Fibromyalgia Pathogenesis and Treatment Options Update.

This review article presents and summarizes up-to-date literature on the clinical manifestations, diagnosis, pathophysiological mechanisms, and treatment options for fibromyalgia patients. First, the most recent diagnostic criteria for fibromyalgia, as put forth by the American College of Rheumatology will be summarized. Clinical features, including chronic widespread pain, hyperalgesia, mood disorders, anxiety, and disturbed sleep patterns will be explored in-depth. The pathogenesis and pathophysiology of fibromyalgia involves alterations in multiple ascending and descending central nervous system pathways, as well as peripheral pathways, leading to heightened pain sensitivity. Risk factors have been studied extensively, and the most recent research focuses on various genetic influences and the contributions of stress and poor sleep. Lastly, the discussion in this article focuses on treatment options for fibromyalgia; some have been mainstay options for many years. Pharmacological agents include tricyclic antidepressants, anti-epileptic drugs, selective serotonin reuptake inhibitors, norepinephrine/serotonin reuptake inhibitors, as well as some investigational agents. The evidence behind non-pharmacologic treatments, including massage therapy, exercise, and acupuncture, are discussed.

Cytokine profiling of young overweight and obese female African American adults with prediabetes.

Approximately 5-10% of subjects with prediabetes become diabetic every year. Inflammation is involved in the development of obesity-related type 2 diabetes (T2D). However, to date, the relationship between inflammation and prediabetes, defined by hemoglobin A1c (HbA1c) ≥5.7 and <6.5%, remains largely unexplored, especially in African Americans. Therefore, in this study we examined a comprehensive panel of 13 cytokines involved in the inflammatory response in overweight/obese subjects with prediabetes. A total of 21 otherwise healthy, overweight/obese, young adult African American females with prediabetes, together with 20 matched overweight/obese controls, were selected for this study. Plasma cytokines were assessed by multiplex cytokine profiling. Plasma concentrations of interleukin (IL)-5, IL-6, IL-7, tumor necrosis factor-α (TNF-α), and granulocyte-monocyte colony-stimulating factor (GM-CSF) were significantly higher in the prediabetic group, as compared to the control group (all p<0.05). Plasma concentrations of all the other cytokines, interferon-γ (IFN-γ), IL-1ß, IL-2, IL-4, IL-8, IL-10, IL-12p70 and IL-13, seemed to be elevated in the prediabetic group, but failed to reach statistical significances. Upon merging both groups, HbA1c was found to be positively correlated with IFN-γ, IL-1ß, IL-2, IL-5, IL-7, IL-8, TNF-α and GM-CSF. This study demonstrates elevated levels of various pro-inflammatory cytokines in overweight/obese young subjects with prediabetes, which place them at higher risk of developing T2D and cardiovascular diseases. Our data also call for further investigations in animal models and population cohorts to establish the roles of a variety of pro-inflammatory cytokines in the early development of obesity-related T2D.

Interventional Treatment of Complex Regional Pain Syndrome.

Complex regional pain syndrome (CRPS) is a rare but debilitating chronic pain disorder characterized by persistent pain disproportionate to any preceding injury. CRPS can have a significant impact on a person's quality of life, often leading to disability and psychological distress. Despite being recognized for over a century, finding the right treatment for CRPS can be challenging. In this article, we will explore the causes, symptoms, and interventional treatment options for CRPS, as well as the latest research on this complex and often misunderstood condition.

Clinical Diagnosis and Treatment of Chronic Pain.

More than 600 million people globally are estimated to be living with chronic pain. It is one of the most common complaints seen in an outpatient setting, with over half of patients complaining of pain during a visit. Failure to properly diagnose and manage chronic pain is associated with substantial morbidity and mortality, especially when opioids are involved. Furthermore, it is a tremendous financial strain on the healthcare system, as over USD 100 billion is spent yearly in the United States on healthcare costs related to pain management and opioids. This exceeds the costs of diabetes, heart disease, and cancer-related care combined. Being able to properly diagnose, manage, and treat chronic pain conditions can substantially lower morbidity, mortality, and healthcare costs in the United States. This review will outline the current definitions, biopsychosocial model, subclassifications, somatosensory assessments, imaging, clinical prediction models, and treatment modalities associated with chronic pain.

Diazaspirocyclic compounds as selective ligands for the α4ß2 nicotinic acetylcholine receptor.

Diazaspirocyclic ligands have been synthesized in four steps as selective α4ß2 nicotinic acetylcholine receptor antagonists. Structural assignment of 1-(pyridin-3-yl)-2-spiropyrrolidino-3,2'-1-azabiclo[2.2.1]heptane 2, was confirmed using a combination of NMR experiments on a key intermediate, spirolactam 9. All three target compounds synthesized in this diazaspirocyclic series exhibited high affinity (K(i)<35 nM) at the human α4ß2 nAChR subtype, and very low affinity for the human α7, α3ß4 (ganglion) and α1ß1γδ (muscle) subtypes (K(i)>500 nM).

Discovery of novel α7 nicotinic acetylcholine receptor ligands via pharmacophoric and docking studies of benzylidene anabaseine analogs.

Based on pharmacophore elucidation and docking studies on interactions of benzylidene anabaseine analogs with AChBPs and α7 nAChR, novel spirodiazepine and spiroimidazoline quinuclidine series have been designed. Binding studies revealed that some of hydrogen-bond donor containing compounds exhibit improved affinity and selectivity for the α7 nAChR subtype in comparison with most potent metabolite of GTS-21, 3-(4-hydroxy-2-methoxybenzylidene)-anabaseine. Hydrophobicity and rigidity of the ligand also contribute into its binding affinity. We also describe alternative pharmacophoric features equidistant from the carbonyl oxygen atom of the conserved Trp-148 of the principal face, which may be exploited to further design diverse focused libraries targeting the α7 nAChR.

Intrusive thoughts and psychopathy in a student and incarcerated sample.

Unwanted intrusive thoughts play an integral role in a number of different disorders including obsessive-compulsive disorder, posttraumatic stress disorder and substance use and abuse disorders. The objectives of this study were twofold. First, we examined intrusive thoughts and impulses in a student and incarcerated sample. Second, in an effort to better understand the non-universality of the intrusive thought experience, we hypothesized that psychopathic traits may be accounting for the 10-20% of individuals who deny the experience of intrusive thoughts. Using the methodology of Rachman, S., and de Silva, P. [(1978). Abnormal and normal obsessions. Behavior Research and Therapy, 16, 233-248] and Salkovskis, P.M., and Harrison, J. [(1984). Abnormal and normal obsessions: a replication. Behavior Research and Therapy, 22, 549-552], the frequency and content of intrusive thinking were extremely similar to the original studies for the student group. Higher levels of psychopathic traits appear to account for a lower number of intrusive thoughts and impulses within the inmate sample. Implications of the findings and directions for future research are discussed.

The Management of Testicular Seminomas, 1979.

The reported results from throughout the world of modern treatment of testicular seminoma are reviewed for the various clinical stages of disease. The three-year survival rate for 1,346 patients with Stage 1 and 2 disease is 91%. Since the review reveals considerable differences in staging methods, a clinically useful staging system is proposed. Treatment methods are described and discussed. Recommendations are made assuming that patients so treated are clinically evaluated for extent of disease before treatment with currently available techniques, including lymphangiography, CT scanning, perhaps ultrasonography, and serum marker determinations. Although the role of cytoreductive surgery in patients with seminoma, even bulky seminoma, now is limited, occasionally when laparotomy is done, debulking may also be helpful. Effective combination chemotherapy regimens have not been identified. The 28% three-year survival rate of patients with Stage 3 disease establishes the real need to identify such therapy. Finally, anaplastic seminoma is considered; a recent review by Percarpio indicates that this subtype perhaps is not unlike classical seminoma as far as stage distribution and prognosis is concerned.

Resolution of long standing tinnitus following radiofrequency ablation of C2-C3 medial branches--a case report.

Tinnitus is described as an auditory phantom perception analogous to central neuropathic pain. Despite the high prevalence of this debilitating symptom, no intervention is recognized that reliably eliminates tinnitus symptoms; a cause has yet to be determined. A 65-year-old healthy man presented with a 3 year history of left-sided tinnitus. Full workup performed by the primary care physician including blood tests for electrolyte imbalance, consultations by 2 independent otholaryngologists, and imaging did not reveal abnormalities to provide etiology of the tinnitus. No other complaints were noted except for occasional minimal left sided neck pain. Cervical spine x-ray showed degenerative changes with facet hypertrophy more pronounced on the left side. Subsequently, the patient underwent diagnostic left-sided C2-C3 medial branch block, resulting in complete resolution of tinnitus for more than 6 hours. After successful radiofrequency ablation of left C2-C3 medial branches, the patient became asymptomatic. At one year follow-up, he continued to be symptom free. Sparce studies have shown interaction between the somatosensory and auditory system at dorsal cochlear nucleus (DCN), inferior colliculus, and parietal association areas. Upper cervical nerve (C2) electrical stimulation evokes potentials in the DCN, eliciting strong patterns of inhibition and weak excitation of the DCN principal cells. New evidence demonstrated successful transcutaneous electrical nerve stimulation (TENS) of upper cervical nerve (C2) for treatment of somatic tinnitus in 240 patients. This case indicates that C2-C3 facet arthropathy may cause tinnitus and radiofrequency ablation of C2-C3 medial branches can provide an effective approach not previously considered.

Docking studies of benzylidene anabaseine interactions with α7 nicotinic acetylcholine receptor (nAChR) and acetylcholine binding proteins (AChBPs): application to the design of related α7 selective ligands.

AChBPs isolated from Lymnaea stagnalis (Ls), Aplysia californica (Ac) and Bulinus truncatus (Bt) have been extensively used as structural prototypes to understand the molecular mechanisms that underlie ligand-interactions with nAChRs [1]. Here, we describe docking studies on interactions of benzylidene anabaseine analogs with AChBPs and α7 nAChR. Results reveal that docking of these compounds using Glide software accurately reproduces experimentally-observed binding modes of DMXBA and of its active metabolite, in the binding pocket of Ac. In addition to the well-known nicotinic pharmacophore (positive charge, hydrogen-bond acceptor, and hydrophobic aromatic groups), a hydrogen-bond donor feature contributes to binding of these compounds to Ac, Bt, and the α7 nAChR. This is consistent with benzylidene anabaseine analogs with OH and NH(2) functional groups showing the highest binding affinity of these congeners, and the position of the ligand shown in previous X-ray crystallographic studies of ligand-Ac complexes. In the predicted ligand-Ls complex, by contrast, the ligand OH group acts as hydrogen-bond acceptor. We have applied our structural findings to optimizing the design of novel spirodiazepine and spiroimidazoline quinuclidine series. Binding and functional studies revealed that these hydrogen-bond donor containing compounds exhibit improved affinity and selectivity for the α7 nAChR subtype and demonstrate partial agonism. The gain in affinity is also due to conformational restriction, tighter hydrophobic enclosures, and stronger cation-π interactions. The use of AChBPs structure as a surrogate to predict binding affinity to α7 nAChR has also been investigated. On the whole, we found that molecular docking into Ls binding site generally scores better than when a α7 homology model, Bt or Ac crystal structure is used.

First total synthesis of (+/-)-3-hydroxy-11-norcytisine: structure confirmation and biological characterization.

The first total synthesis of the natural product 3-hydroxy-11-norcytisine (1), structurally related to cytisine (2), a benchmark ligand at neuronal nicotinic acetylcholine receptors (NNRs), has been achieved. The synthesis permits the unambiguous confirmation of the structure originally proposed for 1 and has enabled initial biological characterization of 1 and its related compounds against NNRs.

Synthesis of 2-(pyridin-3-yl)-1-azabicyclo[3.2.2]nonane, 2-(pyridin-3-yl)-1-azabicyclo[2.2.2]octane, and 2-(pyridin-3-yl)-1-azabicyclo[3.2.1]octane, a class of potent nicotinic acetylcholine receptor-ligands.

In an attempt to generate nicotinic acetylcholine receptor (nAChR) ligands selective for the alpha4beta2 and alpha7 subtype receptors we designed and synthesized constrained versions of anabasine, a naturally occurring nAChR ligand. 2-(Pyridin-3-yl)-1-azabicyclo[2.2.2]octane, 2-(pyridin-3-yl)-1-azabicyclo[3.2.2]nonane, and several of their derivatives have been synthesized in both an enantioselective and a racemic manner utilizing the same basic synthetic approach. For the racemic synthesis, alkylation of N-(diphenylmethylene)-1-(pyridin-3-yl)methanamine with the appropriate bromoalkyltetrahydropyran gave intermediates which were readily elaborated into 2-(pyridin-3-yl)-1-azabicyclo[2.2.2]octane and 2-(pyridin-3-yl)-1-azabicyclo[3.2.2]nonane via a ring opening/aminocyclization sequence. An alternate synthesis of 2-(pyridin-3-yl)-1-azabicyclo[3.2.2]nonane via the alkylation of N-(1-(pyridin-3-ylethylidene)propan-2-amine has also been achieved. The enantioselective syntheses followed the same general scheme, but utilized imines derived from (+)- and (-)-2-hydroxy-3-pinanone. Chiral HPLC shows that the desired compounds were synthesized in >99.5% ee. X-ray crystallography was subsequently used to unambiguously characterize these stereochemically pure nAChR ligands. All compounds synthesized exhibited high affinity for the alpha4beta2 nAChR subtype ( K i < or = 0.5-15 nM), a subset bound with high affinity for the alpha7 receptor subtype ( K i < or = 110 nM), selectivity over the alpha3beta4 (ganglion) receptor subtype was seen within the 2-(pyridin-3-yl)-1-azabicyclo[2.2.2]octane series and for the muscle (alpha1betagammadelta) subtype in the 2-(pyridin-3-yl)-1-azabicyclo[3.2.2]nonane series.

Advanced Cell Technology, Inc.

Advanced Cell Technology, Inc. (OTCBB: ACTC) is a biotechnology company applying novel human embryonic stem cell technologies in the emerging field of regenerative medicine. We believe that regenerative medicine has the potential to revolutionize the field by enabling scientists to produce human cells of any kind for use in a wide array of therapies.

TC-1734: an orally active neuronal nicotinic acetylcholine receptor modulator with antidepressant, neuroprotective and long-lasting cognitive effects.

The development of selective ligands targeting neuronal nicotinic acetylcholine receptors to alleviate symptoms associated with neurodegenerative diseases presents the advantage of affecting multiple deficits that are the hallmarks of these pathologies. TC-1734 is an orally active novel neuronal nicotinic agonist with high selectivity for neuronal nicotinic receptors. Microdialysis studies indicate that TC-1734 enhances the release of acetylcholine from the cortex. TC-1734, by either acute or repeated administration, exhibits memory enhancing properties in rats and mice and is neuroprotective following excitotoxic insult in fetal rat brain in cultures and against alterations of synaptic transmission induced by deprivation of glucose and oxygen in hippocampal slices. At submaximal doses, TC-1734 produced additive cognitive effects when used in combination with tacrine or donepezil. Unlike (-)-nicotine, behavioral sensitization does not develop following repeated administration of TC-1734. Its pharmacokinetic (PK) profile (half-life of 2 h) contrasts with the long lasting improvement in working memory (18 h) demonstrating that cognitive improvement extends beyond the lifetime of the compound. The very low acute toxicity of TC-1734 and its receptor activity profile provides additional mechanistic basis for its suggested potential as a clinical candidate. TC-1734 was very well tolerated in acute and chronic oral toxicity studies in mice, rats and dogs. Phase I clinical trials demonstrated TC-1734's favorable pharmacokinetic and safety profile by acute oral administration at doses ranging from 2 to 320 mg. The bioavailability, pharmacological, pharmacokinetic, and safety profile of TC-1734 provides an example of a safe, potent and efficacious neuronal nicotinic modulator that holds promise for the management of the hallmark symptomatologies observed in dementia.