Severe hypoxia induces complete antifolate resistance in carcinoma cells due to cell cycle arrest.

Antifolates have a crucial role in the treatment of various cancers by inhibiting key enzymes in purine and thymidylate biosynthesis. However, the frequent emergence of inherent and acquired antifolate resistance in solid tumors calls for the development of novel therapeutic strategies to overcome this chemoresistance. The core of solid tumors is highly hypoxic due to poor blood circulation, and this hypoxia is considered to be a major contributor to drug resistance. However, the cytotoxic activity of antifolates under hypoxia is poorly characterized. Here we show that under severe hypoxia, gene expression of ubiquitously expressed key enzymes and transporters in folate metabolism and nucleoside homeostasis is downregulated. We further demonstrate that carcinoma cells become completely refractory, even at sub-millimolar concentrations, to all hydrophilic and lipophilic antifolates tested. Moreover, tumor cells retained sensitivity to the proteasome inhibitor bortezomib and the topoisomerase II inhibitor doxorubicin, which are independent of cell cycle. We provide evidence that this antifolate resistance, associated with repression of folate metabolism, is a result of the inability of antifolates to induce DNA damage under hypoxia, and is attributable to a hypoxia-induced cell cycle arrest, rather than a general anti-apoptotic mechanism. Our findings suggest that solid tumors harboring a hypoxic core of cell cycle-arrested cells may display antifolate resistance while retaining sensitivity to the chemotherapeutics bortezomib and doxorubicin. This study bears important implications for the molecular basis underlying antifolate resistance under hypoxia and its rational overcoming in solid tumors.

Recovery of cyanide in gold leach waste solution by volatilization and absorption.

In this study, the effects of pH, time and temperature in regeneration of cyanide in the leaching waste solution of gold production from disseminated gold ore by cyanidation process were investigated and the optimum conditions, consumptions and cyanide recovery values were determined. The sample of waste solution containing 156 mg/l free CN- and 358 mg/l total CN-, that was obtained from Gümüshane-Mastra/Turkey disseminated gold ores by cyanidation and carbon-in-pulp (CIP) process under laboratory conditions was used in the experiments. Acidification with H2SO4, volatilization of hydrogen cyanide (HCN) with air stripping and absorption of HCN in a basic solution stages were applied and under optimum conditions, 100% of free cyanide and 48% of complex cyanide and consequently 70% of the total cyanide in the liquid phase of gold leach effluent are recovered.

Clozapine in the treatment of obsessive-compulsive symptoms in schizophrenia patients: a case series study.

INTRODUCTION: Obsessive-compulsive (OC) symptoms have been observed in a substantial proportion of schizophrenic patients. There are some reports describing the appearance de novo or reemergence of preexisting OC symptoms under clozapine (CLZ) therapy. However, there are also reports describing a positive effect of CLZ therapy in OC schizophrenic patients. It seems that comorbid OC symptoms are common among CLZ-treated refractory schizophrenic patients and are likely to be an integral part of their illness. The complex nature of the treatment response in this group of schizophrenic patients is as yet unclear. The effects of CLZ on OC symptoms may vary, with evidence of improvement in some and worsening among others. METHODS: The present case series study describes our experience with CLZ as a sole agent (n = 10) or in combination with serotonin reuptake inhibitors (n = 5), in schizophrenic patients with prominent OC symptomatology. RESULTS: Systematic analysis of clinical features of our patients, as well as findings in the literature to date, led us to suggest some factors that may predict response to CLZ treatment in treatment-resistant schizophrenic patients with prominent OC symptoms: 1) schizophrenic patients who began to exhibit OC symptoms within the course of the psychotic process need and might to be successfully treated with CLZ alone; 2) when OC symptomatology preceded the development of schizophrenic process, CLZ monotherapy is inefficient and may even worsen OC symptoms; therefore, it should be treated concomitantly with specific anti-obsessive agents; 3) in both groups there is a definite dose-related pro-obsessive influence of CLZ when it is given in high doses. DISCUSSION: Further controlled investigations in a larger cohort of OC schizophrenic patients are needed to substantiate our hypothesis. OCD:Obsessive-compulsive disorder OCS:Obsessive-compulsive symptoms SRI:Serotonin reuptake inhibitors

Combined electroconvulsive-clozapine therapy.

We reviewed 36 reported psychiatric patients who were treated with a combination of electroconvulsive therapy (ECT) and clozapine. The indication of the ECT-clozapine treatment was resistance to classical antipsychotic agents, clozapine, or ECT alone. Sixty-seven percent of the patients benefited from the combined treatment. In most of the patients, the combined treatment was safe and well tolerated. Adverse reactions occurred in 16.6% of the patients and included prolonged ECT-induced seizures (one case), supraventricular (one case) and sinus tachycardia, and blood pressure elevation. It seems that combined ECT-clozapine treatment is effective and safe. This strategy may be a therapeutic option in treatment-resistant patients.

The effect of long-term antipsychotic treatment on the body weight of patients suffering from chronic schizophrenia: clozapine versus classical antipsychotic agents.

The aim of this study was to evaluate the effect of long-term clozapine treatment on body weight changes in neuroleptic-resistant chronic schizophrenic patients and to compare it with that of classical antipsychotic agents. The body mass index (BMI) of 96 neuroleptic-resistant chronic schizophrenic patients was calculated before the beginning and after long-term (mean +/- SD 1.7 +/- 1.3 years) clozapine treatment. These data were compared to the BMI of 98 chronic schizophrenic patients maintained on classical antipsychotic agents for a similar duration (mean +/- SD 1.9 +/- 1.6 years). A significant elevation in BMI was detected in both groups during these periods (P < 0.0001 versus baseline, for both groups). The change in BMI (delta BMI) was similar in both groups (P < 0.9). We conclude that the increase in body weight caused by long-term (> 6 months) clozapine treatment is comparable to that obtained following long-term classical antipsychotic agents treatment.

Diminished suicidal and aggressive behavior, high plasma norepinephrine levels, and serum triglyceride levels in chronic neuroleptic-resistant schizophrenic patients maintained on clozapine.

Impulsiveness and aggressiveness may be the most common behavioral correlates of central serotonergic dysfunction. The aim of this study was to determine whether clozapine, an atypical antipsychotic agent with a potent serotonergic antagonistic activity, affects impulsiveness and aggression. Its effects on serum lipids, platelet-poor plasma serotonin (5-HT), and norepinephrine (NE) levels were also studied. Thirty neuroleptic-resistant chronic schizophrenic patients, maintained on clozapine for 1 year, were evaluated for aggressiveness, impulsiveness, and suicidality in comparison with 30 chronic schizophrenic patients maintained on classical antipsychotic agents for the same period of time. Clozapine treatment was associated with less impulsiveness (p < 0.05), aggressiveness (p < 0.01) and fewer suicidal attempts (p < 0.05). Serum triglycerides and plasma NE levels were significantly higher (p < 0.01 and p < 0.0001, respectively) in the patients treated with clozapine, as compared with patients treated with classical neuroleptic drugs. The authors conclude that long-term clozapine treatment may be effective in controlling aggressive, impulsive, and suicidal behavior in neuroleptic-resistant chronic schizophrenic patients. The elevated plasma NE levels in patients treated with clozapine as compared to those treated with classical neuroleptic drugs may be relevant for the anti-aggressive/antisuicidal activity of clozapine.

Trihexyphenidyl treatment of clozapine-induced hypersalivation.

The objective of this study was to investigate the efficacy of the anticholinergic agent trihexyphenidyl in the treatment of clozapine-induced hypersalivation. Fourteen chronic schizophrenic patients who exhibited nocturnal hypersalivation during clozapine treatment were coadministered trihexyphenidyl (5-15 mg/day, at bedtime) for 15 days. Salivation was assessed by a single-item 5-point scale. A reduction of 44% in the reported nocturnal hypersalivation was observed after trihexyphenidyl treatment. These results indicate that at least some chronic schizophrenic patients with clozapine-induced nocturnal hypersalivation may benefit from anticholinergic treatment.

Clozapine treatment for neuroleptic-induced tardive dyskinesia, parkinsonism, and chronic akathisia in schizophrenic patients.

BACKGROUND: Previous studies on the use of clozapine in neuroleptic-resistant chronic schizophrenic patients have demonstrated positive effects on tardive dyskinesia but were less conclusive about chronic akathisia and parkinsonism. The aim of the present study was to investigate the short-term (18 weeks) efficacy of clozapine in neuroleptic-resistant chronic schizophrenic patients with coexisting tardive dyskinesia, chronic akathisia, and parkinsonism. METHOD: Twenty chronic, neuroleptic-resistant schizophrenic patients with coexisting tardive dyskinesia, parkinsonism, and chronic akathisia were treated with clozapine. Assessment of tardive dyskinesia, parkinsonism, and chronic akathisia was made once weekly for 18 weeks with the Abnormal Involuntary Movement Scale (AIMS), Simpson-Angus Rating Scale for Extrapyramidal Side Effects, and Barnes Rating Scale for Drug-Induced Akathisia (BAS). RESULTS: At the end of 18 weeks of clozapine treatment, improvement rates were 74% for tardive dyskinesia, 69% for parkinsonism, and 78% for chronic akathisia. A statistically significant reduction in the scores on the AIMS and Simpson-Angus Scale was achieved at Week 5 and on the BAS at Week 6 (p < .0001). CONCLUSION: Relatively low doses of clozapine are effective for the treatment of neuroleptic-induced extrapyramidal syndromes in neuroleptic-resistant chronic schizophrenic patients. The relief of tardive dyskinesia, parkinsonism, and chronic akathisia in this group of patients occurs more rapidly than the reduction in psychotic symptoms. Disturbing, long-term extrapyramidal syndromes in chronic schizophrenic patients should be considered an indication for clozapine treatment.

Neuroleptic malignant syndrome associated with abrupt withdrawal of anticholinergic agents.

Neuroleptic malignant syndrome (NMS) is a severe side-effect of neuroleptic treatment. It is usually related to hypodopaminergic activity. A young schizophrenic patient who developed a typical episode of NMS during abrupt withdrawal of long-acting neuroleptic combined with anticholinergic treatment is described. NMS appeared following combined neuroleptic/ anticholinergic withdrawal and responded to procyclidine administration. The appearance of NMS after discontinuation of antidopaminergic treatment seems to be in conflict with the hypodopaminergic theory of this adverse effect. It is suggested that simultaneous withdrawal of both anticholinergic and neuroleptic medications, mainly long-acting neuroleptics, seems to be a risk factor for NMS.

Problems in implementing the 1991 Treatment of Mental Patients Law in Israel.

The application of the new Treatment of Mental Patients Law, 1991, has been responsible for significant changes in the work of mental health workers, in particular those involved in the often complex process of civil commitment for examination/hospitalization. The experience of implementing this new law shows that some of the clauses related to this process contain controversial concepts. These concepts will be the focus of this paper.

The delusion based will: the question of validity.

The psychiatric evaluation of the testamentary capacities of a delusional person may be hindered by (a) the cognitive, emotional and situational factors affecting the evaluator during the execution of her or his task, and (b) the sometimes very difficult challenge of proving testament invalidity due to the presence of delusions. As an illustration, this article presents a specific case which was recently brought to court in Israel.

The psychiatric patient as consumer.

The rocketing cost of good standard modern medicine and the constant strengthening of the consumers' voice are powerful factors behind the world-wide reorganization of medical services with the aim of improving cost-efficiency, quality and accessibility. The assumption of this article is that financial waste, redundancy and obsolence of medical systems are related to the non-participation of patients in the evaluation of the services they consume. These problems are demonstrated and analysed using examples from psychiatry, where the patients and their families constitute a relatively silent consumer group.

Are confinement and treatment synonyms?

The law deals with the question of compulsory confinement, not with compulsory treatment even if sentences are given commenting on the law. The controversy is whether the confinement's aim is to prevent the patient from harming himself and society or to obtain treatment. In the name of humanity the distinction made by the law between the act of hospitalization and treatment robs medicine of its essence so making the psychiatric ward merely a place of custody. The law has to deal with both the confinement and the treatment as synonyms and their application needs no separate consideration and decision. This dilemma will be discussed further based upon appropriate sentences.

Injuries in attempted suicide by jumping from a height.

This study was undertaken to investigate the pattern of injuries and the management of 28 patients who attempted suicide by jumping from a height. Most of the patients had serious psychiatric disorders. All but two of the patients sustained multiple injuries. The most common injury patterns were fractures of the spine and lower extremities. It was concluded that, in addition to urgent orthopaedic and surgical care, early psychiatric assessment and therapy with transfer to a psychiatric department as soon as possible facilitates the recovery and rehabilitation of these patients.

Platelet [3H]imipramine binding in autism and schizophrenia.

[3H]Imipramine binding to platelet membranes was evaluated in ten autistics, eight schizophrenics and seven normal controls. The schizophrenics and eight out of the ten autistics were maintained on chronic neuroleptic treatment. Diagnosis of autism and schizophrenia was established according to the DSM-III criteria. No significant difference in the maximal binding capacity of [3H]imipramine (Bmax) and Kd values could be found among the three groups. It seems that the imipramine binding site is intact both in autism and schizophrenia.

Effect of chlorpromazine on hypothalamic-pituitary-gonadal function in 10 adolescent schizophrenic boys.

Low basal plasma testosterone levels with normal response to human chorionic gonadotropin (HCG) stimulation and mild hyperprolactinemia and blunted luteinizing hormone (LH) response to luteinizing-releasing hormone (LRH) stimulation were found in 10 adolescent schizophrenic boys who had been treated with chlorpromazine for more than 6 months. These findings may indicate a disturbance of the hypothalamic-pituitary-gonadal function in these patients, probably due to the prolonged administration of chlorpromazine. It remains to be established whether the decrease in basal testosterone secretion is caused directly by chlorpromazine or secondarily by the drug-induced hyperprolactinemia.