Pentacyclo-undecane derived cyclic tetra-amines: Synthesis and evaluation as potent anti-tuberculosis agents

As part of an ongoing effort to develop highly potent anti-tuberculosis agents, fourteen pentacyclo-undecane (PCU) tetra-amine compounds were synthesized and screened for their in vitro anti-mycobacterial activity against two TB strains, H37Rv and XDR 194 [an extensively drug-resistant strain of tuberculosis]. Using the broth macrodilution method, nitrofuranylamide based compounds (6a and 6b) showed almost similar activities against the H37Rv strain of Mycobacterium tuberculosis when compared with the control drug, ethambutol. N-Geranyl piperazine PCU (8a) and trans–trans farnesyl piperazine PCU (8b) were 3.2 and 3.7 times more potent than commercially available ethambutol. Both isoprenyl PCU tetra-amine derivatives and N-decyl piperazine PCU (9a) were highly active against the XDR 194 strain of tuberculosis with MICs in the range of 0.63–3.02 μM. Cytotoxicities (IC₅₀) of isoprenyl based compounds (8a, 8b) and compound 9a were tested on a mammalian cell line [MDBK (Madin Darby bovine kidney epithelium)] with values of 30, 24 and 25 μM respectively.     

Kinetices of polymerization of 1-octene with the catalyst system VOCl3-AlEt3 (or AlEt2Br)

Kinetic studies of the polymerization of 1-octene with the Ziegler-Natta catalyst systems VOCl₃—AlEt₃ (I) and VOCl₃—AlEt₂Br (II) are reported. The effect of the various parameters such as the Al/V ratio, catalyst and monomer concentrations, reaction time, aging time and temperature on rate of reaction and molecular weight of polymer were studied. Each of these parameters has a profound effect on the polymer yield and the rate of the reaction for both systems. The rate of polymerization increases linearly with increasing temperature, catalyst and monomer concentrations. The reaction is first order with respect to both the monomer and the catalyst concentration in the two catalyst systems studied. From the Arrhenius plot the overall activation energy of polymerization for the two systems was found to be 51,2 and 43,5 kJ/mol, respectively. The mechanism of polymerization is discussed on the basis of the dependence of the polymerization rate on the alkylaluminium concentration.     

Anatomy,physiology, and pathophysiology of the pedunculopontine nucleus

The pedunculopontine nucleus is composed of cholinergic and non‐cholinergic neurones and is located in the caudal pontomesencephalic tegmentum. Evidence suggests that the nucleus plays a role in the production and control of movement. The nucleus has dense interconnections with the basal ganglia, as well as with other areas of the brain associated with motor control. Electrical stimulation of the pedunculopontine nucleus in the decerebrate cat or rat produces organized locomotor movements. Physiological studies show that the pedunculopontine nucleus modulates its activity in response to locomotion, as well as voluntary arm and eye movements. Degeneration of the pedunculopontine nucleus is seen in post‐mortem brains in humans with Parkinson's disease and Parkinsonian syndromes. In animal models of Parkinson's disease, metabolic changes are seen in the pedunculopontine nucleus, and chemical inhibition or mechanical disruption of the nucleus can produce an akinetic state in animals and man. In this paper we review the literature in support of the suggestion that some of the symptoms of Parkinson's disease are caused by dysfunction of the pedunculopontine nucleus. In accordance with this view, direct stimulation of the nucleus can ameliorate some symptoms of the disease, as demonstrated in both experimental animals and man. © 2008 Movement Disorder Society     

Minimizing complications of endoscopic ultrasound and EUS-guided fine needle aspiration

Endoscopic ultrasound (EUS) and EUS-guided fine needle aspiration have become important tools in evaluation of patients who have various gastrointestinal and nongastrointestinal disorders, and are being increasingly utilized at many centers. With over 10 years of worldwide published clinical data, the collective experience suggests that EUS is a safe tool. There are various measures that may be undertaken to help minimize the risks. In light of ongoing advances in interventional techniques and recognition of new procedural indications, the safety of all types of procedures and efforts to minimize EUS-related complications need to be periodically reexamined.     

Connectivity of the human pedunculopontine nucleus region and diffusion tensor imaging in surgical targeting

OBJECT: The pedunculopontine nucleus (PPN) region of the brainstem has become a new stimulation target for the treatment of gait freezing, akinesia, and postural instability in advanced Parkinson disease (PD). Because PD locomotor symptoms are probably caused by excessive gamma-aminobutyric acidergic inhibition of the PPN, low-frequency stimulation of the PPN may overcome this inhibition and improve the symptoms. However, the anatomical connections of this region in humans are not known in any detail. METHODS: Diffusion weighted magnetic resonance (MR) images were acquired at 1.5 teslas, and probabilistic tractography was used to trace the connections of the PPN region in eight healthy volunteers. A single seed voxel (2 x 2 x 2 mm) was chosen in the PPN just lateral to the decussation of the superior cerebellar peduncle, and the Diffusion Toolbox of the Oxford Centre for Functional Magnetic Resonance Imaging of the Brain was used to process the acquired MR images. The connections of each volunteer's PPN region were analyzed using a human brain MR imaging atlas. RESULTS: The PPN region was connected with the cerebellum and spinal cord below and to the thalamus, pallidum, subthalamic nucleus, and motor cortex above. The regions of the primary motor cortex that control the trunk and upper and lower extremities had the highest connectivity compared with other parts of motor cortex. CONCLUSIONS: These findings suggest that connections of the PPN region with the primary motor cortex, basal ganglia, thalamus, cerebellum, and spinal cord may play important roles in the regulation of movement by the PPN region. Diffusion tensor imaging tractography of the PPN region may be used preoperatively to optimize placement of stimulation electrodes and postoperatively it may also be useful to reassess electrode positions.     

The HDAC inhibitor trichostatin A inhibits growth of small cell lung cancer cells

BACKGROUND: An estimated 162,460 people will die of lung cancer in the United States in 2006, making it the leading cause of cancer deaths. Small cell lung cancer (SCLC) accounts for 20% of all lung cancers and exhibits aggressive behavior with early metastases. Current treatments yield five-year survival rates of 5 to 10%, indicating a need for novel therapeutic approaches. Histone deacetylase inhibitors (HDACIs) represent a new class of anticancer agents. Trichostatin A (TSA), an HDACI, has been shown to inhibit growth in several cancers. We hypothesized that TSA may inhibit proliferation of SCLC cells. MATERIALS AND METHODS: Human SCLC DMS53 cells were treated with TSA (0 to 400 nM). Light microscopy was used to assess changes in cell morphology. Western analysis was performed for acetylated histone 4 to confirm HDAC inhibition. The effect of TSA treatment on cellular growth was measured by the MTT assay. Finally, levels of BCL-2, cleaved poly(ADP-ribose) polymerase, p21, and p27 proteins were measured to look for induction of cell cycle arrest and/or apoptosis. RESULTS: DMS53 cells treated with TSA underwent dramatic changes in cell appearance. Treated cells assumed round and spindle shapes with distinct cellular borders. Western analysis demonstrated increased levels of acetylated histone 4. TSA treatment resulted in a dose-dependent inhibition of growth. Lastly, elevated p21, p27, and cleaved poly(ADP-ribose) polymerase along with decreased BCL-2 protein levels were observed. CONCLUSIONS: TSA causes morphological differentiation and dose-dependent inhibition of cell growth via cell cycle arrest and subsequent apoptosis. This suggests that TSA and other HDACIs may represent a new potential therapy for patients with SCLC.     

A preclinical and clinical study of lithium in low-grade neuroendocrine tumors

Background.

Low-grade neuroendocrine tumors (NETs) respond poorly to chemotherapy; effective, less toxic therapies are needed. Glycogen synthase kinase (GSK)-3β has been shown to regulate growth and hormone production in NETs. Use of lithium chloride in murine models suppressed carcinoid cell growth, reduced GSK-3β levels, and reduced expression of chromogranin A. This study assessed the efficacy of lithium chloride in patients with NETs.

Design.

Eligible patients had low-grade NETs. A single-arm, open-label phase II design was used. Lithium was dosed at 300 mg orally three times daily, titrated to serum levels of 0.8–1.0 mmol/L. The primary endpoint was objective tumor response by the Response Evaluation Criteria in Solid Tumors. Secondary endpoints included overall survival, progression-free survival, GSK-3β phosphorylation, and toxicity.

Results.

Fifteen patients were enrolled between October 3, 2007 and July 17, 2008, six men and nine women. The median age was 58 years. Patient diagnoses were carcinoid tumor for eight patients, islet cell tumor for five patients, and two unknown primary sites. Eastern Cooperative Oncology Group performance status scores were 0 or 1. Two patients came off study because of side effects. The median progression-free survival interval was 4.50 months. There were no radiographic responses. Because of an early stopping rule requiring at least one objective response in the first 13 evaluable patients, the study was closed to further accrual. Patients had pre- and post-therapy biopsies.

Conclusions.

Lithium chloride was ineffective at obtaining radiographic responses in our 13 patients who were treated as part of this study. Based on the pre- and post-treatment tumor biopsies, lithium did not potently inhibit GSK-3β at serum levels used to treat bipolar disorders.