Two-Stage Cultivation of Dunaliella tertiolecta with Glycerol and Triethylamine for Lipid Accumulation: a Viable Way To Alleviate the Inhibitory Effect of Triethylamine on Biomass.

Microalgae are promising alternatives for sustainable biodiesel production. Previously, it was found that 100 ppm triethylamine greatly enhanced lipid production and lipid content per cell of Dunaliella tertiolecta by 20% and 80%, respectively. However, triethylamine notably reduced biomass production and pigment contents. In this study, a two-stage cultivation with glycerol and triethylamine was attempted to improve cell biomass and lipid accumulation. At the first stage with 1.0 g/liter glycerol addition, D. tertiolecta cells reached the late log phase in a shorter time due to rapid cell growth, leading to the highest cell biomass (1.296 g/liter) for 16 days. However, the increased glycerol concentrations with glycerol addition decreased the lipid content. At the second-stage cultivation with 100 ppm triethylamine, the highest lipid concentration and lipid weight content were 383.60 mg/liter and 37.7% of dry cell weight (DCW), respectively, in the presence of 1.0 g/liter glycerol, which were 27.36% and 72.51% higher than those of the control group, respectively. Besides, the addition of glycerol alleviated the inhibitory effect of triethylamine on cell morphology, algal growth, and pigment accumulation in D. tertiolecta The results indicated that two-stage cultivation is a viable way to improve lipid yield in microalgae.IMPORTANCE Microalgae are promising alternatives for sustainable biodiesel production. Two-stage cultivation with glycerol and triethylamine enhanced the lipid productivity of Dunaliella tertiolecta, indicating that two-stage cultivation is an efficient strategy for biodiesel production from microalgae. It was found that glycerol significantly enhanced cell biomass of D. tertiolecta, and the presence of glycerol alleviated the inhibitory effect of triethylamine on algal growth. Glycerol, the major byproduct from biodiesel production, was used for the biomass accumulation of D. tertiolecta at the first stage of cultivation. Triethylamine, as a lipid inducer, was used for lipid accumulation at the second stage of cultivation. Two-stage cultivation with glycerol and triethylamine enhanced lipid productivity and alleviated the inhibitory effect of triethylamine on the algal growth of D. tertiolecta, which is an efficient strategy for lipid production from D. tertiolecta.

Respiratory Effects of Simultaneous Exposure to Respirable Crystalline Silica Dust, Formaldehyde, and Triethylamine of a Group of Foundry Workers.

BACKGROUND: Foundry workers are occupationally exposed to hazardous substances such as silica dusts and toxic gases. The aim of this study was to examine the effects of simultaneous exposure to complex mixtures of silica dust, formaldehyde, and triethylamine on lung function parameters. STUDY DESIGN: A cross-sectional study. METHODS: This study was conducted on 55 male workers of core making unit of a foundry plant (the case group) and 55 workers in a food industry were enrolled as a control group in 2015. Workers were monitored for personal exposure to crystalline silica respirable dust, according the NIOSH method No.7602. The concentrations of formaldehyde and triethylamine were measured using a PID instrument. Lung function tests were performed according to the ERS/ATS standards. RESULTS: The mean concentrations of personal exposure to silica dust, formaldehyde, and triethylamine in the core making workers were 0.23 mg/m3, 2.85 ppm, and 5.55 ppm and respective exposures of control subjects were less than the LOD (limit of detection). There were significant associations between exposure to silica dust and decreases in FVC (Forced vital capacity) values (P<0.05). The findings showed a statistically significant synergistic effect of silica dust and triethylamine on FVC values (P<0.05). CONCLUSIONS: The mean exposure of all studied substances was higher than occupational exposure limits. Synergistic effects of exposure to silica dust and triethylamine on some lung function parameters were observed. Simultaneous exposure of foundry workers to silica dust and triethylamine could impair lung function.

Pharmacology and Toxicology of N-Benzylphenethylamine ("NBOMe") Hallucinogens.

Serotonergic hallucinogens induce profound changes in perception and cognition. The characteristic effects of hallucinogens are mediated by 5-HT2A receptor activation. One class of hallucinogens are 2,5-dimethoxy-substituted phenethylamines, such as the so-called 2C-X compounds 2,5-dimethoxy-4-bromophenethylamine (2C-B) and 2,5-dimethoxy-4-iodophenethylamine (2C-I). Addition of an N-benzyl group to phenethylamine hallucinogens produces a marked increase in 5-HT2A-binding affinity and hallucinogenic potency. N-benzylphenethylamines ("NBOMes") such as N-(2-methoxybenzyl)-2,5-dimethoxy-4-iodophenethylamine (25I-NBOMe) show subnanomolar affinity for the 5-HT2A receptor and are reportedly highly potent in humans. Several NBOMEs have been available from online vendors since 2010, resulting in numerous cases of toxicity and multiple fatalities. This chapter reviews the structure-activity relationships, behavioral pharmacology, metabolism, and toxicity of members of the NBOMe hallucinogen class. Based on a review of 51 cases of NBOMe toxicity reported in the literature, it appears that rhabdomyolysis is a relatively common complication of severe NBOMe toxicity, an effect that may be linked to NBOMe-induced seizures, hyperthermia, and vasoconstriction.

Combined local blood-brain barrier opening and systemic methotrexate for the treatment of brain tumors.

Despite aggressive therapy, existing treatments offer poor prognosis for glioblastoma multiforme patients, in part due to poor penetration of most drugs across the blood-brain barrier (BBB). We propose a minimal-invasive combined treatment approach consisting of local BBB disruption in the tumor in parallel to systemic drug administration. Local BBB disruption is obtained by convection-enhanced delivery of a novel BBB disruption agent, enabling efficient/targeted delivery of the systemically administered drug by the tumors own vasculature. Various human serum albumin (HSA) analogs were synthesized and screened for BBB disruption efficacy in custom in vitro systems. The candidate analogs were then delivered into naïve rat brains by convection-enhanced delivery and screened for maximal BBB disruption and minimal brain toxicity. These studies found a noncationized/neutralized analog, ethylamine (EA)-HSA, to be the optimal BBB-opening agent. Immunocytochemical studies suggested that BBB disruption by EA-HSA may be explained by alterations in occludin expression. Finally, an efficacy study in rats bearing intracranial gliomas was performed. The rats were treated by convection-enhanced delivery of EA-HSA in parallel to systemic administration of Methotrexate, showing significant antineoplastic effects of the combined approached reflected in suppressed tumor growth and significantly (~x3) prolonged survival.

Pharmacological characterization of memoquin, a multi-target compound for the treatment of Alzheimer's disease.

Alzheimer's disease (AD) is characterized by progressive loss of cognitive function, dementia and altered behavior. Over 30 million people worldwide suffer from AD and available therapies are still palliative rather than curative. Recently, Memoquin (MQ), a quinone-bearing polyamine compound, has emerged as a promising anti-AD lead candidate, mainly thanks to its multi-target profile. MQ acts as an acetylcholinesterase and ß-secretase-1 inhibitor, and also possesses anti-amyloid and anti-oxidant properties. Despite this potential interest, in vivo behavioral studies with MQ have been limited. Here, we report on in vivo studies with MQ (acute and sub-chronic treatments; 7-15 mg/kg per os) carried out using two different mouse models: i) scopolamine- and ii) beta-amyloid peptide- (Aß-) induced amnesia. Several aspects related to memory were examined using the T-maze, the Morris water maze, the novel object recognition, and the passive avoidance tasks. At the dose of 15 mg/kg, MQ was able to rescue all tested aspects of cognitive impairment including spatial, episodic, aversive, short and long-term memory in both scopolamine- and Aß-induced amnesia models. Furthermore, when tested in primary cortical neurons, MQ was able to fully prevent the Aß-induced neurotoxicity mediated by oxidative stress. The results support the effectiveness of MQ as a cognitive enhancer, and highlight the value of a multi-target strategy to address the complex nature of cognitive dysfunction in AD.

Use of recreational drug 1,3 Dimethylamylamine (DMAA) [corrected] associated with cerebral hemorrhage.

Dimethylamylamine (DMAA) was a forgotten pharmaceutical that was patented in 1944 as a nasal decongestant. DMAA has recently gained popularity as a dietary supplement, with claims of effectiveness as an athletic performance enhancer and weight loss aid. It is also sold as a recreational stimulant drug. DMAA is a sympathomimetic and potent pressor agent. This report describes 3 cases of cerebral hemorrhage in adults after the use of DMAA. The status of this substance as a synthetic or naturally occurring compound is also discussed.

Compound A, a plant origin ligand of glucocorticoid receptors, increases regulatory T cells and M2 macrophages to attenuate experimental autoimmune neuritis with reduced side effects.

Experimental autoimmune neuritis (EAN) is a helper T cell-mediated autoimmune demyelinating inflammatory disease of the peripheral nervous system and serves as the animal model for human inflammatory demyelinating polyneuropathies. Compound A, a plant-derived phenyl aziridine precursor, was reported to activate glucocorticoid receptors to exert transrepression but not transactivation properties. In this study, we investigated the effects of Compound A in EAN rats. Compound A greatly suppressed paraparesis in EAN, even when administrated after the appearance of the first neurological signs. Accumulation of macrophages and lymphocytes, demyelination, and mRNA levels of inflammatory molecules in sciatic nerves of EAN were greatly attenuated by Compound A. In addition, Compound A inhibited progression of neuropathic pain and repressed microglia but not astrocyte activation and IL-1beta and TNF-alpha up-regulation in EAN spinal cords. In EAN sciatic nerves, Compound A treatment increased numbers of anti-inflammatory M2 macrophages. Furthermore, Compound A induced the switch of macrophages from inflammatory M1 type to anti-inflammatory M2 type in vitro. In lymph nodes of EAN rats, Compound A depressed Th1 and Th17 cytokines, but increased Th2 cytokine and Foxp3 expression. An increase of Foxp3(+)/CD4(+) regulatory T cells was seen in peripheral blood of EAN rats following Compound A treatment. In addition, Compound A did not cause a hyperglycemia effect in EAN rats as compared with the immunosuppressive steroid prednisolone. Therefore, our data demonstrated that Compound A could effectively suppress EAN with reduced side effects by attenuating inflammation, suggesting that Compound A could be a potent candidate for treatment of autoimmune neuropathies.

Additive impairment of the barrier function and irritation by biogenic amines and sodium lauryl sulphate: a controlled in vivo tandem irritation study.

Biogenic amines are potential irritants e.g. in fish-, meat-, milk- and egg-processing professions like cooks, butchers and bakers. The aim of this study was to test the irritative and barrier-disrupting properties of the biogenic amines ammonium hydroxide (AM), dimethylamine (DMA) and trimethylamine (TMA). A repeated sequential irritation of 30 min twice per day was performed over a total of 4 days (tandem repeated irritation test) on the back of 20 healthy volunteers of both sexes with AM, DMA, TMA and sodium lauryl sulphate (SLS). The epidermal barrier function was assessed with a Tewameter TM 210, stratum corneum surface pH was measured with a Skin-pH-Meter 900, inflammation was assessed with a Chromameter CR-300 on the a* axis for redness and a visual score was recorded. All tested biogenic amines (AM, DMA and TMA) induced a barrier disruption and a pH increase paralleled with a 1-day-delayed onset of inflammatory signs. These effects were further enhanced and accelerated by a sequential application of SLS together with the biogenic amines, and inflammation occurred earlier than with the single compounds. Acetic acid (AA) in contrast did only show mild barrier disruption and no significant inflammatory signs. Our system allowed a ranking of the different compounds in their irritative potential in the tandem irritation with SLS: SLS > NaOH > TMA > AA > AM > DMA. The results are suggestive that in the food-processing industry the simultaneous contact with biogenic amines and harmful detergents like SLS should be minimized.

The role of captodiamine in the withdrawal from long-term benzodiazepine treatment.

BACKGROUND AND OBJECTIVES: Discontinuation of benzodiazepines can be associated with the emergence of a withdrawal syndrome which compromises successful termination of treatment. The objective of the present study was to evaluate whether a six week administration of captodiamine during benzodiazepine discontinuation could prevent emergence of a benzodiazepine withdrawal syndrome and thus facilitate discontinuation of these drugs. SUBJECTS AND METHODS: A controlled, randomised, double-blind trial of captodiamine versus placebo was conducted in 81 subjects presenting mild to moderate anxiety and treated for at least 6 months with a stable dose of benzodiazepine. Each subject was gradually weaned from benzodiazepines over a 14 day period using a tapering dose schedule and received captodiamine (150 mg/d) or placebo for 45 days from the beginning of the weaning period. OUTCOME MEASURES: The primary outcome criterion was the extent of withdrawal symptoms assessed using the Tyrer Benzodiazepine Withdrawal Symptom Questionnaire. Secondary outcome criteria were; self-evaluation of tension, anxiety, drowsiness and slowing of physical and mental performance using visual analogue scales; quality of sleep using the Spiegel questionnaire; anxiety using the Hamilton Anxiety Rating Scale; and cognitive function using a driving stimulation test. RESULTS: Analysis of the primary study criterion revealed a statistically significant difference (p < 0.0001) in the emergence of withdrawal symptoms between the two groups in favour of captodiamine at two, six and eight weeks following initiation of therapy. These results were supported by significant beneficial effects of captodiamine on the majority of secondary outcome measures. The switch to captodiamine was associated with an improvement in vigilance, which may be an advantage for the overall safety of the anxiolytic treatment, for example with regard to road safety. Discontinuation of captodiamine was not associated with the emergence of rebound anxiety. CONCLUSION: Captodiamine represents an interesting strategy for achieving benzodiazepine substitution with a low risk of dependence or impairment of cognitive function. Further clinical studies addressing the anxiolytic activity and safety of captodiamine in such subjects are merited.

Effects of experimental exposure to triethylamine on vision and the eye.

OBJECTIVES: To determine the effect of triethylamine (TEA) on the cornea and to evaluate the cause of blurred vision. To find the lowest observed effect concentration of exposure to TEA. METHODS: Four people were exposed to TEA for 4 hours at concentrations of 40.6, 6.5, and 3.0 mg/m3. Before and after every exposure, symptoms and ocular microscopy findings were recorded. Binocular visual acuity and contrast sensitivity at 2.5% contrast were also measured. Also, before and after the 40.6 mg/m3 exposure, corneal thickness was measured and ocular dimensions were recorded by ultrasonography, endothelial cells of the cornea were analysed, and serum and lacrimal specimens were collected for the analysis of TEA. RESULTS: After exposure to 40.6 mg/m3 TEA there was a marked oedema in the corneal epithelium and subepithelial microcysts. However, corneal thickness increased only minimally because of the epithelial oedema. The lacrimal concentrations of TEA were, on average (range) 41 (18-83) times higher than the serum TEA concentrations. The vision was blurred in all subjects and visual acuity and contrast sensitivity had decreased in three of the four subjects. After exposure to TEA at 6.5 mg/m3 two subjects experienced symptoms, and contrast sensitivity had decreased in three of the four subjects. There were no symptoms or decreases in contrast sensitivity after exposure to a TEA concentration of 3.0 mg/m3. CONCLUSIONS: TEA caused a marked oedema and microcysts in corneal epithelium but only minor increases in corneal thickness. The effects may be mediated by the lacrimal fluid owing to its high TEA concentration. Four hour exposure to a TEA concentration of 3.0 mg/m3 seemed to cause no effects, whereas exposure to 6.5 mg/m3 for the same period caused blurred vision and a decrease in contrast sensitivity.

Headache and blood pressure among triethylamine-exposed foundry workers.

This study attempted to determine whether cold box core makers exposed to triethylamine in foundries experienced headaches or had elevated blood pressure more often than workers without TEA exposure, as proposed by earlier reports. Forty-one core makers in three foundries and 82 referents were interviewed according to a structured questionnaire, and their blood pressure was measured. TEA exposure was determined from breathing-zone measurements. The 8-h time-weighted average TEA exposure varied between 0.3-60 mg/m3. The core makers did not report that they had the general symptoms of headaches more often than the referents. However, they had mild weekly headaches more often (44% vs. 17%). The core makers also reported headaches more often during the workweeks (45% vs. 19%). It seems likely that TEA exposure provokes mild headache among persons prone to suffer from vascular headaches. There was no difference in the occurrence of severe headaches or in the duration of headaches between the groups. The blood pressures were similar in both groups.

Contrast sensitivity measurement in evaluations of visual symptoms caused by exposure to triethylamine.

OBJECTIVES: To determine whether blurred vision caused by exposure to triethylamine (TEA) can be detected by the measurement of contrast sensitivity. METHODS: 41 cold box core makers of three foundries and 82 control workers were examined. A detailed ocular and medical history was obtained from the subjects. The contrast sensitivity of the core makers was measured on Monday and Friday of the same week both before and immediately after work and also on a third day, when air samples of TEA were collected. Contrast sensitivity and visual acuity were measured by optotype figures at full contrast, 2.5% contrast, and 0.6% contrast. The changes in contrast sensitivity were used for the analysis. The results of binocular vision and the results of the dominant eye were analysed. Urine specimens for the analysis of TEA were collected on every occasion when contrast sensitivity was measured. RESULTS: 78% of the core makers had had symptoms of blurred vision, and 31% had had trouble driving or working. The breathing zone eight hour time weighted average TEA concentrations were 0.3-60 mg/m3. The mean urinary TEA concentration after the shift was 35 mmol/mol creatinine. Continuous monitoring showed high peaks of TEA leakage at a core making machine. Changes in binocular visual acuity did not differ between the exposed and unexposed workers. The contrast sensitivity decreased in 49% of the core makers and 21% of the controls (P = 0.002). CONCLUSIONS: The blurred vision caused by exposure to TEA can be documented by measuring contrast sensitivity. The mechanism by which TEA produces symptoms remains an issue of further study.

Ocular effects of exposure to triethylamine in the sand core cold box of a foundry.

OBJECTIVES: To assess the acute and chronic ophthalmological effects of triethylamine exposure among foundry workers. METHODS: Ocular effects on people currently, previously, and never exposed to triethylamine in a foundry cold box were studied at two points in time. The initial phase included an ocular examination with a slit lamp to assess corneal health, a visual acuity test, and a questionnaire to assess vision symptoms. The follow up included measurements of corneal thickness with an ultrasonic pachymeter and the vision symptoms questionnaire before and after the shift and at the beginning and end of the week. Personal air measurements for triethylamine were also obtained during the follow up. RESULTS: The vision symptoms of blurriness, halos around lights, and blue hazy vision occurred more often in currently exposed workers than those previously or never exposed to triethylamine. Air concentrations of triethylamine ranged from < 0.33 mg/m3 to 20.3 mg/m3. Among currently exposed workers, symptoms were more common among those with exposure to > 10 mg/m3 of triethylamine (odds ratio (OR) = 3.0, 95% confidence interval (95% CI) 0.35-25.6). No differences in corneal thickness were found in currently or previously exposed workers and those never exposed. No increase in corneal thickness was found after v before the shift. CONCLUSION: Despite low concentrations of triethylamine and no corneal oedema, workers exposed to triethylamine reported vision symptoms. Possible explanations for these symptoms without corneal oedema are that triethylamine affects ciliary muscle function or that the corneal oedema was transient and not present when corneal thickness measurements were taken. No chronic effects were found in previously exposed workers. Further research is needed to elucidate the mechanism for the reported vision symptoms, which occurred below the current United States eight hour time weighted standard of 100 mg/m3 and the American Conference of Governmental Industrial Hygienists (ACGIH) recommended value at the time of our study of 40 mg/m3. We recommend that air concentrations be maintained to meet the current recommended ACGIH threshold of 4.1 mg/m3.

[Randomized double-blind comparative study of the efficacy and tolerance of medifoxamine and imipramine in depressed patients]. / Etude randomisée en double aveugle comparant l'efficacité et la tolérance de la médifoxamine et de l'imipramine chez des patients déprimés.

Medifoxamine (Clédial TM), a non tricyclic non MAOI antidepressant drug with a dopaminergic and serotoninergic mechanism of action, was compared to imipramine in a multicenter double blind trial. Patients suffering from DSM III-R major depression (without psychotic features), with a minimum inclusion score of 25 at the MADRS after an initial 7-day wash-out period, were randomly assigned to a 4-week treatment by either imipramine or medifoxamine, with flexible doses of at least 100 mg after 2 weeks of treatment. No associated treatment was permitted except for lorazepam 2 to 5 mg per day. Ninety eight patients were recruited by 20 centers throughout France. Eighty four terminated the 4-week protocol. Early terminations were due to serious adverse events (3), death on imipramine (1), protocol violation (1), refusal to continue (1), loss to follow up (1). The 2 groups of patients were comparable on inclusion. In the medifoxamine group (receiving a daily dose of 194 mg at day 28) the percentage of improvement in MADRS scores, the number of patients with a MADRS improvement of a least 50% and a final MADRS score inferior to 8, were not significantly different from the imipramine group (daily dose: 161 mg at day 28). No more difference appeared when several clinical variables were analyzed, in particular the DSM III-R melancholic, the Newcastle endogenous subtypes and the in or out patient status. The two treatment groups were also comparable on other scales (HDRS, HARS assessing anxiety, CGI).(ABSTRACT TRUNCATED AT 250 WORDS)

Visual disturbances in man as a result of experimental and occupational exposure to dimethylethylamine.

Experimental exposure of four volunteers to 40-50 mg/m3 of dimethylethylamine (DMEA) for eight hours caused irritation of the mucous membrane of their eyes, subjective visual disturbances (haze), and slight oedema of the corneal epithelium. The thickness of the cornea showed a slight but consistent increase in all four subjects at these exposures and in two subjects exposed to 10 mg/m3. Concentrations of 80 and 160 mg/m3 for 15 minutes caused eye irritation but no visual disturbances or corneal oedema. Occupational exposure for eight hours to about 25 mg/m3 of DMEA (with peaks above 100 mg/m3) was also associated with eye irritation, haze, and corneal oedema. The divergence between our findings and other reports in which visual disturbances occurred at lower concentrations during occupational exposure may be due to peak concentrations.

Sulfur-containing amino acids that increase renal glutathione protect the kidney against papillary necrosis induced by 2-bromoethylamine.

Papillary necrosis was observed in the kidneys of rats, 72 h after receiving a single injection of bromoethylamine (BEA). This effect was associated with renal glutathione (GSH) depletion 1 h after the administration of BEA. Stimulation of renal GSH synthesis by pretreatment of the animals either with glutamine + glycine + cystine or N-acetyl-L-cysteine was attempted. Low doses of these precursors administered previously to BEA, respectively, decreased or abolished the GSH depletion. Nevertheless, both pretreatments failed to modify the magnitude of renal papillary necrosis. High doses of these precursors did not modify the BEA-induced GSH depletion, but they significantly increased GSH levels 24 h after BEA administration. At this time, although a smaller intensity of renal papillary necrosis was observed with the amino acid mixture pretreatment, N-acetyl-L-cysteine pretreated rats showed no papillary necrosis. It is suggested that the observed protective effects against BEA-induced renal papillary injury may be ascribed in some measure, to a mechanism independent of GSH.