Innovative Pilot Studies of Novel Mechanism of Action Compounds for Treating Psychiatric Disorders (U01): Grant# PAR-12-007

2012 ◽  
1990 ◽  
Vol 4 (7) ◽  
pp. 420-423 ◽  
C Ó'Moráin ◽  
A Tobin ◽  
T McColl ◽  
Y Suzuki

Patients with active ulcerative colitis have increased levels of leukotriene B4 in their rectal mucosa. Eicosapentaenoic acid (EPA) competitively inhibits the cyclo-oxgenase pathway and reduces the formation of cyclo-oxygenase pathway products. EPA is a good substrate for lipoxygenase enzymes and is efficiently converted to leukotriene 85, which is less biologically active. The conversion of EPA to leukotriene B5 is as efficient as that of arachidonic acid to teukotriene B4. Two pilot studies showed benefit of EPA in the treatment of ulcerative colitis. Two of three controlled studies suggest that EPA is more effective than placebo in the treatment of active chronic ulcerative colitis. The mechanism of action is probably reduction of leukotriene B4, but EPA could increase cell and lysosomal membrane stability, or it may exert its effect by reducing interleukin-l. More controlled studies and detailed investigation into the mode of action of EPA are required.

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 3637-3637
Guerry J Cook ◽  
Howard L Elford ◽  
Timothy Pardee

Abstract Abstract 3637 Acute Myeloid Leukemia (AML) is an aggressive, genetically heterogeneous disease wherein immature myeloid progenitors crowd out the normal hematopoietic cells leading to marrow failure and ultimately death. Each year in the United States there are approximately 12,000 new cases and 9,000 deaths from AML. Combination chemotherapy of an anthracycline and cytarabine has remained the mainstay of frontline treatment despite decades of active research. Treatment will often lead to a remission; however, the majority of patients relapse with chemoresistant disease. This highlights the need for the development of new therapies for patients. The Ribonucleotide Reductase (RR) reaction facilitates the conversion of ribonucleotides to deoxyribonucleotides via a free radical intermediate and is the rate-limiting step in DNA replication. The anti-tumor activity of Hydroxyurea is due to its ability to quench the free radical intermediate generated at the M2 subunit of RR ultimately resulting in a depletion of the cell's deoxyribonucleotide pool. This chemotherapeutic is useful for the palliative treatment of AML; however, its myelosuppressive effects are dose limiting. 3,4-Dihydroxybenzohydroamic acid (Didox) is a RR inhibitor with a mechanism of action similar to that of Hydroxyurea that has been shown to be less myelosuppressive in an animal model. Didox has been examined for toxicity in Phase I and Phase II trials in the United Kingdom in several malignancies. These clinical trials have reported Didox to be well tolerated at 6 g/m2. Major dose limiting organ toxicities were hepatic and renal. Given this low toxicity and mechanism of action we tested the activity of Didox in pilot studies of human and murine leukemias. In vitro studies were done to assess the Inhibitory Concentration (IC50) against five human AML cell lines, KG1a, OCI-AML3, THP-1, HL60 and K562. Cells were exposed to a titration of Didox for 72 hours and viability determined. The average IC50 of Didox was 5.76 μM (Range 3.62–7.37 μM). Initial In vivo studies were carried out in a syngeniec, therapy resistant MLL-ENL driven AML model. Murine leukemias were injected into sublethally irradiated recipients and allowed to engraft. Animals were given five days of Didox 425 mg/kg or a control treatment via intraperitoneal injection. Response and survival data were collected. A nimals tolerated the therapy well. Treated animals demonstrated a significant survival benefit in two separately derived MLL leukemias (one expressing the Flt3-ITD and one expressing NRasG12D) with p values of 0.0094 and 0.009 respectively. To determine the efficacy of Didox against a murine Acute Lymphoblastic Leukemia (ALL) model we injected syngeniec Balb/c mice with Baf3 cells engineered to express the p210 BCR-ABL fusion protein. We found that while the animals tolerated Didox, treatment did not provide a survival benefit, p =0.3581. This suggests that the use of Didox would be more efficacious in the treatment of AML than in ALL. Didox is a novel ribonucleotide reductase inhibitor with IC50 values in the low micromolar range for a panel of human and murine cell lines. Pilot studies in our syngeneic mouse models show that Didox is well tolerated in AML and ALL. Moreover, Didox demonstrates a survival benefit in chemoresistant murine AMLs. This data would imply Didox has activity in AML and additional studies to further characterize its activity are underway. Disclosures: Elford: Molecules for Health: Equity Ownership, Patents & Royalties.

2017 ◽  
Vol 16 (04) ◽  
pp. 87-92
Waheed ashokatkassam Kara ◽  
Khamis Hassan Bakari ◽  
Henry Anselmo Mayala ◽  
Bing Shao ◽  
Mao Jing

2021 ◽  
Vol 11 (1) ◽  
Lukas Frase ◽  
Lydia Mertens ◽  
Arno Krahl ◽  
Kriti Bhatia ◽  
Bernd Feige ◽  

AbstractTranscranial direct current stimulation (tDCS) is increasingly used as a form of noninvasive brain stimulation to treat psychiatric disorders; however, its mechanism of action remains unclear. Prolonged visual stimulation (PVS) can enhance evoked EEG potentials (visually evoked potentials, VEPs) and has been proposed as a tool to examine long-term potentiation (LTP) in humans. The objective of the current study was to induce and analyze VEP plasticity and examine whether tDCS could either modulate or mimic plasticity changes induced by PVS. Thirty-eight healthy participants received tDCS, PVS, either treatment combined or neither treatment, with stimulation sessions being separated by one week. One session consisted of a baseline VEP measurement, one stimulation block, and six test VEP measurements. For PVS, a checkerboard reversal pattern was presented, and for tDCS, a constant current of 1 mA was applied via each bioccipital anodal target electrode for 10 min (Fig. S1). Both stimulation types decreased amplitudes of C1 compared to no stimulation (F = 10.1; p = 0.002) and led to a significantly smaller increase (PVS) or even decrease (tDCS) in N1 compared to no stimulation (F = 4.7; p = 0.034). While all stimulation types increased P1 amplitudes, the linear mixed effects model did not detect a significant difference between active stimulation and no stimulation. Combined stimulation induced sustained plastic modulation of C1 and N1 but with a smaller effect size than what would be expected for an additive effect. The results demonstrate that tDCS can directly induce LTP-like plasticity in the human cortex and suggest a mechanism of action of tDCS relying on the restoration of dysregulated synaptic plasticity in psychiatric disorders such as depression and schizophrenia.

2019 ◽  
Vol 42 ◽  
Hanna M. van Loo ◽  
Jan-Willem Romeijn

AbstractNetwork models block reductionism about psychiatric disorders only if models are interpreted in a realist manner – that is, taken to represent “what psychiatric disorders really are.” A flexible and more instrumentalist view of models is needed to improve our understanding of the heterogeneity and multifactorial character of psychiatric disorders.

Crisis ◽  
1999 ◽  
Vol 20 (2) ◽  
pp. 64-70 ◽  
Tamás Zonda

The author examined completed suicides occurring over a period of 25 years in a county of Hungary with a traditionally low (relatively speaking) suicide rate of 25.8. The rates are clearly higher in villages than in the towns. The male/female ratio was close to 4:1, among elderly though only 1.5:1. The high risk groups are the elderly, divorced, and widowed. Violent methods are chosen in 66.4% of the cases. The rates are particularly high in the period April-July. Prior communication of suicidal intention was revealed in 16.3% of all cases. Previous attempts had been undertaken by 17%, which in turn means that 83% of suicides were first attempts. In our material 10% the victims left suicide notes. Psychiatric disorders were present in 60.1% of the cases, and severe, multiple somatic illnesses (including malignomas) were present in 8.8%. The majority of the data resemble those found in the literature.

Crisis ◽  
2005 ◽  
Vol 26 (2) ◽  
pp. 73-77 ◽  
Dinesh Bhugra

Abstract. Sati as an act of ritual suicide has been reported from the Indian subcontinent, especially among the Hindus, for several centuries. Although legally proscribed, these acts occur even now in modern India. The principle behind such acts has been put forward as the principle of good wife. There is little evidence to suggest that women who commit this act suffer from a formal mental illness. Cultural factors and gender role expectations play a significant role in the act and its consequences. Using recent examples, this paper illustrates the cultural factors, which may be seen as contributing to the act of suicide. Other factors embedded in the act also emphasize that not all suicides have underlying psychiatric disorders and clinicians must take social causation into account while preparing any prevention strategies.

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