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The authors present the development of the concept of mental disease and treatment in Serbian medicine. Serbian medieval medicine did not acknowledge fortune telling, sorcery, the use of amulets and magical rituals and formulas. These progressive concepts were confirmed by the Church and the Serbian state in what is known as Dusan's Code. The Historical data on the establishment of the first psychiatric hospital in the Balkans "Home for the Unsound of Mind" at Guberevac, Belgrade, in 1861 and its founders is reviewed. After World War I, in 1923, the Faculty of Medicine was established in Belgrade to which the coryphaei of Serbian medicine educated in Europe, mostly in France and Germany, flocked and that same year the Psychiatry Clinic of the Faculty of Medicine in Belgrade was set up. Its first seat was on the premises of the Mental Hospital in Belgrade, and it became a training base and laid the foundations of the future Neuropsychiatry Clinic in Belgrade, which in time evolved into the nursery of psychiatric professionals for all of Serbia. The most important data on the further development of psychiatry up to date are presented.

Background: Taking the Initiative to evaluate students' affinity toward psychiatry seems to be a global issue and is an essential part of programs to improve the status of the profession. The aim of this study is to explore medical students' attitudes toward psychiatry in comparison to other residencies (internal medicine, surgery, pediatrics, gynecology and general medicine) in the pre-clinical year and to observe which factors influence the creation of these attitudes., Subjects and Methods: The survey included 114 students of the second year, School of Medicine in Belgrade (academic year 2007/08). The data was collected trough a 23-item questionnaire., Results: Fifteen percent of students stated that psychiatry was their career of choice, while 25% expressed a strong aversion. Psychiatry was ranked less attractive than internal medicine, surgery and pediatrics, but more attractive than general medicine or gynecology. Those who like psychiatry attributed more importance to an interesting and challenging job than to prestige and financial reward. Also, they found this field to be intellectually challenging and to rapidly expand the frontier of medicine. Students with negative attitude were convinced that psychiatry was lacking in scientific foundation and was clinically inefficient, they disliked intensive emotional involvement, exposure to stress and frequent unpleasant situations and had prejudices toward the patients or simply a lack of the interest., Conclusion: The present study is the first of its kind in Serbia which used a precise and internationally comparable methodological instrument and It shows that pre-clinical medical students at the University of Belgrade, have a stronger affinity towards psychiatry when compared to their peers from most countries worldwide. Also, the study points out the fact that prejudices toward patients with mental dysfunctions and lack of confidence in the efficacy of psychiatric treatment should be specially targeted by the curriculum in the later part of undergraduate education. How this will affect the attitude of clinical students and graduates is to be examined.

Introduction: This paper deals with medicolegal aspects of the hospital treatment of patients suffering from severe mental disorders and who are prone to violent behaviour, dangerous to self and others. Violent acts in this study were defined as deliberate and nonconsensual acts of actual, attempted or threatened harm to a person or persons, and classified into categories of any type of violence, physical violence and non-physical violence, which is in accordance with approaches used in other risk assessment researches,, Outline of Cases: The authors present four cases of mentally ill inpatients whose violent behaviour toward self or other persons resulted in self-destruction and physical aggression against other persons. The presented cases involved: 1) self-injury in a patient with acute organic mental disorder after jumping through a hospital window, 2) suicide by drowning of a patient with acute mental disorder after escaping from intensive care unit, 3) suicide in a depressive patient after escaping from a low-security psychiatry unit, 4) physical violence against body and life of other persons in a patient with chronic mental disorder., Conclusion: The presented cases are considered to be rare in clinical practice and risk of violent behaviour and the consequent danger of mentally ill inpatients may be efficiently predicted and prevented with appropriate hospital management based on 1) repeated escalation of violent behaviour and 2) protection of the patient and others. Hence, if the physician in order to prevent harmful consequences, does not apply all the necessary measures, including appropriate diagnostic and therapeutic procedures, as well as treatment in an adequate setting, such act is against the Criminal Law of the Republic of Serbia which sanctions physician's negligence. Also, according to the Law on Obligations of the Republic of Serbia this presents a legal ground for damage claim and the requirement of liability for nonmaterial damage within a civil procedure.

Objectives: The aim of this study was to establish the morbidity structure among testators whose wills were challenged as well as to reveal if there is a specific relationship between certain diagnostic categories in the testators' health status and forensic psychiatry expert opinion on testamentary incapacity., Subjects and Methods: The authors analyzed 156 consecutive forensic psychiatry reports on retrospective, determination of testamentary capacity made in the Forensic Psychiatry Centre, Institute of Psychiatry, Belgrade in the period 1965 - 2005. The wills covered by this study were mostly made by male, 65 years old or older testators, with primary education, who executed a holograph will and survived it for less than a year., Results: Testamentary incapacity for medical reasons was established in 47% of the testators, while a strong, statistically significant relationship between a diagnostic category and testamentary incapacity was established among the testators suffering from an organic mental disorder (Chi-square=133.256, p=0.000) or a substance induced mental disorder (Chi-square=6.971, p=0.008)., Conclusion: Testamentary capacity is a specific focus of medical assessment given that the evidence for overturning a will is generally dependent upon medical assessment. In that respect, much litigation and expenses could be avoided if medical experts were given a chance to correctly assess the testamentary capacity of a person at the time of making a will. The fact remains that our findings may not be a representative cross-section of the general population, and this important issue certainly deserves to be addressed by future research based on a larger sample.

Objective: Fifty years ago, craving was defined as an "urgent and overpowering desire, or irresistible impulse", but subsequently, craving definitions have been modified by many authors and no unique definition of this phenomena, or a consensus in regards to its manifestation and significance exists. This review discusses the contemporary views of alcohol craving. Issues such as definition and different types, dynamics of craving, its mediators and moderators and clinical correlations are explored., Subjects and Methods: We focused on the literature search (MEDLINE, PSYCHLIT, and EMBASE) and new findings in the addiction field, especially paying attention on the study of craving., Findings: There is growing evidence to suggest that craving is associated with different aspects of addiction (i.e. withdrawal, relapse) and clinical characteristics such as depression and anxiety. These different phenomena contribute individual differences in intensity, frequency and types of craving. At present, there are several different models to better describe the complexity of craving., Conclusions: Craving is not an exact, precisely measurable value but it is rather an uncertain, descriptive phenomenon. Further research (biological, sociological and psychological) should be orientated primarily toward exploration of the relationship between environmental factors and personality variables and craving and its maintenance, with special attention to gender differences.

Introduction: Parricide is defined as a murder of parents by their children; the patricide is murder of father, while matricide is murder of mother. This entity is classified as homicide, but it differs in the fact that victims are parents and the killers are their children. Mostly, it is associated with psychiatric morbidity., Objective: To describe sociodemographic and psychopathological characteristics of parricide committers and to analyze circumstances of parricide and psychiatric morbidity in order to achieve better recognition and prevention of risks., Method: This retrospective study included all homicide autopsy records (1991-2005) performed at the Institute of Forensic Medicine, Medical School, University of Belgrade. For further analyses, all parricide records were selected out. The study analyzed all available parameters, which concerned parricide committers, victims and the act itself. Methods of descriptive statistics were used., Results: Between 1991 and 2005, there were 948 cases of homicide; of these, 3.5% were parricides. The committers of parricide were on average 31.2 +/- 11.9-years-old, 87.8% were males, 60.6% with psychiatric symptoms most commonly with schizophrenia, alcohol dependence, personality disorder etc. Victims were on average 63.7 +/- 11.9-years-old, 54.5% males, and 21.2% had a diagnosed mental illness., Conclusion: Parricide is a rare kind of homicide accounting for 3% of all homicides. Committers are mostly unemployed males in early adulthood who have mental disorder. The phenomenon of parricide deserves a detailed analysis of the committer (individual bio-psycho-social profile) and the environmental factors (family, closely related circumstances) to enable a precise prediction of the act and prevention of the fatal outcome, which logically imposes the need of further studies.

Introduction: Olanzapine is a second generation antipsychotic (SGA) with a high level of therapeutic effectiveness in schizophrenia and other psychotic disorders. Along with the positive therapeutic effects, an increase of the body weight frequently occurs. According to the literature, the average weight gain is about 6-7 kg during several months of treatment. This could be valued as a moderate weight increase., Case Outline: This article presents a case of a young female with schizophrenia, without clinical improvement with several antipsychotics (clozapine, risperidone, haloperidol) and with the occurrence of significant neurological side effects. The treatment started with olanzapine (baseline) was associated with good initial response (PANSS reduction 20% in the first two weeks) and the improvement was maintained further on (PANSS reduction 50% after 16 weeks). Significant increase (20 kg, 40%) in weight appeared during the following 16 weeks (BMI at baseline 17.9 kg/m2; BMI 16 weeks later 25.1 kg/m2)., Conclusion: High effectiveness of olanzapine in schizophrenia symptoms reduction was accompanied by a significant weight gain. However, this drug leads to impaired glucoregulation, dyslipidaemia etc. It also increases the risk of diabetes and cardio-vascular diseases, i.e. the main causes of mortality in schizophrenia after a suicide. Therefore, clinicians are suggested to focus on possible predictors of weight gain during olanzapine therapy, and act accordingly in order to prevent serious health consequences.

Introduction: Schizophrenia patients are at greater risk of obesity, diabetes mellitus (DM), lipid abnormalities and cardiovascular disorders. The metabolic complications in patients are associated with several risk factors: family history of DM, lifestyle, smoking, dietary habits, physical inactivity, but also with antipsychotic medication. In literature, most publications have been focused on the effects of the second generation antipsychotics (SGA) on glucose metabolism. However, less attention has been paid to abnormality in glucoregulation, patients with schizophrenia treated with the first generation antipsychotics (FGA)., Objective: The present study evaluated glucose metabolism in normal weight schizophrenia patients treated with FGA., Method: The cross-sectional study included 18 patients (FGA treated) and 20 healthy controls with neither group differences in sex distribution, age, nor in BMI. Inclusion criteria were normal BMI (20-25 kg/m2). The glucose levels, insulin levels and growth hormone levels during oral glucose tolerance test (OGTT) were measured., Results: Fasting glucose and insulin levels did not differ significantly between groups. Groups differed in OGTT glucose and insulin peak and area under curve (AUC), level of significance p < 0.05 (patients vs. controls: glucose peak 8.3 +/- 0.4 vs. 6.9 +/- 0.5 mmol/l, glucose AUC 758 +/- 28 vs. 640 +/- 36 mU/l/120 min; insulin peak in patients 92.7 +/- 15.6 mU/l; insulin AUC 6060 +/- 1016 mU/l/120 min, insulin peak in controls 47.9 +/- 6.5 mU/l; insulin AUC 2597 +/- 256 mU/l/120 min)., Conclusion: Patients with schizophrenia, although with normal body mass index, are at high risk of abnormal glucose regulation. Not only SGA increase the risk of impaired glucoregulation and metabolic syndrome, but this may also be due to FGA or schizophrenia per se.

The paper analyzes some issues on the comorbidity between schizophrenia and cancer. Epidemiological studies have reported contradictory results, but it is certain that patients with schizophrenia are more likely to suffer from risk factors for cancer development, such as increased alcohol abuse, obesity, nicotine dependence and decreased physical activity. The paper gives guidelines for the treatment of cancer in patients with schizophrenia, and discusses possible interactions between chemotherapy and psychotropic drugs. Particular attention is paid to the use of antipsychotics which increase the level of prolactin, in view of the possible risk of breast and endometrial cancer in patients with schizophrenia.

There are very few investigations about sex differences in suicide which include some other variables (e.g. age, profession etc). Data which concern suicide sex differences are obscure and usually are given in statistical accounts of causes of death. The aim of our study was to investigate sex differences in realized suicides within the city of Belgrade during the last eight year period. Data was taken from the index records of suicide in the city of Belgrade held at the Institute for Informatics and Statistics. We took sex as the main observed variable, and analyzed nine other variables as related to sex. Statistical analysis was done by using the crude specific rate. The variability of the rate was estimated by computing a confidence interval. The results of our study gave the profile of males and females who committed suicide in Belgrade in the period of the last eight years. Although there were significant quantitative differences, the female/male profile of completed suicides is similar, and differs only in the method of suicide: both males and females choose hanging, drowning and suffocation as the most common method of suicide, while poisoning is on the second most common method chosen by females and firearms the second most common method for males. The frequency of suicide, in both sexes, showed a tendency to decrease over the observed period (the highest suicide rate was in 2000- females 9.7, males 19.7, and the lowest in 2004- females 4.5 males 9.1). Male to female suicide rate ratio was 2 to 1. Sex differences were registered in all of the observed nine variables.

Unlabelled: Currently available evidence reveals comparatively few studies of the psychological and social effects of acquired hearing impairment, in spite of the fact that clinicians have for a long time been aware of a connection between acquired hearing impairment and mental disorders. The existing data indicate that psychological disorders are significantly more frequent in a population with hearing impairment than in the average population and are accompanied by disharmony in interpersonal and social relations., Aim: Establishing the presence and the type of mental disorders in patients with hearing impairment due to otosclerosis, before and 6 months after corrective surgery, as well as finding the role of adaptation style (personal adjustment) and facing strategy (communication strategies) as mediating variables between the acquired hearing impairment and observed psychical changes., Methodology: in 60 subjects, potential candidates for stapedectomy, MMPI-201 has been applied before and after surgery, in order to evaluate the mental state. For assessments of personal adjustment to the impairment and communication strategies, a communication personal profile has been applied preoperatively., Results: more psychiatric disorders are present in the preoperative group compared to the general population and the postoperative group. These disorders are of exclusively a neurotic nature; the most frequent are depressive, anxious depressive and anxious reactions. A connection was found between adaptation style and facing strategies whether in the presence or absence of psychological disorders., Conclusion: the findings indicate a need for professional psychiatric-psychological support as a part of a rehabilitation program designed to reduce psychological difficulties, i.e. to help individuals to become adapted to the acoustic environment and to prevent or at least minimize the negative consequences of hearing impairment by efficient communication strategies.

Introduction: Currently available evidence reveals comparatively few studies of psychological effects of hearing impairments, in spite of the fact that clinicians have for a long time been aware of a connection between the acquired hearing impairment and mental disorders. They are focused on the investigation of dysfunction in general. Thus, three domains of the auditory imbalance may be distinguished: disorder, disability and handicap. 'Handicap', according to the definition of the World Health Organization, is a hindrance in an individual that results from an impairment or disability and represents psychological response of the individual to the impairment., Objective: Validation of acquired hearing impairment as a risk factor of psychical disorders as well as an analysis of relation of some demographic factors (sex, age, education) and audiological factors (degree and duration of the impairment) with the frequency of hearing handicap., Method: MMPI-201 has been applied in 60 subjects affected with otosclerosis, potential candidates for stapedectomy, before and after the surgery., Results: Individuals with acquired hearing impairment manifest more frequent disorders of psychical functioning in comparison with general population, while demographic and audiometric parameters did not correlate with acquired hearing handicap., Conclusion: It may be assumed that the very recognition of demographic and audiological factors can not help much in the understanding of the psychological stress associated with hearing impairment.

Aim: This open-label, multicentre study investigated the clinical efficacy of liquid peroral risperidone in psychotic disorders, the patients' attitudes toward the study medication vs. previous antipsychotic medication and also psychiatrists' opinion of it., Method: Eighty one patients with psychotic disorder entered the study during 2004. At the baseline (T0), the treatment started with peroral risperidone liquid and lasted for 6 months (T2), with one visit a month after the baseline (T1). Clinical improvement was evaluated using PANSS and CGI, while extrapyramidal side effects were measured by the AIMS scale. The patients' attitudes were evaluated by 3-choice 3-item questionnaire designed for the purposes of present study. Moreover, psychiatrists were asked about their opinion regarding clinical improvement and compliance comparing liquid peroral versus risperidone-tablets., Results: PANSS and CGI scores yielded clinical improvement (p<0.001, DF=151 and p<0.001, DF=151, respectively). Eighty three per cent of patients preferred peroral liquid risperidone for continuation of treatment. The psychiatrists agreed with the patients in deciding to continue treatment with peroral liquid risperidone (83%) because of better tolerability in 88% patients, better cooperation in 82% and more precise dosage in 80% patients. In terms of mental state, it was observed that during the study symptomatology had worsened in 3% of the study patients, in 6% there were no changes, while all others improved (26% moderately, 65% highly). conclusions: Peroral risperidone liquid was effective and well tolerated in patients with psychotic disorders. The patients' as well as their doctors' attitudes expressed satisfaction with the use of the risperidone peroral formulation. This is the only SAG available in peroral liquid formulation.

Objective: The multicentric prospective study was conducted to examine patients' attitudes toward risperidone in comparison to any previous antipsychotic treatment., Subjects and Method: Ninety three subjects with a schizophrenia or schizoaffective psychotic disorder (ICD-10), previously treated with any antipsychotics, were included in the study and treated with risperidone during 8 weeks. At the baseline, symptoms were assessed by PANSS and history of previous medication was recorded. At the end of the study, patients' attitudes were examined by eight-items questionnaire and PANSS was scored., Results: Ninety five percent of patients previously treated with FGA (80%), SGA(5%) or combination (10%) completed the study, with improvement expressed in 62% change of the total PANSS score. Eight items questionnaire yielded risperidone to be superior to other regarding all questions. For continuation of the treatment, 83% of patients had chosen risperidone., Conclusion: Patients' attitudes and satisfaction with treatment should be monitored carefully because it appears to be related strongly to their readiness to take medication as prescribed, and thereby to outcome.

Cognitive impairment is the hallmark of progressive neurodegenerative process observed in Alzheimer's disease (AD). Acetylcholine (Ach) deficiency is considered to be one of major factors underlying cognitive dysfunction in AD. Several lines of evidence suggest that sigma receptor ligands can elevate Ach extracellular levels in prefrontal cortex rat brain. Since all selective serotonin reuptake inhibitors (SSRIs) show affinity for sigma receptors, it has been assumed that fluoxetine could improve cognition in AD. The aim of study was to investigate the effects of fluoxetine on learning and memory processes in experimental model of AD in rats. Experiments were carried out on adult male Wistar rats divided into three major groups: intact control, sham-operated and nucleus basalis-lesioned rats. Bilateral electrolytic lesions of nucleus basalis Meynert (NBM) (experimental model of AD) were made by 1 mA direct current passed through unipolar electrode for 30 sec. The behavioural test (active avoidance) was performed after recovery period of 10 days from the lesion. The effects of several doses of fluoxetine (3, 5 and 10 mg/kg) on these processes were investigated after 7 days of administration. The results showed that lesion of NBM in rats markedly impaired learning and memory processes compared with controls (intact and sham). Fluoxetine in 5 mg/kg daily doses significantly improved (p<0.05) these processes in lesioned animals. These findings suggest that fluoxetine could be useful as symptomatic therapy in the treatment of AD.

Schizophrenia is characterized by diffuse brain abnormalities, some of them involving volumes of three intracranial compartments: gray matter (GM), white matter (WM) and cerebrospinal fluid (CSF). Novel methods, such as Statistical Parametrical Mapping, provide an automated means of comparing structural features across high quality MRI scans and the measurement based on the principles of voxel based morphometry. For the purposes of the present study, we selected sex balanced group of young adults with recent onset illness to assess the effects of the illness on the volumes of compartments and also to minimize the effects of chronicity, medication, sex and aging. Sixty-four subjects were selected from a larger sample (inclusion criteria: age range 18-31). Thirty-one had DSM IV diagnosis of schizophrenia or schizoaffective disorder, 33 were controls. T1 weighted MRI images were acquired on two scanners (1.5T both): a) fast gradient echo sequence, FLASH, 40 msec repetition time, 5 ms echo time, 40 degree flip angle and b) turbo gradient echo, 12 msec repetition time, 4 msec echo time, 20 degree flip angle, 1 excitation). The resulting data set consisted of: a) 128 consecutive slices with 1.17 mm thickness and 256 x 256 pixels per slice and b) 160 consecutive slices of 1 mm thickness and 256 x 256 pixels per slice. All 64 images were processed by ANALZYE, and normalized and segmented by SPM99. Following the automatic segmentation of the images into the three intracranial compartments, volumetry was performed based on the principles of voxel analysis. Results were expressed relative to whole brain volume, and MANOVA analyses were performed to correct the confounding effects of MRI acquisition center differences and age difference between diagnostic groups. Young adults with recent onset schizophrenia had 6% reduction in GM volume and 14% increase in the volume of CSF, after all confounders were included into analyses (MANCOVA: p = 0.006 and 0.0002, respectively). No significant changes in WM volume were evident. In comparison to a few similar studies published recently, all results yielded similar scores regarding effects of recent onset illness and young adult population, thus confirming the reliability of the procedure. In conclusion, global neuropil reduction was discussed as a consequence of the cortical neurodevelopmental disgenesis. It was suggested that neuropil reduction i.e. synaptic and dendritic changes were to induce functional abnormalities and the expression of schizophrenia.

The lectin-like protein analogous to bovine conglutinin was purified from human serum. The carbohydrate-binding ability of conglutinin-like protein was inhibited by D-mannose, N-acetylglucosamine and L-fucose as well as by mannan-containing oligosaccharides. By applying a lectin-based ELISA system it was demonstrated that conglutinin-like protein binds to human immunodeficiency virus-1 (HIV-1) glycoprotein 120 (gp120) via its carbohydrate binding site. In vitro experiments with T-lymphoblastoid CEM cells revealed that conglutinin-like protein abolishes infection by HIV-1; a 50% cytoprotective concentration of 23.9 micrograms/ml was measured. These findings demonstrate that human conglutinin-like protein binds to HIV-gp120 and inhibits, under the described in vitro conditions, CEM cell infection.

Infection of monocytes with human immunodeficiency virus type 1 (HIV-1) (strain Ada-M) caused increased levels of leukotriene B4 (LTB4) and prostaglandin E2 (PGE2) in vitro. These two products result from the activities of the two enzymes cyclooxygenase and 5-lipoxygenase. The addition of the sesquiterpenoid hydroquinone Avarol, an HIV inhibitor, strongly reduced the levels of LTB4 and PGE2 via inhibition of both cyclooxygenase and lipoxygenase in monocytes. The 50% inhibition concentrations (IC50) for the enzymes were determined to be 2.26 microM (cyclooxygenase) and 1.97 microM (lipoxygenase). A 50% reduction of the extent of PGE2 and LTB4 production in HIV-infected monocytes was measured at a concentration of 0.9 microM Avarol, a dose which caused an 80% anti-HIV effect in vitro (50% inhibition of virus release from infected cells: 0.3 microM). We conclude that Avarol inhibits the enzymes cyclooxygenase and lipoxygenase and suggest that, in general, inhibitors of these enzymes are promising anti-HIV compounds.

The article deals with the psychosexually disturbed identity known as transsexualism. The medical practice is occupied with this problem and phenomenon since the sixth decennium of this century. However, in this country it was not present at that time. In Serbia the treatment of transsexualism began at the beginning of 1989, and there have not yet been published articles on this problem. This paper is the first article dealing with transsexualism in Serbia. It is based on personal authors' experience. The essential characteristic of transsexualism is the existence of such psychical grasp and conduct which do not correspond to bodily sexual characteristics. The difference is so great that the patient must force himself (herself) to accept the existing psychical properties or inborn bodily particularities which do not harmonize. Therefore the patient decides to take psychial things as they are but to alter his (her) body. Psychiatry cannot alter his (her) soul but surgery and endocrinology can alter his (her) body. In that case the patients body is first shaped with hormonal therapy according to his (her) wishes (female or male), and then genital organs are appropriately formed by surgery. The popular nema of this procedure is sex reassignment. The whole problem and the therapeutic procedure are considered as hermaphroditism. In true hermaphroditism ovarian or testicular tissue is present in the same patient; in false hermaphroditism female or male organs predominate; and in transsexualism only one way of alteration is possible i.e. bodily sexual alteration. The latter is the most complex form and physicians finally realized that spiritual feelings can be the property of one sex and bodily characteristics of the other.(ABSTRACT TRUNCATED AT 250 WORDS)

Avarone and avarol are novel cytostatic agents which have potent antileukemic activity both in vitro and in vivo (mice). Cell culture experiments revealed that the cytostatic activity of these two compounds on L5178Y mouse lymphoma cells was 13- to 14-fold higher than that determined for HeLa cells and 40- to 43-fold higher than that for human melanoma cells. Nontumor cells (human fibroblasts and human gingival cells) were highly resistant against the two compounds. The inhibitory potency of avarone on L5178Y cells (50% inhibitory concentration, 0.62 microM) was significantly higher than the avarol activity (50% inhibitory concentration, 0.93 microM). Modification of the molecule at the quinone ring or the double bond in the terpenoid skeleton resulted in a significant loss of activity. In vivo studies with L5178Y cells in the ascites of mice confirmed the strong antileukemic effect determined in vitro. At doses of 10 mg/kg given i.p. once daily for 5 days to mice bearing approximately 10(8) leukemia cells, avarone was found to be curative in about 70% of the mice (20% for avarol). The optimal daily i.p. dose of avarone increased life span over controls by 146% when treatment was begun 1 day after tumor implantation and by 87% when treatment was delayed until day 8. Avarol, although active, was less effective. Based on the determined log10 kill values, avarone can be classified as a highly active and avarol as a markedly active cytostatic agent. The efficacy of the two compounds is also emphasized by the therapeutic index of 11.7 for avarone and of 4.5 for avarol. The two agents were determined not to be either direct mutagens or premutagens in the Ames test.

The hydroquinone-containing cytostatic compound avarol inhibits predominantly growth of those cell lines which have a low level of superoxide dismutase. The substrate of this enzyme, the superoxide anion, was found to be formed during the in vitro oxidation reaction of avarol to its semiquinone radical in the presence of oxygen. Under the same incubation conditions plasmid DNA (pBR322) was converted from the fully supercoiled circular form mainly to the nicked circular form, indicating that the compound causes primarily single-strand breaks. Using Friend erythroleukemia cells (FLC) it was found that avarol induces a dose-dependent DNA damage; the maximum number of DNA strand breaks was observed at 5 h after addition of the compound to the cells. Removal of avarol resulted in a rapid DNA rejoining with biphasic repair kinetics [first half-time, 8 min (90% of the breaks) and a second half-time, 40 min (10% of the breaks)]. When the degree of avarol-induced DNA damage in FLC was compared with the drug-caused inhibition of cell growth a close correlation was established. Avarol displayed no effect on dimethyl sulfoxide-induced erythrodifferentiation of FLC as determined by the benzidine reaction and by dot blot hybridization experiments. From incubation studies of FLC with [3H]avarol no hint was obtained for the formation of an adduct between DNA and the compound. The subcellular distribution of [3H]avarol was studied in liver cells after i.v. application of the compound. The predominant amount of the compound was present in the cytosolic fraction; little avarol was associated with plasma membranes, nuclei, and mitochondria. Using (a) oxidative phosphorylation and (b) oxygen uptake as parameters for mitochondria function, no effect of the compound on the activity of this organelle was determined. These results suggest that avarol forms superoxide anions (and in consequence possibly also hydroxyl radicals) especially in those cells which have low levels of superoxide dismutase. Moreover, evidence is provided that the active oxygen species cause DNA damage resulting in the observed cytotoxic effect.

The antileukemic and anti-HTLV-III (anti-HIV) agent avarol, a sesquiterpenoid hydroquinone, was determined to be converted into its corresponding quinone derivative avarone via the semiquinone free radical. Its g-value was 2.0047; after hyperfine splitting the energy levels revealed 16 isotropic Hfs. The redox reaction products were identified at the pH values 4.0, 7.0 and 12.0 and the overall reaction pathways were formulated. In vivo experiments with L5178y mouse lymphoma cells in the ascites of mice revealed that the cytostatic potencies of avarol and avarone cannot be augmented by lowering the pH value. Incubation studies with L5178y cells in vitro showed that the intracellular levels of superoxide dismutases (SODases) and of glutathione (GSH) peroxidase activities significantly change after avarol administration. While both the Mn-SODase and the Cu/Zn-SODase activities dropped significantly, the GSH peroxidase activity increased inversely. From these experiments we assume that the anti-tumour and the antiviral effects of avarol/avarone may be due to an increase, induced by the drug, of the intracellular concentrations of superoxide radicals.

The two antileukemic agents, avarone and avarol, were determined to be neither direct nor indirect mutagenic agents in the Ames microsomal test. Moreover, the two sesquiterpenoid compounds drastically reduced the mutagenic effect of benzo[a]pyrene in the same system. Subsequent enzymic studies demonstrated that avarone and avarol are powerful inhibitors of benzo[a]pyrene monooxygenase.

The sesquiterpenoid hydroquinone and quinone, Avarol and Avarone, were previously found to be potent antitumor agents (Müller et al., 1984). In the present study it is reported that in aqueous solution (pH 7.2), in the presence of dimethylsulfoxide, Avarol is converted to Avarone. Avarone and to a smaller extent also Avarol were active against a variety of grampositive bacterial species. The highest activity was determined for Streptococcus pneumoniae and Erysipelothrix rhusiopathiae (MIC 0.781 mg/l). The antibacterial activity can be augmented 2 to 4-fold by lowering the pH in the culture medium from 7.0 to 6.0. The efficiency of Avarone and Avarol was abolished in the presence of serum. No antibacterial activity was determined in gramnegative bacterial species. In addition, Avarol and to a smaller extent also Avarone displayed an antifungal activity on Trichophyton species and Microsporum canis (MIC: 15.6-62.5 mg/l), while Avarone and not Avarol was active on Aspergillus niger, no activity was found against Candida species. These data indicate that the antitumor agents Avarol/Avarone display also antibacterial- and antifungal activities against a limited range of microorganisms.

A new lectin has been isolated from the coral Gerardia savaglia by affinity chromatography, using locust gum as an absorbent, and D-mannose as eluant. Final purification was achieved by Bio-Gel P300 gel filtration. The agglutinin is a protein composed of two polypeptide chains with a Mr of 14800; the two subunits are not linked by disulfide bond(s). The isoelectric point is 4.8, the amino acid composition is rich in the acidic amino acids aspartic acid and glutamic acid. The absorption maximum for the protein was at 276 nm; with a molar absorption coefficient of 1.27 X 10(5) M-1 cm-1. The lectin precipitated erythrocytes from humans (A, B and O), sheep, rabbit and carp with a titer between 2(5) and 10(10); the affinity constant for lectin binding to sheep red blood cells was 2.8 X 10(8) M-1 and the number of binding sites, 3.2 X 10(5)/cell. Ca2+ ions are required for full activity; the pH optimum lies in the range between 6 and 11. Inhibition experiments revealed that the lectin is specific for D-mannose. The lectin is mitogenic only for those spleen lymphocytes from mice which had been activated by lipopolysaccharide. An interesting feature of this lectin is its ability to bind to glycoproteins present in nuclei from CV-1 monkey kidney cells. The fluorescein-isothiocyanate-labelled lectin reacted with six polypeptides in the nuclear envelope from rat liver (Mr 190,000, 115,000, 80,000, 62,000, 56,000 and 42,000) and with two polypeptides in the nuclear matrix or pore complex lamina fraction (Mr 190,000 and 62,000). The lectin inhibited the nuclear envelope mRNA translocation system in vitro. It is suggested that this effect is due to an interaction of the lectin with the nuclear glycoproteins gp190 and/or gp62.

A main metabolic product of the sponge Dysidea avara was isolated and purified and subsequently identified as avarol by applying a series of analytical techniques, e.g. [13C]NMR, [1H]NMR and i.r. spectroscopy. This sesquiterpenoid hydroquinone was found to possess strong cytostatic activity. Using the L5178y mouse lymphoma cell system in vitro (roller tube assays) avarol reduced cell growth to 50% at a concentration of 0.9 microM. Avarol treated cells did not show "unbalanced growth". Avarol interfered with mitotic processes, preventing telophase formation. Incorporation studies with precursors for DNA, RNA, protein and glycoprotein syntheses revealed increased incorporation rates in response to avarol treatment. From these results and further autoradiographical experiments it is suggested that inhibition of cell growth is due to changes of the intracellular pools and/or alterations of the permeability properties of the cell membrane for the precursors. Avarol diacetate caused the same cytostatic effect as avarol.