The compound 2-(naphthalene-2-thio)-5,8-dimethoxy-1,4-naphthoquinone induces apoptosis via reactive oxygen species-regulated mitogen-activated protein kinase, protein kinase B, and signal transducer and activator of transcription 3 signaling in human gastric cancer cells.

Hit, Lead & Candidate Discovery It is reported that 1,4-naphthoquinones and their derivatives have potent antitumor activity in various cancers, although their clinical application is limited by observed side effects. To improve the therapeutic efficacy of naphthoquinones in the treatment of cancer and to reduce side effects, we synthesized a novel naphthoquinone derivative, 2-(naphthalene-2-thio)-5,8-dimethoxy-1,4-naphthoquinone (NTDMNQ). In this study, we explored the effects of NTDMNQ on apoptosis in gastric cancer cells with a focus on reactive oxygen species (ROS) production. Our results demonstrated that NTDMNQ exhibited the cytotoxic effects on gastric cancer cells in a dose-dependent manner. NTDMNQ significantly induced mitochondrial-related apoptosis in AGS cells and increased the accumulation of ROS. However, pre-treatment with N-acetyl-L-cysteine (NAC), an ROS scavenger, inhibited the NTDMNQ-induced apoptosis. In addition, NTDMNQ increased the phosphorylation of p38 kinase and c-Jun N-terminal kinase (JNK) and decreased the phosphorylation of extracellular signal-regulated kinase (ERK), protein kinase B (Akt), and Signal Transducer and Activator of Transcription 3 (STAT3); these effects were blocked by mitogen-activated protein kinase (MAPK) inhibitor and NAC. Taken together, the present findings indicate that NTDMNQ-induced gastric cancer cell apoptosis via ROS-mediated regulation of the MAPK, Akt, and STAT3 signaling pathways. Therefore, NTDMNQ may be a potential treatment for gastric cancer as well as other tumor types.

Randomized, Double-Blind, Placebo-Controlled Studies to Assess Safety and Prophylactic Efficacy of Naphthoquine-Azithromycin Combination for Malaria Prophylaxis in Southeast Asia.

New prophylactic drugs against malaria infections are urgently needed. We conducted randomized, double-blind, placebo-controlled, phase 2 trials of a new antimalarial drug combination, naphthoquine-azithromycin (NQAZ), to determine its safety and protective efficacy in a low-endemicity area of Southeast Asia. In the first trial, 127 healthy volunteers were randomized to receive two single doses of either 400 mg of NQAZ (200 mg of each drug), 800 mg of NQAZ (400 mg of each drug), or placebo on day 0 and day 30. Weekly follow-ups were performed for 2 months, and physical and clinical laboratory exams were done during the second and eighth week. Both drug regimens were well tolerated, without any serious adverse events. Four adverse events (transient and slight elevations of serum transaminase concentrations) were found only in the two drug-treated groups and thus might be drug-related. In the second trial, 353 volunteer villagers were randomized into the same three groups as in the first trial, and malaria infections were followed for a month. For the intention-to-treat analysis, both regimens offered greater than 90% prophylactic efficacies against all malaria infections. When the analysis was done according to parasite species, 400 mg and 800 mg NQAZ provided 81.63 and 90.59% prophylactic efficacies, respectively, against Plasmodium falciparum infections, whereas both offered 100% prophylactic efficacy against Plasmodium vivax and Plasmodium ovale These trials showed that NQAZ had a good safety profile, and monthly single doses of 400 mg or 800 mg for adults offered excellent prophylaxis against malaria infections, especially the two relapsing species.

Natural and synthetic modulators of SK (K(ca)2) potassium channels inhibit magnesium-dependent activity of the kinase-coupled cation channel TRPM7.

BACKGROUND AND PURPOSE: Transient receptor potential cation channel subfamily M member 7 (TRPM7) is a bifunctional protein comprising a TRP ion channel segment linked to an α-type protein kinase domain. TRPM7 is essential for proliferation and cell growth. Up-regulation of TRPM7 function is involved in anoxic neuronal death, cardiac fibrosis and tumour cell proliferation. The goal of this work was to identify non-toxic inhibitors of the TRPM7 channel and to assess the effect of blocking endogenous TRPM7 currents on the phenotype of living cells. EXPERIMENTAL APPROACH: We developed an aequorin bioluminescence-based assay of TRPM7 channel activity and performed a hypothesis-driven screen for inhibitors of the channel. The candidates identified were further assessed electrophysiologically and in cell biological experiments. KEY RESULTS: TRPM7 currents were inhibited by modulators of small conductance Ca²âº -activated K⁺ channels (K(Ca)2.1-2.3; SK) channels, including the antimalarial plant alkaloid quinine, CyPPA, dequalinium, NS8593, SKA31 and UCL 1684. The most potent compound NS8593 (IC50 1.6 µM) specifically targeted TRPM7 as compared with other TRP channels, interfered with Mg²âº -dependent regulation of TRPM7 channel and inhibited the motility of cultured cells. NS8593 exhibited full and reversible block of native TRPM7-like currents in HEK 293 cells, freshly isolated smooth muscle cells, primary podocytes and ventricular myocytes. CONCLUSIONS AND IMPLICATIONS: This study reveals a tight overlap in the pharmacological profiles of TRPM7 and K(Ca)2.1-2.3 channels. NS8593 acts as a negative gating modulator of TRPM7 and is well-suited to study functional features and cellular roles of endogenous TRPM7.

Biological activity resulting from exposure to aquatic environmental genotoxic pollutants in northern Egypt.

We estimated pollution in Lake Edku and the Mediterranean Sea, El-Maadiya Region, with 3 aromatic amines (1-naphthylamine, 2-naphthylamine and benzidine) in the muscle tissue of fish. There were marked seasonal variations in the aromatic amine levels. We also determined oxidative stress (blood glutathione, and catalase activity) and genotoxic effects (chromosomal aberrations and urinary metabolites) in fishermen from each area. The fishermen suffered from oxidative stress and had high levels of the urinary metabolite sulfanilamide [mean (microg/mg creatinine): Lake Edku 20.7, Mediterranean 14.5, controls 5.3]. Frequencies for total chromosomal aberrations were significantly raised in the peripheral blood lymphocytes of fishermen in both areas [frequency (per 100 metaphases): Mediterranean 67, Lake Edku 45, controls 14].

The micronucleus assay in human exfoliated urothelial cells: application in a genotoxicity study of workers exposed to a mineral jelly containing sodium nitrite and N-phenyl-1-naphthylamine.

Exposure to certain chemical agents in occupational settings has been identified as carcinogenic to the human bladder. Micronucleus (MN) analysis in exfoliated urothelial cells is an interesting method for biomonitoring genetic damage in human populations. However, few studies have been performed in an occupational context. The aim of this study was to examine whether the occupational use of a mineral jelly induced a genotoxic risk for workers employed at a single factory producing bearings using the MN test on exfoliated urothelial cells. The prevalence of micronucleated exfoliated urothelial cells (MNC) was determined in 35 female workers with dermal exposure to the jelly and 41 female controls. The mean percentage of MNC (expressed as percent cells with MN per 1000 cells scored) observed in the exposed worker group was 0.46 +/- 0.11% (range 0-2.8) and in the control group 0.14 +/- 0.03% (range 0-0.8). There is a significant job effect (P = 0.0018, MANCOVA) on the prevalence of MNC, whereas age and smoking habit had no significant effect (P = 0.90 and 0.91, respectively). There is no interaction between job and smoking habit (P = 0.4421). Exposure to the mineral jelly appeared to be the main factor inducing the increased prevalence of MNC. This may be due to the presence of mutagens/carcinogens in the jelly: an aromatic amine, N-phenyl-1-naphthylamine (CAS no. 90-30-2), which is carcinogenic in mice, or sodium nitrite (CAS no. 7632-00-0), which is genotoxic in human cell systems. In conclusion, these results suggest that use of the mineral jelly could present a genotoxic risk for workers. We think that the MN assay on exfoliated cells could be valuable for biological monitoring purposes in occupational contexts as a marker of significant exposure to bladder mutagenic/carcinogenic agents.

The role of serotonin re-uptake inhibitors in preventing recurrent unexplained childhood syncope -- a preliminary report.

UNLABELLED: To assess the efficacy of a serotonin re-uptake inhibitor, sertraline hydrochloride, in preventing recurrent neurocardiogenic syncope, we studied 15 patients (10 female; mean age 12.9 +/- 2 years) with positive head-upright tilt test and resistant to standard pharmacotherapy, atenolol or disopyramide. The patients were given 50 mg oral sertraline hydrochloride daily for 6 weeks. Intolerance to the drug was seen in 3 patients and 2 had syncopal episodes during the therapy. A head-upright tilt table test was then repeated in 10 patients. Six were tilt negative and asymptomatic over a mean follow up period of 7 +/- 3 months while four remained tilt positive: two experienced marked hypotension and bradycardia, characterized as mixed type syncope, and two had cardiac asystole, lasting > 10 s, during tilting, thereby exhibiting a cardio-inhibitory response. CONCLUSION: Sertraline hydrochloride may be useful in preventing recurrent neurocardiogenic syncope resistant to standard pharmacotherapy but careful clinical studies are essential before such a treatment strategy can be recommended since serious asystole could develop.

Double-blind comparison of bupropion sustained release and sertraline in depressed outpatients.

BACKGROUND: A sustained-release formulation of bupropion (bupropion SR), developed with an improved pharmacokinetic profile to permit less frequent dosing than the immediate-release form, has not been evaluated in active comparator trials. This randomized, double-blind, parallel-group trial was conducted to compare the efficacy and safety of bupropion SR and sertraline. METHOD: Outpatients with moderate to severe major depressive disorder (DSM-IV) received bupropion SR (100-300 mg/day) or sertraline (50-200 mg/day) for 16 weeks. Psychiatric evaluations, including the Hamilton Rating Scale for Depression (HAM-D), the Hamilton Rating Scale for Anxiety (HAM-A), the Clinical Global Impressions scale for Severity of Illness (CGI-S), and for Improvement (CGI-I) were completed, and adverse events were assessed in the clinic periodically throughout treatment. Patients' orgasm function was also assessed. RESULTS: Mean HAM-D, HAM-A, CGI-I, and CGI-S scores improved over the course of treatment in both the bupropion SR group and the sertraline group; no between-group differences were observed on any of the scales. Orgasm dysfunction was significantly (p < .001) more common in sertraline-treated patients compared with bupropion SR-treated patients. The adverse events of nausea, diarrhea, somnolence, and sweating were also experienced more frequently (p < .05) in sertraline-treated patients. No differences were noted between the two treatments for vital signs and weight. CONCLUSION: This double-blind comparison of bupropion SR and sertraline demonstrates that bupropion and sertraline are similarly effective for the treatment of depression. Both compounds were relatively well tolerated, and orgasm dysfunction, nausea, diarrhea, somnolence, and sweating were reported more frequently in sertraline-treated patients.

Bupropion treatment of serotonin reuptake antidepressant-associated sexual dysfunction.

Serotonin reuptake inhibitor (SRI)-induced sexual dysfunction is common, and a number of pharmacologic adjunctive strategies have been employed to treat this vexing problem. This open label study tested the efficacy of adjunctive bupropion across several measures of sexual function. Patients taking SRIs for various mood or anxiety disorders who reported prospective decline in sexual function after at least 2 months on SRIs were offered treatment with bupropion, 75 mg/day. Eight patients were treated, and sexual function was measured by use of a visual analog scale at 1 month of treatment. Four of eight patients experienced marked improvement in sexual dysfunction following adjunctive bupropion treatment. Bupropion may be a pharmacologic option for treating SRI-associated sexual dysfunction, though controlled clinical trials are needed.

Effects of comorbidity and polypharmacy on the clinical usefulness of sertraline in elderly depressed patients: an open multicentre study.

Antidepressant therapy in the elderly age group is frequently complicated by medical comorbidity, polypharmacy and increased sensitivity to drug effects. A nonblind, noncomparative, observational, multicentre study over 8 weeks was conducted to assess the effectiveness and tolerability of sertraline (50-200 mg/day) in 1437 elderly depressed outpatients with a mean (S.D.) age of 68 (6.3) years (range 60-92) in routine clinical practise. Depressive symptoms were monitored using the Montgomery Asberg Depression Rating Scale (MADRS) at baseline and at weeks 2, 4, 6 and 8. The mean dose of sertraline at the final visit was 85.2 mg/day (48% of patients were given the initial dose throughout the study). At the end of the study, mean percentage change of MADRS score from baseline was 61% (P < 0.001). A > or = 50% decrease in MADRS score was obtained in 70% of patients. Sertraline was well tolerated. Side effects occurred in 23% of patients, although only 5.1% withdrew because of adverse events. There were no significant differences in the antidepressant effectiveness or occurrence of side effects when patients with and without concomitant pathologic conditions or with and without concurrent medications were compared. These findings indicate the absence of clinically important drug interaction and confirm the effectiveness and safety of sertraline in routine clinical practise for treating elderly depressed outpatients.

Cancer occurrence among dyestuff workers exposed to aromatic amines. A long term follow-up study.

BACKGROUND: Although the occupational exposure to some aromatic amines is recognized to cause bladder carcinoma, the long term effect of such exposure on the risk for disease, including other malignant tumors, remains unknown. METHODS: A total of 442 dyestuff workers exposed to one or more substances including benzidine (BZ), beta-naphthylamine (beta-N), alpha-naphthylamine (alpha-N), and dianisidine were followed completely until December 1992 (average time since first exposure, 39.4 years). Besides the underlying cause of death, the incidence of urothelial carcinoma was determined by periodic urologic screenings. RESULTS: Analyses of site-specific cancer mortality revealed a remarkable increased risk for bladder carcinoma for those engaged in BZ manufacture (standardized mortality ratio [SMR] = 63.6), BZ use (SMR = 27.0) and beta N manufacture (SMR = 48.4), but not for those who were exposed to alpha-N. The increased risk of cancer mortality for other organs was not significant for any exposure classes. The crude incidence rate per 1000 person-years of bladder carcinoma was estimated to be 8.7 for those engaged in BZ manufacture, 2.9 in BZ use, 7.7 in beta-N manufacture and 1.0 in beta-N use. Regardless of the class or type of exposure, the adjusted incidence rate of urothelial carcinoma increased with the duration of exposure. The adjusted incidence rate for BZ manufacture remained high (3.8-12.8) during the entire observation period, whereas that for BZ use increased from 0.0 to 4.4 as the time since first exposure increased from less than 10 years to 30+ years. CONCLUSIONS: Occupational exposure to either BZ or beta-N demonstrated an extremely strong and prolonged effect on workers' risk for urothelial carcinoma, particularly for bladder carcinoma, but not for malignant neoplasms of other organs.

Comparison of the tolerability of bupropion, fluoxetine, imipramine, nefazodone, paroxetine, sertraline, and venlafaxine.

Drug development in psychiatry has evolved from a process dependent on chance discovery to one based on rationally targeting specific mechanisms of action believed to be important in the pathophysiology underlying psychiatric syndromes. Antidepressant pharmacotherapy is the first area to have substantially benefited from this evolution. Serotonin selective reuptake inhibitors (SSRIs) were the first class of psychiatric medications developed based on such molecular targeting. Nefazodone is a new antidepressant that combines blockade of the serotonin-2 receptor with serotonin uptake inhibition. Perhaps as a result of this dual action, nefazodone caused fewer complaints of nervousness (e.g., agitation, anxiety), insomnia, and tremors and a higher incidence of confusion, dizziness, and vision disturbance than do other advanced generation antidepressants based on several different ways of assessing the relative incidence of these adverse effects. Reports of sexual dysfunction on nefazodone and bupropion treatment were lower than on treatment with other recently released antidepressants.

Sertraline-phenelzine drug interaction: a serotonin syndrome reaction.

OBJECTIVE: To report a serious drug interaction possibly occurring with the monoamine oxidase inhibitor phenelzine and the selective serotonin reuptake inhibitor sertraline. CASE SUMMARY: A 61-year-old woman with treatment-refractory major depressive disorder was being treated unsuccessfully with lithium, phenelzine, thioridazine, and doxepin. Sertaline 100 mg/d was added to the patient's therapy. Within three hours of ingesting the first dose, the patient experienced a dramatic increase in her temperature, pulse, and respirations along with labile blood pressure, and symptoms of rigidity, diaphoresis, shivering, and decreased sensorium. The patient was transported to the emergency room and treated with diazepam 10 mg iv, followed by midazolam 10 mg iv for control of rigidity. She was also intubated. The patient then experienced precipitous falls in her blood pressure and respiratory rate. Ice packs combined with a cooling blanket and dantrolene 80 mg iv were administered to control fever and rigidity, respectively. She had an initial working diagnosis of neuroleptic malignant syndrome, which was later changed to serotonin syndrome. Dantrolene was continued for 72 hours at which time the patient was extubated and transferred to a psychiatric unit. CONCLUSIONS: Selective serotonin reuptake inhibitor antidepressants should not be combined with monoamine oxidase inhibitor antidepressants because of the risk of serotonin syndrome.

[Some properties of aromatic amines]. / Alcune proprietà delle ammine aromatiche.

The human carcinogenic activity of 4-4' amino diphenyl and 2 amino naphthalene, drew occupational physician's attention to "aromatic amines" as potentially carcinogenic compounds. The chemical-physical and biological properties of groups of products with structure very similar to them, show that the expression "aromatic amines" cannot define a class of compounds, but that it is necessary to consider only individual substances. The solutions carried out in industry for the replacement of some human cancerogenic products are reported.

A cohort study on cancer among workers exposed to an antirust oil.

An epidemiologic study in an engineering company was prompted by the observation of three cases of cancer; it revealed several more cancers among women who wrapped bearing rings covered with antirust oil, i.e., 12 cases vs 3.9 expected. The 12 tumors were situated in different organs, including the uterus, ovaries, breast, thyroid, brain, colon, and bladder. No known carcinogenic substance was found that could explain the increased incidence of cancer. If the increased incidence is not a random phenomenon, N-phenyl-1-naphthylamine or its nitroso derivative is likely to be the causative agent.