School refusal and depression with school inattendance in children and adolescents: comparative assessment between the Children's Depression Inventory and somatic complaints.

School refusal has become a relatively common problem of increasing magnitude in Japan. Although clarification of the relationship between 'school refusal' and 'depression with school inattendance' is crucial in light of the difference in treatment modalities involved, it is not clear whether the two are to be regarded along the same tangent or as disparate entities. For clarification, a comparison was made between clinical diagnosis, Children's Depression Inventory (CDI) scores, and scores for the three subordinate scales of the CDI in 34 cases of school refusal, 10 cases of depression with school inattendance, and normal students. Significant difference in CDI score was noted between the three groups: highest among depression cases, followed by school refusers, and lowest in normal students. A larger proportion of school refusers expressed somatic complaints together with low CDI scores. The typical case of school refusal appears to exhibit somatic complaints in the foreground rather than depression, both clinical characteristics and CDI scores indicate school refusal and depression to be separate entities. Although many approaches are being taken in the treatment of school refusal, the results appear to justify primacy of the psychotherapeutic approach with the possible adjuvant use of pharmacological agents, for the phenomenon as it presents in Japan.

Inhibition of multidrug resistance by a new staurosporine derivative, NA-382, in vitro and in vivo.

The effects of a newly synthesized compound, N-ethoxycarbonyl-7-oxo-staurosporine (NA-382), on multidrug resistance in tumor cells were investigated. Protein kinase-inhibitory activity of NA-382 was lower but more selective to Ca2+/phospholipid-dependent protein kinase than that of staurosporine. NA-382 at noncytotoxic concentrations effectively reversed in vitro multidrug resistance of Adriamycin-resistant P388 (P388/ADR) cells, without influencing the drug sensitivity of sensitive P388 cells. NA-382 inhibited extrusion of vinblastine (VBL) and increased intracellular accumulation of VBL, more in P388/ADR cells than in sensitive P388 cells, with higher potency than staurosporine. This compound also reduced VBL resistance of other multidrug-resistant cell lines, AH66 and K562/ADR, by inhibiting VBL efflux and promoting VBL accumulation. NA-382 also dose dependently potentiated the effects of VBL and Adriamycin in P388/ADR-bearing mice. The toxicity of staurosporine was too high to use the combination with VBL in vitro and in vivo. NA-382 accumulated VBL in P388/ADR cells even after desensitization of Ca2+/phospholipid-dependent protein kinase by treatment with 12-O-tetradecanoylphorbol-13-acetate and 18 h, while being suppressed by 12-O-tetradecanoylphorbol-13-acetate added simultaneously or shortly before NA-382. Both staurosporine and NA-382 inhibited the photolabeling of [3H]azidopine on M(r) 140,000 P-glycoprotein in the plasma membrane from P388/ADR cells. These results indicate that this new staurosporine analogue, NA-382, reverses multidrug resistance by directly inhibiting the drug binding to P-glycoprotein, but not by Ca2+/phospholipid-dependent protein kinase inhibitory action.

Effect of staurosporine derivatives on protein kinase activity and vinblastine accumulation in mouse leukaemia P388/ADR cells.

Inhibition by staurosporine derivatives of cyclic AMP-dependent protein kinase (A-kinase) and protein kinase C (C-kinase), and drug resistance has been investigated. The substitution of an acetyl or an ethoxycarbonyl group for the amine N-ethoxycarbonyl-7-oxostaurosporine moiety on the tetrahydropyran ring of staurosporine decreased inhibition of both protein kinases, but increased selectivity for C-kinase by further modification of the lactam moiety to the imide (NA-382). The activities of SF-2370 on protein kinases were decreased by decarboxylation and hydroxyalkylation. These staurosporine derivatives enhanced accumulation of vinblastine in adriamycin-resistant P388 (P388/ADR) cells in a dose-dependent manner. The potency for the drug accumulation of these compounds was correlated with their inhibitory activity on the drug efflux, but was not correlated with their activity on protein kinases. Staurosporine and NA-382, with high potency for vinblastine accumulation, inhibited the photolabelling of [3H]azidopine on 140 kDa P-glycoprotein in the plasma membrane. The tetrahydrofuran compounds and NA-357, which had low potency for the drug accumulation, hardly interacted with azidopine on P-glycoprotein. Most of these compounds were highly cytotoxic by themselves, and only NA-382 was less cytotoxic among them and completely reversed the vinblastine-resistance of P388/ADR cells at a non-cytotoxic concentration. These results suggest that staurosporine derivatives can enhance drug accumulation and inhibit drug resistance through their direct action on the P-glycoprotein.

Sensitivity to antitumor drugs and vinblastine binding to membrane in rat ascites hepatoma AH66 cells.

Rat ascites hepatoma AH66 cells have lower sensitivity to Vinca alkaloids and anthracycline antibiotics than AH66F cells, a subline of AH66 cells. AH66 cells expressed P-glycoprotein, while the protein was not detectable in AH66F cells. There are two affinity sites for [3H]vinblastine binding in the AH66 cell membrane, while AH66F cells have only one affinity site. The high affinity [3H]vinblastine binding in AH66 cells was inhibited by Adriamycin, verapamil, nicardipine, and reserpine. The high affinity site of the binding may be the multidrug transporter, P-glycoprotein. [3H]Vinblastine binding was not influenced by adenosine 3'-5'-monophosphate (AMP), adenosine triphosphate (ATP), or guanosine triphosphate (GTP). The multidrug resistance in AH66 cells may depend on P-glycoprotein which is not modulated by nucleotide.

Reversal of vinblastine resistance by a new staurosporine derivative, NA-382, in P388/ADR cells.

Activities of a newly synthesized compound, N-ethoxycarbonyl-7-oxo-staurosporine (NA-382), on cyclic AMP-dependent protein kinase (A-kinase), Ca2+/phospholipid dependent protein kinase (C-kinase), and drug resistance were investigated and compared with those of staurosporine. Protein kinase-inhibitory activity of NA-382 was lower but more selective to C-kinase than that of staurosporine. NA-382 was less toxic to P388 cells and at a non-cytotoxic concentration completely reversed the vinblastine (VBL) resistance of Adriamycin-resistant P388 (P388/ADR) cells without influence on the effect of VBL on the parental P388/S cells. However, the cytotoxicity of staurosporine was too high to give the combination effect with VBL. NA-382 dose-dependently increased VBL-accumulation and inhibited VBL-efflux in P388/ADR with higher potency than staurosporine. Both compounds inhibited the photolabeling of [3H]azidopine on 140-kDa P-glycoprotein in the plasma membrane from the resistant cells. These results suggest that a staurosporine analog, NA-382, reverses multidrug resistance by inhibiting the drug-efflux system or P-glycoprotein.

Obsessive-compulsive symptoms in childhood and adolescence.

We investigated 61 patients (38 boys and 23 girls) under 18 years of age with obsessive-compulsive symptoms seen in the Department of Psychiatry, Nagoya University Hospital, from 1982 until 1986. In this period, a total of 1293 patients under 18 years of age visited the clinic. The percentage of patients with obsessive-compulsive symptoms was 5%. The earliest onset of symptoms was at age 3 years, and the average age of onset was 11.6 years. We found no particular tendency in terms of the number of siblings and the birth order of the patients. Obsessive traits were the fundamental personality traits of patients. Moreover, according to the other characteristics of personality, the patients were subdivided into schizothymic, viscous temperament, and cyclothymic. Parents of the patients were more apt than usual to have obsessive-compulsive personalities. Psychiatric disturbances and occupations were also investigated. Incidents related to school situations commonly triggered obsessive-compulsive symptoms. The most frequently noted obsessive thought was dirt phobia, and the most common compulsive behavior was washing. School refusal and violence at home were especially common as associated symptoms of obsessive-compulsive symptoms. We also describe the treatment regimen and the outcomes of the patients.