Slater G.,King's College London |
Levy P.,King's College London |
Andrew Chan K.L.,Institute of Pharmaceutical Science |
Larsen C.,King's College London
Journal of Neuroscience | Year: 2015
Chemotaxis is important for the survival of most animals. How the brain translates sensory input into motor output beyond higher olfactory processing centers is largely unknown.Wedescribe a group of excitatory neurons, termedOddneurons, which are important for Drosophila larval chemotaxis. Odd neurons receive synaptic input from projection neurons in the calyx of the mushroom body and project axons to the central brain. Functional imaging shows that some of the Odd neurons respond to odor. Larvae in which Odd neurons are silenced are less efficient at odor tracking than controls and sample the odor space more frequently. Larvae in which the excitability of Odd neurons is increased are better at odor intensity discrimination and odor tracking. Thus, the Odd neurons represent a distinct pathway that regulates the sensitivity of the olfactory system to odor concentrations, demonstrating that efficient chemotaxis depends on processing of odor strength downstream of higher olfactory centers. © 2015 Slater et al.
News Article | February 22, 2017
- Selection of lead compound for AM-102 program planned for 2017 ZUG, Switzerland, Feb. 22, 2017 (GLOBE NEWSWIRE) -- Auris Medical Holding AG (NASDAQ: EARS), a clinical-stage company dedicated to developing therapeutics that address important unmet medical needs in otolaryngology, today announced the extension of its collaboration with King's College London. The collaboration is focused on the discovery of small molecule compounds for a second generation tinnitus treatment. "Together with King's College London, we have made great progress on our second generation tinnitus project," commented Thomas Jung, MD, PhD, Auris Medical's Chief Development Officer. "The team's drug discovery expertise has generated interesting leads that have been tested in vitro and in vivo. The extension of our collaboration allows for further development with the aim of selecting a lead compound for our AM-102 program by the end of 2017." Professor David E. Thurston of the Institute of Pharmaceutical Science is leading the team at King's to develop and optimize a range of specific small molecules for Auris Medical's AM-102 project. The project builds on earlier work performed at King's for Auris Medical by Professor Pat Doherty and Dr. Gareth Williams. The AM-102 compounds bind to a novel, undisclosed drug target for treating certain types of tinnitus. Tinnitus is the perception of sound without external acoustic stimulation. Tinnitus of the inner ear may be caused by various injuries to the cochlea, the organ of hearing, such as overexposure to noise. Tinnitus that has been present for less than three months is considered acute, while tinnitus that has been present for over three months is considered chronic. Tinnitus of the inner ear often has a serious impact on ability to sleep, relax or concentrate, which may lead to tiredness, irritation, anxiety or depression. There is no universal standard of care for tinnitus of the inner ear and efficacy of a pharmacological treatment for tinnitus of the inner ear has not yet been conclusively demonstrated. Auris Medical is a Swiss biopharmaceutical company dedicated to developing therapeutics that address important unmet medical needs in otolaryngology. The Company is focused on the Phase 3 development of treatments for acute inner ear hearing loss (AM-111) and for acute inner ear tinnitus (Keyzilen®; AM-101) by way of intratympanic administration with biocompatible gel formulations. In addition, Auris Medical is pursuing intranasal betahistine for Meniere's disease and vestibular vertigo (AM-125) and early-stage research and development projects. The Company was founded in 2003 and is headquartered in Zug, Switzerland. The shares of Auris Medical Holding AG trade on the NASDAQ Global Market under the symbol "EARS." King's College London is one of the top 25 universities in the world (2016/17 QS World University Rankings) and among the oldest in England. King's has more than 27,600 students (of whom nearly 10,500 are graduate students) from some 150 countries worldwide, and some 6,800 staff. King's has an outstanding reputation for world-class teaching and cutting-edge research. In the 2014 Research Excellence Framework (REF) King's was ranked 6th nationally in the 'power' ranking, which takes into account both the quality and quantity of research activity, and 7th for quality according to Times Higher Education rankings. Eighty-four percent of research at King's was deemed 'world-leading' or 'internationally excellent' (3* and 4*). The university is in the top seven UK universities for research earnings and has an overall annual income of more than £684 million. For further information, please visit the website. This press release may contain statements that constitute "forward-looking statements" within the meaning of Section 27A of the Securities Act of 1933 and Section 21E of the Securities Exchange Act of 1934. Forward-looking statements are statements other than historical fact and may include statements that address future operating, financial or business performance or Auris Medical's strategies or expectations. In some cases, you can identify these statements by forward-looking words such as "may," "might," "will," "should," "expects," "plans," "anticipates," "believes," "estimates," "predicts," "projects," "potential," "outlook" or "continue," and other comparable terminology. Forward-looking statements are based on management's current expectations and beliefs and involve significant risks and uncertainties that could cause actual results, developments and business decisions to differ materially from those contemplated by these statements. These risks and uncertainties include, but are not limited to, the timing and conduct of clinical trials of Auris Medical's product candidates, the clinical utility of Auris Medical's product candidates, including the likelihood that the TACTT3 trial may not meet its endpoints, the timing or likelihood of regulatory filings and approvals, Auris Medical's intellectual property position and Auris Medical's financial position, including the impact of any future acquisitions, dispositions, partnerships, license transactions or changes to Auris Medical's capital structure, including future securities offerings. These risks and uncertainties also include, but are not limited to, those described under the caption "Risk Factors" in Auris Medical's Annual Report on Form 20-F and future filings with the Securities and Exchange Commission. Forward-looking statements speak only as of the date they are made, and Auris Medical does not undertake any obligation to update them in light of new information, future developments or otherwise, except as may be required under applicable law. All forward-looking statements are qualified in their entirety by this cautionary statement.
Bauer R.,Institute of Pharmaceutical science |
Franz G.,University of Regensburg
Planta Medica | Year: 2010
The actual concern about the safety and efficacy of herbal drugs originating from traditional Chinese medicine (TCM) is based on observations that these medicinal plants may have a high risk potential due to insufficient definitions, problems with identity, purity and falsifications. No uniform legal status for these groups of herbal drugs currently exists in the European Union. For quality control, monographs for TCM herbs can mainly be found in the Pharmacopoeia of the Peoples Republic of China. Based on these facts the Commission of the European Pharmacopoeia decided in 2005 to establish TCM-herbal drug monographs for the most important medicinal plants imported from Far East. These new monographs had to be established and evaluated on the basis of existing monographs in the Chinese Pharmacopoeia (ChP), English edition 2005. Due to important differences in the overall features of EP and ChP, a simple adapt/adopt procedure was not feasible. Therefore, specialist groups were mandated with a corresponding working programme. Some results and actual problems related to this working programme will be presented and discussed. © Georg Thieme Verlag KG Stuttgart - New York.
Prescott T.A.K.,Royal Botanic Gardens |
Panaretou B.,Institute of Pharmaceutical Science |
Veitch N.C.,Royal Botanic Gardens |
Simmonds M.S.J.,Royal Botanic Gardens
FEBS Letters | Year: 2014
The phosphatase enzyme calcineurin controls gene expression in a variety of biological contexts however few potent inhibitors are currently available. A screen of 360 plant extracts for inhibition of calcineurin-dependent gene expression in the model organism Saccharomyces cerevisiae identified the compound 3,4,5-trimethoxybenzyl isothiocyanate as an inhibitor. The compound was subsequently shown to inhibit human calcineurin via a mixed inhibition mechanism. To gain further mechanistic insight a yeast haploinsufficiency screen of 1152 deletion strains was carried out using a novel liquid medium screening method. The resulting haploinsufficiency profile is similar to that reported for the known calcineurin inhibitor FK506.
Jenner P.,Institute of Pharmaceutical science |
McCreary A.C.,Brains On Line |
Scheller D.K.A.,UCB Pharma
Journal of Neural Transmission | Year: 2011
The treatment of the motor symptoms of Parkinson's disease (PD) is dependent on the use of dopamine replacement therapy in the form of l-dopa and dopamine agonist drugs. However, the development of dyskinesia (chorea, dystonia, athetosis) can become treatment limiting. The initiation of dyskinesia involves a priming process dependent on the presence of nigral dopaminergic cell loss leading to alterations in basal ganglia function that underlie the expression of involuntary movements following the administration of each drug dose. Once established, dyskinesia is difficult to control and it is even more difficult to reverse the priming process. Dyskinesia is more commonly induced by l-dopa than by dopamine agonist drugs. This has been associated with the short duration of l-dopa causing pulsatile stimulation of postsynaptic dopamine receptors compared to the longer acting dopamine agonists that cause more continuous stimulation. As a result, the concept of continuous dopaminergic stimulation (CDS) has arisen and has come to dominate the strategy for treatment of early PD. However, CDS has flaws that have led to the general acceptance that continuous drug delivery (CDD) is key to the successful treatment of PD. Studies in both experimental models of PD and in clinical trials have shown CDD to improve efficacy, but reduce dyskinesia induction, and to reverse established involuntary movements. Two key clinical strategies currently address the concept of CDD: (1) in early-, mid- and late-stage PD, transdermal administration of rotigotine provides 24 h of drug delivery; (2) in late-stage PD, the constant intraduodenal administration of l-dopa is utilized to improve control of motor symptoms and to diminish established dyskinesia. This review examines the rationale for CDD and explores the clinical benefit of using such a strategy for the treatment of patients with PD. © 2011 Springer-Verlag.
Anthopoulou E.,Institute of Pharmaceutical science
Pharmaceutical Medicine | Year: 2016
Electronic cigarettes are nicotine delivery devices that have rapidly penetrated into the market since their invention in 2003. Their remarkably rapid spread has raised questions concerning their safety and efficacy as smoking cessation aids. However, despite this uncertainty, the number of users is increasing, especially among smokers and ex-smokers who are trying to keep away from tobacco cigarettes. Several chemical studies have been conducted and a safer profile compared with tobacco cigarettes has been recognized. Clinical and population studies have given a first insight into the efficacy of e-cigarettes as smoking cessation aids, supporting their potential. Nonetheless, these preliminary findings cannot lead to reliable conclusions about their long-term safety and efficacy and further research is warranted. The burden of tobacco-related diseases is a major cause of morbidity and mortality worldwide and further measures are needed in order to reduce tobacco harm. At the moment, e-cigarettes are categorized as consumer products in the UK because the Medicines and Healthcare Products Regulatory Agency’s (MHRA’s) recommendation to regulate e-cigarettes as medicines did not get the adequate response; however, very soon e-cigarettes will be regulated under the EU’s Tobacco Product Directive. E-cigarettes are widely used and the preliminary findings on safety and efficacy, in combination with the need for new tobacco harm reduction strategies, suggest that the investigation of e-cigarettes’ potential as a smoking cessation aid is imperative. © 2016, Springer International Publishing Switzerland.
Iravani M.M.,Institute of Pharmaceutical science |
Mccreary A.C.,Brains On Line |
Jenner P.,Institute of Pharmaceutical science
Parkinsonism and Related Disorders | Year: 2012
Striatal function adapts to the loss of nigrostriatal dopaminergic input in Parkinson's disease (PD) to initially maintain voluntary movement, but subsequently changes in response to drug treatment leading to the onset of motor complications, notably dyskinesia. Alterations in presynaptic dopaminergic function coupled to changes in the response of post-synaptic dopaminergic receptors causing alterations in striatal output underlie attempts at compensation and the control of movement in early PD. However, eventually compensation fails and persistent changes in striatal function ensue that involve morphological, biochemical and electrophysiological change. Key alterations occur in cholinergic and glutamatergic transmission in the striatum and there are changes in motor programming controlled by events involving LTP/LTD. Dopamine replacement therapy with L-DOPA modifies altered striatal function and restores motor function but nonphysiological dopamine receptor stimulation leads to altered signalling through D1 and D2 receptor systems and changes in striatal function causing abnormalities of LTP/LTD mediated through glutamatergic/nitric oxide (NO) mechanisms. These lead to the onset of dyskinesia and underlie the priming process that characterise dyskinesia and its persistence. © 2011 Elsevier Ltd.
Yamada K.,Kyowa Hakko Kirin Co. |
Kobayashi M.,Kyowa Hakko Kirin Co. |
Mori A.,Kyowa Hakko Kirin Co. |
Jenner P.,Institute of Pharmaceutical science |
Kanda T.,Kyowa Hakko Kirin Co.
Pharmacology Biochemistry and Behavior | Year: 2013
Rationale Depression is common in Parkinson's disease (PD) but its response to classical antidepressants is not clear. The adenosine A2A antagonist istradefylline is effective in the treatment of the motor symptoms of PD but inhibition of the adenosine A2A receptor may also induce antidepressant-like effects. Objective We have investigated whether istradefylline might be effective in treating depression in PD using the forced swimming test (FST) and the tail suspension test (TST) in rodents. Results Istradefylline significantly decreased immobility time in the FST in both rats and mice (0.16 mg/kg and higher) with comparable efficacy to an equivalent dose of the tricyclic antidepressants, desipramine and imipramine. Both 8-OH-DPAT (5-HT1A agonist) and quinpirole (D2 agonist) also reduced the immobility time. The istradefylline-induced reduction of immobility time was attenuated by corticosterone. In addition, the combined use of a sub-threshold dose of istradefylline and the serotonin-noradrenaline reuptake inhibitor venlafaxine ameliorated depression-like behavior in the mouse FST. In the mouse TST, istradefylline (0.08 mg/kg and higher) decreased immobility time. Moreover, co-administration of istradefylline with paroxetine or fluoxetine (selective serotonin reuptake inhibitors) or deprenyl (MAO-B inhibitor) at doses that did not show antidepressant-like effects when administered alone, resulted in a significant reduction in immobility time. Conclusions Istradefylline alone or co-administered with currently available antidepressants, may be useful for the treatment of depression as well as motor symptoms of PD. Its effects might be, at least in part, attributable to modulation of hypothalamic-pituitary-adrenal axis. © 2013 Published by Elsevier Inc.
Iravani M.M.,Institute of Pharmaceutical science |
Jenner P.,Institute of Pharmaceutical science
Journal of Neural Transmission | Year: 2011
A significant proportion of patients with Parkinson's disease (PD) receiving dopamine replacement therapy in the form of levodopa develop dyskinesia that becomes a major complicating factor in treatment. Dyskinesia can only be effectively treated by a reduction in drug dose, which limits efficacy, by co-administration of the weak NMDA antagonist amantadine or by surgical treatment (pallidotomy, DBS). This raises the important question of why dyskinesia occurs in PD and how it can be avoided or suppressed by pharmacological treatment. This review assesses some of the mechanisms that underlie dyskinesia induction and expression from presynaptic changes in dopaminergic neurones to postsynaptic alterations in basal ganglia function and examines potential approaches to prevention and treatment. These include glutamatergic approaches where agents that directly or indirectly alter glutamatergic neurotransmission modify the intracellular influx of Ca 2+ and reduce the formation of nitric oxide by neuronal nitric oxide synthase that may form an integral component of the complex cascade of events leading to dyskinesia. There is increasing evidence for the role of serotoninergic neurones in dyskinesia induction related to non-physiological formation and release of dopamine and serotoninergic agonists can modify dyskinesia expression. Similarly, noradrenergic receptors may serve to alter dyskinesia intensity and α-2-adrenoceptor antagonists alter the expression of levodopa-induced dyskinesia in both experimental models of PD and in man. Finally, other potential approaches to dyskinesia treatment based on manipulation of opiate, cannabinoid, adenosine and histamine receptors are considered. The conclusion is that the cause of levodopa-induced dyskinesia remains to be fully elucidated and that new approaches to treatment through non-dopaminergic mechanisms are required to control the onset and expression of involuntary movements. © 2011 Springer-Verlag.
Rogers G.B.,Institute of Pharmaceutical Science |
Bruce K.D.,Institute of Pharmaceutical Science
Epidemiology and Infection | Year: 2013
SUMMARY The incidence, morbidity, and mortality associated with Clostridium difficile gastrointestinal infections has increased greatly over recent years, reaching epidemic proportions; a trend due, in part, to the emergence of hypervirulent and antibiotic-resistant strains. The need to identify alternative, non-antibiotic, treatment strategies is therefore urgent. The ability of bacteria in faecal matter transplanted from healthy individuals to displace pathogen populations is well recognized. Further, there is growing evidence that such faecal microbiota transplantation can be of benefit in a wide range of conditions associated with gut dysbiosis. Recent technical advances have greatly increased our ability to understand the processes that underpin the beneficial changes in bacterial community composition, as well as to characterize their extent and duration. However, while much of the research into faecal microbiota transplantation focuses currently on achieving clinical efficacy, the potential for such therapies to contribute to the transmission of infective agents also requires careful consideration. Copyright © Cambridge University Press 2013.