Multifunctional thioxanthone derivatives with acetylcholinesterase, monoamine oxidases and ß-amyloid aggregation inhibitory activities as potential agents against Alzheimer's disease.

A series of 1-hydroxyl-3-aminoalkoxy-thioxanthone derivatives were designed, synthesized and evaluated as potential multifunctional agents against Alzheimer's disease (AD). The results indicated that most of these compounds exhibited good AChE and MAOs inhibitory activities, significant inhibition of self- and Cu2+-induced Aß1-42 aggregation, and moderate to good antioxidant activities. Specifically, compound 9e displayed high inhibitory potency toward AChE (IC50=0.59±0.02µM), MAO-A and MAO-B (IC50=1.01±0.02µM and 0.90±0.01µM respectively), excellent efficiency to block both self- and Cu2+-induced Aß1-42 aggregation (74.8±1.2% and 87.7±1.9% at 25µM, respectively), good metal-chelating property and a low toxicity in SH-SY5Y cells. Furthermore, kinetic and molecular modeling studies revealed that compound 9e binds simultaneously to the catalytic active site and peripheral anionic site of AChE, and could penetrate the BBB. Collectively, these results suggested that 9e might be a potential multifunctional agent for further development in the treatment of AD.

Reposicionamento de fármacos no câncer de boca: Identificação de possíveis agentes / Drug repositioning for oral cancer: Identifying candidate therapeutic agents

O objetivo deste estudo foi o de identificar compostos seletivamente tóxicos ao carcinoma espinocelular de boca in vitro por meio do reposicionamento de fármacos. Material e Métodos: Por meio de um escaneamento baseado na viabilidade celular de 1.280 fármacos, nós selecionamos três princípios ativos (luteolin, metixene hydrochloride e nitazoxanide) letais às células de câncer de boca SCC-25 e pouco tóxicos às células de queratinócitos cutâneos imortalizados HaCaT. Os fármacos candidatos foram investigados quanto à sua dose- e tempo-resposta bem como comparados e combinados à agentes quimioterápicos padrão por meio do ensaio por colorimetria com brometo de tiazolil azul de tetrazolio (MTT). O impacto dos fármacos na motilidade do SCC-25 e do HaCaT foi verificado pelo ensaio de migração celular e seus mecanismos de ação também foram explorados por meio da verificação dos níveis das proteínas fosforiladas pelo western blotting. Todos os experimentos foram realizados em triplicata e, pelo menos, três vezes independentes. O teste t de student foi utilizado para confrontar as variáveis e nível de significância de 5% foi estabelecido para todos os testes. Resultados: O flavonoide natural luteolin exerceu citotoxicidade potente contra as células de câncer de boca in vitro, apresentando baixa toxicidade ao HaCaT e alta eficiência quando comparado a quimioterápicos como a cisplatina e o AG1478. Do ponto de vista molecular, a luteolin ativou a via de sinalização do dano do DNA e, combinada com um inibidor do Chk, apresentou efeitos potencializados. Além disso, nós demonstramos que a nitazoxanide e o metixene hydrochloride são capazes de destruir células SCC-25 porém não as HaCaT de maneira proporcional à dose e ao tempo de tratamento. As combinações entre os três fármacos hit e com a cisplatina ou o AG1478 potencializaram seus efeitos contra as células malignas. Conclusões: O presente estudo traz a luteolin, o metixene hydrochloride e a nitazoxanide como...

Here we aimed at identifying and reposition approved drugs that could be selectively toxic towards oral squamous cell carcinoma cells. Materials and Methods: Through a cell-based drug screening of 1,280 chemical molecules, we selected 3 compounds (luteolin, metixene hydrochloride, and nitazoxanide) lethal to oral cancer SCC-25 cells, while sparing immortalized keratinocyte HaCaT cells. The drugs were then further challenged for their time- and dose-responses, as well as their comparison and combination to standard chemotherapeutic agents by colorimetric assay 1-(4,5-Dimethylthiazol-2-yl)-3,5-diphenylformazan, Thiazolyl blue formazan (MTT). The impact on SCC-25 and HaCaT motility as well as the mode of action of the drugs was then further explored by scratching assay and western blotting, respectively. All the experiments were performed in triplicated and, at least, three independent times. Students t test was performed to verify the differences among the variables and the level of significance was set at 5%. Results: The natural flavonoid luteolin was a potent cytotoxic agent against oral cancer cells in vitro, presenting low toxicity against HaCaT cells and high efficiency as compared to standard-of-care, such as cisplatin and AG1478. From a molecular standpoint, luteolin coopted the DNA-damage pathway and could be efficiently combined with Chk pharmacological inhibitor. Moreover, we demonstrated that nitazoxanide and metixene hydrochloride kill the SCC-25 but not the HaCaT cells in a dose- and time-dependent. The combinations among the three drugs hit and with cisplatin and AG1478 improved their effect against the malignant cells. Conclusions: Luteolin, metixene hydrochloride, and nitazoxanide emerge as strong cytotoxic and/or adjuvant therapy in oral cancer, as these compounds present higher efficiency and lower toxicity against oral cancer cells in vitro than conventional chemotherapeutic agents...

Reposicionamento de fármacos no câncer de boca: Identificação de possíveis agentes / Drug repositioning for oral cancer: Identifying candidate therapeutic agents

Objetivos: O objetivo deste estudo foi o de identificar compostos seletivamente tóxicos ao carcinoma espinocelular de boca in vitro por meio do reposicionamento de fármacos. Material e Métodos: Por meio de um escaneamento baseado na viabilidade celular de 1.280 fármacos, nós selecionamos três princípios ativos (luteolin, metixene hydrochloride e nitazoxanide) letais às células de câncer de boca SCC-25 e pouco tóxicos às células de queratinócitos cutâneos imortalizados HaCaT. Os fármacos candidatos foram investigados quanto à sua dose- e tempo-resposta bem como comparados e combinados à agentes quimioterápicos padrão por meio do ensaio por colorimetria com brometo de tiazolil azul de tetrazolio (MTT). O impacto dos fármacos na motilidade do SCC-25 e do HaCaT foi verificado pelo ensaio de migração celular e seus mecanismos de ação também foram explorados por meio da verificação dos níveis das proteínas fosforiladas pelo western blotting. Todos os experimentos foram realizados em triplicata e, pelo menos, três vezes independentes. O teste t de student foi utilizado para confrontar as variáveis e nível de significância de 5% foi estabelecido para todos os testes. Resultados: O flavonoide natural luteolin exerceu citotoxicidade potente contra as células de câncer de boca in vitro, apresentando baixa toxicidade ao HaCaT e alta eficiência quando comparado a quimioterápicos como a cisplatina e o AG1478. Do ponto de vista molecular, a luteolin ativou a via de sinalização do dano do DNA e, combinada com um inibidor do Chk, apresentou efeitos potencializados. Além disso, nós demonstramos que a nitazoxanide e o metixene hydrochloride são capazes de destruir células SCC-25 porém não as HaCaT de maneira proporcional à dose e ao tempo de tratamento. As combinações entre os três fármacos hit e com a cisplatina ou o AG1478 potencializaram seus efeitos contra as células malignas. Conclusões: O presente estudo traz a luteolin, o metixene hydrochloride e a nitazoxanide como...

Objectives: Here we aimed at identifying and reposition approved drugs that could be selectively toxic towards oral squamous cell carcinoma cells. Materials and Methods: Through a cell-based drug screening of 1,280 chemical molecules, we selected 3 compounds (luteolin, metixene hydrochloride, and nitazoxanide) lethal to oral cancer SCC-25 cells, while sparing immortalized keratinocyte HaCaT cells. The drugs were then further challenged for their time- and dose-responses, as well as their comparison and combination to standard chemotherapeutic agents by colorimetric assay 1-(4,5-Dimethylthiazol-2-yl)-3,5-diphenylformazan, Thiazolyl blue formazan (MTT). The impact on SCC-25 and HaCaT motility as well as the mode of action of the drugs was then further explored by scratching assay and western blotting, respectively. All the experiments were performed in triplicated and, at least, three independent times. Students t test was performed to verify the differences among the variables and the level of significance was set at 5%. Results: The natural flavonoid luteolin was a potent cytotoxic agent against oral cancer cells in vitro, presenting low toxicity against HaCaT cells and high efficiency as compared to standard-of-care, such as cisplatin and AG1478. From a molecular standpoint, luteolin coopted the DNA-damage pathway and could be efficiently combined with Chk pharmacological inhibitor. Moreover, we demonstrated that nitazoxanide and metixene hydrochloride kill the SCC-25 but not the HaCaT cells in a dose- and time-dependent. The combinations among the three drugs hit and with cisplatin and AG1478 improved their effect against the malignant cells. Conclusions: Luteolin, metixene hydrochloride, and nitazoxanide emerge as strong cytotoxic and/or adjuvant therapy in oral cancer, as these compounds present higher efficiency and lower toxicity against oral cancer cells in vitro than conventional chemotherapeutic agents.

Inhibition of spleen tyrosine kinase as treatment of postoperative ileus.

OBJECTIVE: Intestinal inflammation resulting from manipulation-induced mast cell activation is a crucial mechanism in the pathophysiology of postoperative ileus (POI). Recently it has been shown that spleen tyrosine kinase (Syk) is involved in mast cell degranulation. Therefore, we have evaluated the effect of the Syk-inhibitor GSK compound 143 (GSK143) as potential treatment to shorten POI. DESIGN: In vivo: in a mouse model of POI, the effect of the Syk inhibitor (GSK143) was evaluated on gastrointestinal transit, muscular inflammation and cytokine production. In vitro: the effect of GSK143 and doxantrazole were evaluated on cultured peritoneal mast cells (PMCs) and bone marrow derived macrophages. RESULTS: In vivo: intestinal manipulation resulted in a delay in gastrointestinal transit at t=24 h (Geometric Center (GC): 4.4 ± 0.3). Doxantrazole and GSK143 significantly increased gastrointestinal transit (GC doxantrazole (10 mg/kg): 7.2 ± 0.7; GSK143 (1 mg/kg): 7.6 ± 0.6), reduced inflammation and prevented recruitment of immune cells in the intestinal muscularis. In vitro: in PMCs, substance P (0-90 µM) and trinitrophenyl (0-4 µg/ml) induced a concentration-dependent release of ß-hexosaminidase. Pretreatment with doxantrazole and GSK143 (0.03-10 µM) concentration dependently blocked substance P and trinitrophenyl induced ß-hexosaminidase release. In addition, GSK143 was able to reduce cytokine expression in endotoxin-treated bone marrow derived macrophages in a concentration-dependent manner. CONCLUSIONS: The Syk inhibitor GSK143 reduces macrophage activation and mast cell degranulation in vitro. In addition, it inhibits manipulation-induced intestinal muscular inflammation and restores intestinal transit in mice. These findings suggest that Syk inhibition may be a new tool to shorten POI.

Improved ATM kinase inhibitor KU-60019 radiosensitizes glioma cells, compromises insulin, AKT and ERK prosurvival signaling, and inhibits migration and invasion.

Ataxia telangiectasia (A-T) mutated (ATM) is critical for cell cycle checkpoints and DNA repair. Thus, specific small molecule inhibitors targeting ATM could perhaps be developed into efficient radiosensitizers. Recently, a specific inhibitor of the ATM kinase, KU-55933, was shown to radiosensitize human cancer cells. Herein, we report on an improved analogue of KU-55933 (KU-60019) with K(i) and IC(50) values half of those of KU-55933. KU-60019 is 10-fold more effective than KU-55933 at blocking radiation-induced phosphorylation of key ATM targets in human glioma cells. As expected, KU-60019 is a highly effective radiosensitizer of human glioma cells. A-T fibroblasts were not radiosensitized by KU-60019, strongly suggesting that the ATM kinase is specifically targeted. Furthermore, KU-60019 reduced basal S473 AKT phosphorylation, suggesting that the ATM kinase might regulate a protein phosphatase acting on AKT. In line with this finding, the effect of KU-60019 on AKT phosphorylation was countered by low levels of okadaic acid, a phosphatase inhibitor, and A-T cells were impaired in S473 AKT phosphorylation in response to radiation and insulin and unresponsive to KU-60019. We also show that KU-60019 inhibits glioma cell migration and invasion in vitro, suggesting that glioma growth and motility might be controlled by ATM via AKT. Inhibitors of MEK and AKT did not further radiosensitize cells treated with KU-60019, supporting the idea that KU-60019 interferes with prosurvival signaling separate from its radiosensitizing properties. Altogether, KU-60019 inhibits the DNA damage response, reduces AKT phosphorylation and prosurvival signaling, inhibits migration and invasion, and effectively radiosensitizes human glioma cells.

Acute psychotic stress is associated with decreased adiponectin serum levels.

OBJECTIVE: To determine the effect of acute psychotic stress on adipokine secretion in non-diabetic subjects. RESEARCH DESIGN AND METHODS: Adiponectin, leptin, and cortisol serum levels were determined in 39 non-diabetic patients with acute psychotic stress reaction admitted to a psychiatric ward. The clinical global impression (CGI) score was used to evaluate the level of psychotic stress. Insulin sensitivity (IS) was determined by the homeostasis model assessment (HOMA). Patients were re-assessed 2 weeks after admission. During hospitalization patients were treated for variable times with either phenothiazines or thioxanthenes. RESULTS: The mean CGI score decreased significantly with time: 5.3+/-0.8 and 2.6+/-0.8 on admission and after 2 weeks respectively (p<0.001). On admission, the mean adiponectin level was significantly lower in patients compared to normal controls: 15.3+/-8.2 mug/ml and 26+/-12.8 mug/ml, respectively (p=0.02). It increased significantly after 2 weeks to 18.2+/-10 mug/ml (p=0.003). By contrast, the leptin and cortisol levels did not change significantly. No correlation was found between the changes in individual CGI scores and adiponectin levels. However, female patients with the highest stress on admission demonstrated the lowest adiponectin levels and insulin sensitivity: p=0.002 and 0.03 respectively. CONCLUSIONS: These data suggest a link between acute psychotic stress reaction and decreased serum adiponectin levels. Further studies are recommended to determine the strength of this association.

Phase I dose-escalation study of a novel antitumor agent, SR271425, administered intravenously in split doses (d1-d2-d3) in patients with refractory solid tumors.

BACKGROUND: SR271425 is a novel DNA-binding cytotoxic agent with a broad spectrum of antitumor activity in preclinical models,across a variety of the schedule of administration. In toxicological studies, it has been reported to prolong QTc proportionally to C (max). In order to circumvent this C (max)-related QTc prolongation, 5 phase I studies were initiated to investigate 1-h, 24-h, weekly, and split iv infusions. This phase I study assessed a split-dose regimen (a 1-h infusion on each of Days 1 to 3, repeated every 3 weeks) to establish the dose limiting toxicities (DLT), to recommended a phase II dose, and to characterize PK/PD. METHODS: Patient with advanced solid tumors, adequate bone marrow, hepatic, renal function and on specific cardiac criteria were eligible and "3 + 3" design was used for dose escalation. That dose escalation was guided by PK data, toxicities observed and information from other ongoing phase I studies with SR271425. SR271425 plasma levels (PK samples) were measured using a validated LC-MS/MS method. Careful monitoring of ECGs was done, and ECGs were read centrally. RESULTS: Three centers enrolled 19 heavily pretreated patients to six dose levels, from 75 to 450 mg/m(2)/day (i.e., 225-1,350 mg/m(2)/cycle): 12 males and 7 females. Median age 56. Median ECOG, PS = 1. Main tumor types were brain, breast, gynecological, and urological. Patients received a median of 2 cycles (range: 1-6). NCI-CTC Grade 1-2 toxicities included nausea, vomiting, asthenia, rash, and yellow skin discoloration. No DLTs were reported, and there were no dose-limiting prolongations of QTc. Both C (end) and AUC increased in a dose-related manner, with no evidence of accumulation between Day 1 and Day 3, consistent with the mean (+/-SD) terminal elimination half-life of 5.11 +/- 1.21 h. Stable disease was observed in five cases. CONCLUSION: Split doses allow high cumulative exposure to SR271425 without significant toxicity, especially without QTc prolongation. MTD was not reached due to the early termination of the SR271425 program by the sponsor.

Studies on reaction of amino acids and triplet thioxanthone derivatives by laser flash photolysis.

Excitation of the thioxanthone derivatives (TXs), 2, 4-diethylthioxanthone (DETX) and 2-(2,3-epoxypropyloxy) thioxanthone (ETX) in acetonitrile/water mixture solution (1:1, v/v) upon 355 nm laser flash produced the triplet of TXs ((3)TXs(*)). Characteristic absorption spectra of (3)TXs(*)(590 nm) were recorded and rate constants of (3)TXs(*) quenched by O(2) and by its ground state were determined (9.8 x 10(9) M(-1) s(-1), 7.3 x 10(9) M(-1) s(-1) and 2.6 x 10(8) M(-1) s(-1), 2.2 x 10(8) M(-1) s(-1) respectively). The reactions of some amino acids oxidized by (3)TXs(*) were carried out. It has been found that tryptophan (Trp) and tyrosine (Tyr) can quench (3)TXs(*) via electron transfer process and related quenching rate constants were obtained. (3)TXs(*) induced protein damage was investigated using electrophoresis and significant levels of dimerisation were observed under aerobic and anaerobic conditions. The influence of photo-sensitizer's structure on photo-oxidation of amino acid and protein has been discussed.

[Progress in researches on drugs for prostate cancer].

In the recent years, researches on drugs for prostate cancer have received more attention than ever before. This article reviews the mechanism and efficacy of such prostate cancer drugs as bicalutamide, medroxyprogesterone acetate, megestrol acetate, flutamide and so on, as well as the clinical data and clinical uses of calcitriol analogue EB1089, SR233377, etc.

Spasmocanulase in irritable bowel syndrome.

OBJECTIVES: Irritable bowel syndrome is a functional gastro intestinal disorder, with various symptomatology and difficult to treat using several medications. Spasmocanulase, which has an anti-spasmodic and anti-flatulence effect and contains several ingredients, was tried in patients with irritable bowel syndrome, who had been on other medications previously without improvement. METHODS: At the gastroenterology out-patient clinic, Armed Forces Hospital, Riyadh, Kingdom of Saudi Arabia, 21 patients who were diagnosed with irritable bowel syndrome for more than 2 years on treatment and did not benefit from these medications, received spasmocanulase one tablet 3 times a day and followed in the gastroenterology out-patient clinic, every 6 weeks for 6 months. Their previous medications were discontinued which, had been used for different durations and in different combinations included Mebeverine, Colpermin, Normacol, Importal, Librax. The main symptoms were different types of abdominal pain, bloating, flatulence, diarrhea, constipation or both. RESULTS: There was improvement or disappearance of the symptoms in more than 50% of the patients who were not improved on previous medication used for more than 2 years. The overall improvement in symptoms ranged between 43-75% in these patients, when followed up in the clinic at 6 weeks and 3 months. Spasmocanulase caused improvement in abdominal pain, flatulence and bloating compared to their previous medications. Only 43% of patients with diarrhea, showed improvement on spasmocanulase. CONCLUSION: Although the number of patients, we studied is small, this study has shown that spasmocanulase is beneficial in improving symptoms of irritable bowel syndrome.

Phase I pharmacokinetic study of the novel antitumor agent SR233377.

SR233377 is a novel thioxanthenone analogue that demonstrated solid tumor selectivity in vitro with activity confirmed in vivo against several murine tumors including those of colon, pancreas, and mammary origin. Its primary preclinical dose-limiting toxicities included myelosuppression and neurological toxicity. The neurological toxicity was acute and could be ameliorated in mice when the drug was administered as a 1-h infusion instead of rapid i.v. injection. As a result of its preclinical efficacy profile, SR233377 entered Phase I clinical investigation. The compound was administered i.v. over 2 h on day 1 repeated every 28 days. The starting dose was 33 mg/m2 (one-tenth the mouse LD10). Escalations continued to 445 mg/m2 (six escalations), where dose-limiting toxicity was observed. At this dose, acute ventricular arrhythmias, including one patient with torsades de pointes and transient cardiac arrest, occurred. Because this toxicity might have been related to the plasma peak, the protocol was amended to a 24-h infusion beginning at 225 mg/m2. With this dose, prolongation of the corrected QT interval (QTc) over the pretreatment levels resulted. Because prolonged QTc is a known forerunner to acute ventricular arrhythmias, clinical development of SR233377 was stopped. However, preclinical antitumor and toxicity studies with analogues are underway with hopes of identifying a new clinical candidate with similar antitumor effects that is devoid of cardiac toxic effects.

Preclinical efficacy of thioxanthone SR271425 against transplanted solid tumors of mouse and human origin.

A highly active and broadly active thioxanthone has been identified: N-[[1-[[2-(Diethylamino)ethyl]amino]-7-methoxy-9-oxo-9H-thioxanthen++ +-4-yl] methylformamide (SR271425, BCN326862, WIN71425). In preclinical testing against a variety of subcutaneously growing solid tumors, the following %T/C and Log10 tumor cell kill (LK) values were obtained: Panc-03 T/C = 0, 5/5 cures; Colon-38 (adv. stage) T/C = 0, 3/5 cures, 4.9 LK; Mam-16/C T/C = 0, 3.5 LK; Mam-17/0 T/C = 0, 2.8 LK; Colon-26 T/C = 0, 1/5 cures, 3.2 LK; Colon-51 T/C = 0, 2.7 LK; Panc-02 T/C = 0, 3.1 LK; B16 Melanoma T/C = 13%, 4.0 LK; Squamous Lung-LC12 (adv. stage) T/C = 14%, 4.9 LK; BG-1 human ovarian T/C = 16%, 1.3 LK; WSU-Brl human breast T/C = 25%, 0.8 LK. The agent was modestly active against doxorubicin (Adr)-resistant solid tumors: Mam-17/AdrT/C =23%, 0.8 LK; and Mam-16/C/Adr T/C = 25%, 1.0 LK, but retained substantial activity against a taxol-resistant tumor: Mam-16/C/taxol T/C = 3%, 2.4 LK. SR271425 was highly active against IV implanted leukemias, L1210 6.3 LK and AML1498 5.3 LK. The agent was equally active both by the IV and oral routes of administration, although requiring approximately 30% higher dose by the oral route. Based on its preclinical antitumor profile, it may be appropriate to evaluate SR271425 in clinical trials.

Pharmacokinetic studies in mice of two new thioxanthenones (183577 and 232759) that showed preferential solid tumor activity.

Two new thioxanthenones, 183577 and 232759, have rekindled interest in the development of representatives from this class of structures as useful anticancer agents. Although the mechanism of action is unknown, both compounds demonstrated a similar spectrum of solid tumor selectivity. 232759 was selected for clinical development because it showed no hepatotoxicity in preliminary studies, whereas 183577 showed hepatotoxicity but only at the maximum tolerated dose (MTD). The limiting toxicity for the clinical candidate was myelosuppression in preliminary studies. Plasma and tissue drug levels, as well as protein binding, were studied in mice using optimal administration times at the MTD for each drug (for 183577, this was a 4-h infusion at 1350 mg/m2 and for 232759, it was a 5-min injection at 240 mg/m2), as well as at one-half the MTD for the clinical candidate. The drugs were 96-100% bound by plasma proteins. The peak drug concentrations, half-life, and area under the concentration-time curve in plasma for 183577 were 3483 ng/ml, 465 min, and 2018 microgram/ml. min, respectively. The peak drug concentration, half-life, and area under the concentration-time curve in plasma for 232759 were 5257 ng/ml, 44 min, and 276 microgram/ml. min, respectively, at the MTD and 2810 ng/ml, 40 min, and 110 microgram/ml. min at one-half the MTD. In all instances of simultaneous measurements, drug concentrations were equal or higher in tissues than they were in plasma. Unlike the plasma and kidney concentrations of 183577, the liver concentrations did not show a declining trend over the 8-h observation period. Declines in plasma, liver, kidney, and tumor levels of 232759 were detected over the 8-h observation period. The sustained high 183577 concentration in liver is believed to be responsible for its prolonged half-life and hepatotoxicity. Evidence for metabolism of the parent drugs was based on the finding of additional peaks on the high-pressure liquid chromatography tracings. Future studies will focus on identification and antitumor studies of these presumed metabolites in hopes of a better understanding of the solid tumor activity profiles and toxic effects of these compounds.

A double-blind comparison of oral amitriptyline and low-dose intramuscular flupenthixol decanoate in depressive illness.

Fifty-seven hospital out-patients with depressive symptoms were studied in a double-blind manner for up to 4 weeks, 30 whilst being treated with intramuscular flupenthixol decanoate (5 to 10 mg/fortnight) and 27 with oral amitriptyline (75 to 150 mg/day). The results of assessment using the Hamilton Rating Scale for Depression, the Leeds Self-Rating Scale for Depression and the Clinical Global Impressions severity scale showed that both therapies were effective in resolving depression in the patients studied. The two treatments were well tolerated and side-effect profiles were similar, dry mouth, faintness/dizziness and drowsiness being the most frequently reported adverse events. Extrapyramidal signs were seen in similar numbers of patients in each treatment group. One patient from each of the two groups was withdrawn from therapy before the end of the study because of adverse events.

Zuclopenthixol acetate (5% in 'Viscoleo'): single-dose treatment for acutely disturbed psychotic patients.

Twenty-five acutely disturbed psychotic patients were treated in an open study with a single injection of zuclopenthixol acetate 5% in 'Viscoleo, a thin vegetable oil. Patients were assessed post-injection for 3 days using the BPRS, CGI, and a specially designed behaviour/activity scale. Doses of 50 to 150 mg proved effective in 24 (96%) of 25 patients, with pronounced and rapid reduction in psychotic symptoms over the study period. The mean total BPRS score after 72 hours was reduced by over 57%. Tranquillization and sedation appeared within 15 to 90 minutes of injection. Unwanted symptoms were generally mild and of low incidence. The results showed that a single injection of zuclopenthixol acetate 5% in 'Viscoleo' provided rapid tranquillization and sedation coupled with an antipsychotic effect over 3 days. This profile offers a distinct advantage over neuroleptic preparations conventionally used for the initial treatment of acutely disturbed psychotic patients.

The Scottish first episode schizophrenia study. VII. Two-year follow-up. Scottish Schizophrenia Research Group.

Of 49 schizophrenic patients followed up 2 years after their first admission to hospital, 37% were well, 47% had been readmitted to hospital at some time over the 2 years, and 38% showed schizophrenic symptoms at follow-up. A poor outcome at 2 years was associated with male sex, poor outcome after the first 5 weeks of the first admission, negative schizophrenic symptoms on first admission, and a diagnosis of definite or probable schizophrenia using the Feighner criteria. Only 23% were in employment. A small double-blind discontinuation study of maintenance antipsychotic medication during the second year found more relapses in those switched to placebo medication. Repeat psychometric assessment at 2 years confirmed modest improvements found at 12 months; that is, there was no evidence of intellectual decline. Relatives showed no more psychosocial distress than that found in a normal community sample; what distress there was correlated with patients' schizophrenic symptoms.

Clinical and pharmacokinetic evaluation of zuclopenthixol acetate in Viscoleo.

The purpose of the present study was to evaluate zuclopenthixol acetate in Viscoleo, a new preparation to be administered once every 3 days, in the early treatment of acute psychotic episodes and acute deterioration of chronic psychosis. 21 cases were included in the study: patients received 1 to 3 injections. Clinical evaluation was made at 24, 48 and 72 hours after each injection, using the Clinical Global Impressions (CGI) and the Brief Psychiatric Rating Scale (BPRS). Results at end-point indicated a marked or moderate therapeutic effect in the 11 cases of acute psychosis. A statistically significant decrease was observed for the total BPRS score as well as for its subscales. Among 8 cases of exacerbation of chronic psychosis, 4 patients showed a moderate therapeutic effect, and minimal or no effect was found in the other 4 subjects. The total BPRS decreased significantly, but to a lesser extent than for acute psychosis. Two patients suffering from mania showed a moderate therapeutic effect according to CGI. 8 cases of acute psychosis and 5 cases of chronic psychosis did not suffer from any neurological side-effects. Plasma concentration measurements suggest that a dose of 50 mg per 3 days may be sufficient for early treatment of most acutely ill psychotic patients.

Schistosoma mansoni-induced mesangiocapillary glomerulonephritis: influence of therapy.

Schistosomiasis mansoni has been well documented as one of the causes of infectious glomerulopathy, with mesangiocapillary glomerulonephritis being the most frequent lesion observed in this condition. Twenty-one patients with hepatosplenic schistosomiasis mansoni and biopsy-documented mesangiocapillary glomerulonephritis (MCGN) were studied and compared with 19 patients with the idiopathic form of MCGN. Nephrotic syndrome was the most frequent clinical presentation in both groups. At the time of diagnosis nine patients with hepatosplenomegaly (4 with associated arterial hypertension) and 12 (8 with arterial hypertension) among the patients with idiopathic MCGN had renal insufficiency. At the end of the follow-up period 16 patients with hepatosplenic schistosomiasis and MCGN (75.2 months) and 15 with the idiopathic form (52.1 months) had renal failure. Also, when compared at 48 months of follow-up, no difference in renal function could be detected in both groups. No benefits related to anti-parasitic treatment in the schistosomiasis group and immunosuppression therapy in either group could be documented. The progression of the renal disease, as assessed by the reciprocal of serum creatinine versus time, and the survival curve, were not different between the two groups. It is concluded that MCGN in patients with the hepatosplenic form of schistosomiasis mansoni is a progressive disease not influenced by anti-parasitic or immunosuppressive therapy, and presents a clinical course similar to that of the idiopathic form.

Outpatient treatment of 'crack' cocaine smoking with flupenthixol decanoate. A preliminary report.

"Crack" cocaine abuse often produces severe cocaine dependence that is refractory to available pharmacological and outpatient psychotherapeutic treatments. We conducted two preliminary investigations evaluating the efficacy of flupenthixol decanoate, a depot xanthene requiring infrequent intramuscular administration, in the treatment of cocaine withdrawal. Ten outpatient crack cocaine smokers with poor prognoses were administered flupenthixol decanoate in an open-label, open-ended trial. Flupenthixol decanoate was well tolerated and appeared to decrease cocaine craving and use markedly and rapidly, producing a 260% increase in the average time retained in treatment among these subjects. These promising but preliminary data, combined with the magnitude of problems presented by crack, warrant rapid, expanded double-blind assessment of flupenthixol decanoate in cocaine-abuse treatment.