.1-1-5 micrograms/ml) for 2, 4, 8, 16, 18 and 24 hours in order to determine its dose-time effect. Secondly, exponentially or non-growing HT29 cells were exposed to graded doses of Paclitaxel (0.001-5 micrograms/ml) for 18 hours at 37 degrees C, and in combination experiments the cells were pre- or posttreated with 1% NMF for 72 hours. The results demonstrated that only proliferating cells were responsive to Paclitaxel and that its cytotoxicity is strictly related to exposure time. The combination studies showed that only the Paclitaxel-->NMF sequence causes a powerful reduction in the surviving fraction of HT29 cells, whereas the reverse sequence had a protective effect on cell killing. The flow cytometry evaluation has indicated that synergism with NMF in HT29 cells was observed only at the same Paclitaxel concentrations required for mitotic arrest, suggesting that the mechanism underlying the synergic interaction was a Paclitaxel-induced alteration of cell cycle kinetics. This study stresses the importance of the administration sequence in the protocols involving NMF as a cytotoxic effect modulator as well as the role of cell kinetics in determining the effectiveness of this modulation.

In vivo unwinding fluorimetric assay as evidence of the damage induced by fenarimol and DNOC in rat liver DNA.

Five pesticides [amitraz, cyanazine, cyhexatin, dinitro-o-cresol (DNOC), and fenarimol] were tested as pure active ingredients for in vivo induction of DNA strand breaks on rat hepatocytes after intraperitoneal (ip) treatment. Two pesticides, fenarimol and DNOC, were capable of inducing DNA damage because they significantly increased the DNA unwinding rate. On the contrary, amitraz, cyanazine, and cyhexatin were not DNA-damaging agents.

Evaluation of genotoxic effects of the herbicide dicamba using in vivo and in vitro test systems.

The genotoxic effects of the herbicide dicamba have been studied by measuring 1) the unwinding rate of liver DNA from intraperitoneally (i.p.) treated rats (fluorimetric assay); 2) DNA repair as unscheduled DNA synthesis (UDS) induced in cultured human peripheral blood lymphocytes (HPBL); and 3) sister chromatid exchanges (SCE) in HPBL. Results show that dicamba is capable of inducing DNA damage since it significantly increases the unwinding rate of rat liver DNA in vivo and also induces UDS in HPBL in vitro in the presence of exogenous metabolic activation (S-9 mix). Furthermore, dicamba causes a very slight increase in SCE frequency in HPBL in vitro.