Psychiatric drug discovery and development

This new conference on Psychiatric Drug Research was organised by the Strategic Research Institute and was chaired by P McGonigle (Wyeth Research, USA) and D Schoepp (Eli Lilly, USA). The 2-day meeting featured presentations from an international assembly of industrial and academic experts who have significantly contributed to the current body of knowledge in the field of psychotherapeutics. D Weinberger (NIMH, USA) gave an elegant keynote lecture on the application of genomics in psychopharmacology. Other presentations covered the latest technological advances, animal models and mechanistic approaches utilised in drug discovery for neuropsychiatric disorders and reviewed the current status of numerous novel targets resulting from these strategies.     

Symposium report: the Waters Bioanalysis World Tour

Applied Pharmaceutical Analysis, Baltimore, MD, USA, 19 September 2010. As part of the Waters Corporation Bioanalysis World Tour [101] , an evening symposium was held at the Applied Pharmaceutical Analysis meeting in Baltimore (MD, USA) on 19 September 2010 [102,103] . The evening was chaired by Robert Plumb (Waters, MA, USA) and Christopher Evans (GlaxoSmithKline, PA, USA), and included three presentations from expert speakers. The talks covered diverse areas of bioanalysis unified by the theme of increasing sensitivity and data quality. Brian Hoffman (Advion, NY, USA) spoke about sample extraction plates for phospholipid depletion, Rand Jenkins (PPD Inc., VA, USA) discussed the use of 2D UPLC for enhancing the power and selectivity of UPLC-MS/MS bioanalysis, and Christopher Evans gave a presentation on increasing assay sensitivity for dried blood spot sample analysis, using a microfluidic chip-based column and a new mass spectrometer source. Following the presentations, all three speakers took to the stage again to respond to questions from the audience.     

Neurotoxicity as a Mechanism for Neurodegenerative Disorders: Basic and Clinical Aspects

This three day meeting focused on chronic neurodegenerative diseases such as Parkinson’s disease (PD), Alzheimer’s disease (AD) and amylotrophic lateral sclerosis (ALS). It attracted 69 participants from 10 countries with dominance of Chile and USA. Neurodegeneration and its prevention increasingly gain in importance as the number of people affected increases year-by-year. The meeting addressed various basic aspects having pragmatic implications such as: oxidative stress, inflammatory reaction, glial activation, role of glutamatergic system and apoptosis using a plethora of in vitro and in vivo methods.     

Neuronal apoptosis as a therapeutic target in neurodegenerative disease

Apoptosis is a form of physiological or programmed cell death. It has been speculated that this process might account for the death of selective neuronal populations in certain progressive neurodegenerative disorders, including Alzheimer’s disease (AD) and Parkinson’s disease (PD) and some circumstantial evidence to support this view has been forthcoming. Increased understanding of the molecular pathophysiology of neuronal apoptosis may therefore present significant new therapeutic targets, to slow or halt neurodegeneration. This article reviews patents from the last five years which claim the use of apoptotic modulators in neurodegenerative disease. Although there are a significant number of claims, very few are buttressed with strong experimental evidence; this is usually from cell culture studies, rather than animal models of neurodegenerative disease; only a single human clinical study was identified. Thus, although treatment of neurodegenerative disease by means of manipulating apoptosis is an area of much activity and holds promise for the future, clinical application of current patents is unlikely in the near future. Extant medications may conceivably exert some of their action through effects on apoptosis.     

18th International Conference on Antiviral Research

The 18th International Conference on Antiviral Research (ICAR) was held at the Princess Sofia Hotel in Barcelona, Spain, from 11th-14th April, 2005. This is a yearly international meeting sponsored by the International Society for Antiviral Research (ISAR). The current president of ISAR is John A Secrest 3rd of the Southern Research Institute. The scientific programme committee was chaired by John C Drach from the University of Michigan. ISAR was founded in 1987 to exchange prepublication basic, applied and clinical information on the development of antiviral, chemical and biological agents as well as to promote collaborative research. The ISAR has had a major role in the significant advances of the past decade in the reduction of the societal burdens of viral diseases by the focus of ICAR on the discovery and clinical application of antiviral agents. The 18th ICAR was organised as a series of focus presentations on specific viral groups consisting of oral and poster presentations of original research findings. In addition, the conference included plenary speakers, award presentations, a minisymposium on bioterrorism, and a satellite symposium on clinical antiviral drug developments. The size of the conference (> 50 oral and 250 poster presentations) necessitates limitation to the most noteworthy in the judgment of this reviewer. The current membership of the ISAR is approximately 700 with approximately 50% the membership in attendance.     

Combating psychosis in Parkinson’s disease patients: the use of antipsychotic drugs

Parkinson’s disease (PD) patients commonly experience psychotic symptoms, with the most frequent manifestation being visual hallucinations. In PD, psychosis is predominantly drug induced and an important issue for clinicians to address as it increases the risk of nursing home placement as well as mortality. This review summarises the current knowledge regarding the clinical manifestations, pathophysiology and risk factors for drug-induced psychosis in patients with PD and focuses on treatment, especially with regard to the atypical antipsychotics.     

Deriving health utility values from a randomized,double-blind,placebo-controlled trial of siltuximab in subjects with multicentric Castleman’s disease

Purpose: To estimate health utility values, explore predictors of utility values, and estimate the quality-adjusted life years (Q.A.L.Y.s) gained by treatment in multicentric Castleman’s disease (M.C.D.). Methods: The SF-36 was administered to 79 patients enrolled in a randomized, double-blind, placebo-controlled, multi-national study to determine the safety and efficacy of siltuximab plus best supportive care (B.S.C.) compared with B.S.C., in subjects with symptomatic M.C.D. Utility (SF-6D) scores were derived from the SF-36. Sensitivity analyses using utilities obtained by mapping the SF-36 to the EQ-5D were also conducted. Repeated measures, mixed effects models were conducted to estimate effects of treatment, responder status and?≥?Grade 3 adverse events (A.E.s) on changes in utility values over time, controlling for baseline utility value. Additionally, differential Q.A.L.Y. gain was assessed in the trial using multiple regression. Results: Patients on siltuximab and those who experienced a complete or partial response had higher mean utility values over time than those on placebo or those with stable disease. After an initial response to treatment, the mean utility remained relatively stable for patients on siltuximab and those who experienced a complete or partial response during the period when most patients were on study. A significantly different Q.A.L.Y. gain was found for patients on siltuximab (versus placebo) as calculated by SF-6D (0.070 Q.A.L.Y.s, p?<?.05) scores at 6 months (EQ-5D 0.096 Q.A.L.Y.s, p?<?0.05). Conclusions: Siltuximab demonstrated improved, durable health utility gains in this rare disease over B.S.C. The main SF-6D results were supported by EQ-5D sensitivity analysis. These findings are limited by the small study sample size and substantial missing data caused predominantly by crossover. A longitudinal, multisite international observational study capturing clinical, safety and health-related quality of life (H.R.Q.L.) endpoints are needed to confirm these findings.     

罗替戈汀透皮贴剂的研究进展

罗替戈汀为选择性多巴胺D1/D2/D3受体激动剂,其透皮贴剂是第一个非麦角类多巴胺受体激动剂贴剂。罗替戈汀贴剂24h有效,能对帕金森病人持续提供多巴胺能刺激,目前获得FDA和EMA批准上市。对罗替戈汀贴剂研究情况进行简要综述。     

American Association for Cancer Research: potential target antigens for cancer immunotherapy. April 1-5, 2000, San Francisco, CA, USA

The 91st annual meeting of the American Association for Cancer Research (AACR) convened this year in San Francisco, USA. Nearly 5600 abstracts were published within ten broad research categories ranging from basic molecular, cellular and pharmaceutical research to cancer epidemiology and prevention. The largest number of poster presentations belonged in the 'Pharmacological and Experimental Therapeutics' section, followed closely by 'Molecular Biology' and 'Cell and Tumour Biology'. Novel tumour antigens and their potential application in cancer immunotherapy were displayed primarily in a section categorised as 'Immunology/Preclinical and Clinical'. This article reports some of the significant tumour antigen-related studies presented at this meeting.     

Importance of the long-acting partner drug in artemisinin-based combination therapy

The 1st African Health Research Organization International Malaria Symposium on Clinical Pharmacology of Antimalarial Drugs collected approximately 60 health professionals, scientists, policy makers and nongovernmental organization representatives from Africa, Europe and the USA for updates on recent developments in malaria therapy. It was the first African Health Research Organization symposium in Africa aimed at taking an African leadership in the fight against malaria. The intention is to start a tradition of annually recurring symposia that will eventually grow to become a leading international event in malaria research. Apart from scientific presentations, substantial time was dedicated to discussions and brainstorming, with a view to developing tools that can realistically be used to address challenges relating to all aspects of malaria treatment and control. The meeting was funded partly by the Medicines for Malaria Venture and Dafra Pharma International Ltd., Belgium, both of which were represented by some of the speakers.     

Bisphosphonates: Future perspective for neurological disorders

Neurodegenerative disorders and osteoporosis share some common underlying pathological features including calcium overload, accumulation of toxic chemicals, inflammation and impaired protein prenylation by isoprenoids (farnesyl pyrophosphate and geranylgeranyl pyrophosphate) appear later stage of life. Substantial number of pre-clinical and clinical reports as well as in vitro data univocally acknowledged the negative impact of altered post-translational modification (prenylation) of proteins like small GTPases (Rffhes, Rho, Rac etc.) and cholesterol levels in both serum and brain on CNS integrity. Bisphosphonates (BPs), referred to as gold standard for osteoporosis treatment, have well established role in attenuation of bone resorption and osteoclast apoptosis by inhibition of farnesyl pyrophosphate synthase enzyme (FPPS) in mevalonate pathway. BPs mainly nitrogen containing BPs (NBPs) have potential to offer new therapeutic targets for neurological disorders and received increasing attention in recent years. A year back clinical and pre-clinical studies revealed that NBPs have the potential to alleviate the symptoms of neurological disorders like brain calcification, Alzheimer’s disease and Huntington’s disease by targeting mevalonate pathway. Though these drugs have well developed role in inhibition of isoprenoids synthesis, these were demonstrated to inhibit acetyl cholinesterase enzyme and cholesterol synthesis in brain that are considered as the critical factors for impairment of cognitive functions which is the hallmark of several neurological disorders. Still the current understanding of BPs' effect in CNS is limited due to lack of studies focusing the molecular and cellular mechanism. The present review aims to reveal the updated discussion on the mechanism contributing BPs' effect in CNS disorders.     

Apoptosis modulators in the therapy of neurodegenerative diseases

Apoptosis is a prerequisite to model the developing nervous system. However, an increased rate of cell death in the adult nervous system underlies neurodegenerative disease and is a hallmark of multiple sclerosis (MS) Alzheimer’s- (AD), Parkinson- (PD), or Huntington’s disease (HD). Cell surface receptors (e.g., CD95/APO-1/Fas; TNF receptor) and their ligands (CD95-L; TNF) as well as evolutionarily conserved mechanisms involving proteases, mitochondrial factors (e.g., Bcl-2-related proteins, reactive oxygen species, mitochondrial membrane potential, opening of the permeability transition pore) or p53 participate in the modulation and execution of cell death. Effectors comprise oxidative stress, inflammatory processes, calcium toxicity and survival factor deficiency. Therapeutic agents are being developed to interfere with these events, thus conferring the potential to be neuroprotective. In this context, drugs with anti-oxidative properties, e.g., flupirtine, N-acetylcysteine, idebenone, melatonin, but also novel dopamine agonists (ropinirole and pramipexole) have been shown to protect neuronal cells from apoptosis and thus have been suggested for treating neurodegenerative disorders like AD or PD. Other agents like non-steroidal anti-inflammatory drugs (NSAIDs) partly inhibit cyclooxygenase (COX) expression, as well as having a positive influence on the clinical expression of AD. Distinct cytokines, growth factors and related drug candidates, e.g., nerve growth factor (NGF), or members of the transforming growth factor-β (TGF-β ) superfamily, like growth and differentiation factor 5 (GDF-5), are shown to protect tyrosine hydroxylase or dopaminergic neurones from apoptosis. Furthermore, peptidergic cerebrolysin has been found to support the survival of neurones in vitro and in vivo. Treatment with protease inhibitors are suggested as potential targets to prevent DNA fragmentation in dopaminergic neurones of PD patients. Finally, CRIB (cellular replacement by immunoisolatory biocapsule) is an auspicious gene therapeutical approach for human NGF secretion, which has been shown to protect cholinergic neurones from cell death when implanted in the brain. This review summarises and evaluates novel aspects of anti-apoptotic concepts and pharmacological intervention including gene therapeutical approaches currently being proposed or utilised to treat neurodegenerative diseases.     

SMi 4th Annual Conference on Neurodegenerative Disorders: a focus on Alzheimer’s and Parkinson’s disease

This was a small (~ 50 people) focused meeting on neurodegenerative disorders, with most of the speakers being from biotechnology or major pharmaceutical companies. The meeting covered a range of topics including introductions to Alzheimer’s disease and Parkinson’s disease, examples of targeting particular receptors/pathways, animal models and preclinical studies, clinical trial design and the use of biomarkers and imaging modalities. The major focus in the Alzheimer’s disease area was finding symptomatic treatments that are superior to acetylcholinesterase inhibitors and the extensive efforts that are ongoing to develop disease-modifying therapies. In terms of Parkinson’s disease there are now several reports examining the effects of dopamine agonists versus 3,4-dihydroxyphenylalanine on disease progression, and ongoing work with growth factors (e.g., glial cell line-derived neurotrophic factor) and mixed lineage/c-Jun N-terminal kinase inhibitors, such as CEP-1347. Small molecules that enhance endogenous signalling and repair pathways were also discussed.     

Safety and effectiveness of istradefylline in patients with Parkinson’s disease: interim analysis of a post-marketing surveillance study in Japan

ABSTRACT

Background: Istradefylline is a first-in-class, non-dopaminergic, selective adenosine A_2A receptor antagonist for the treatment of Parkinson’s disease (PD) in patients experiencing the wearing-off phenomenon with levodopa (L-DOPA). The authors present an interim report from a post-marketing surveillance (PMS) evaluating the safety and effectiveness of long-term istradefylline in a real-world setting.

Research design and methods: Istradefylline safety was assessed by the incidence of adverse events (AE) and adverse drug reactions (ADRs). Effectiveness was assessed using the physician’s assessment of off-time, off-time symptoms and motor dysfunction, unified PD rating scale (UPDRS) Part III score, and the physician’s global assessment.

Results: This analysis evaluated 476 patients. Istradefylline was generally well tolerated, despite dyskinesia and hallucination being the most common ADRs. Reduction in off-time was observed in 38.2% of patients, off-time symptoms were improved or markedly improved in 44.7%, and motor dysfunction was improved or markedly improved in 48.5%. The mean UPDRS Part III score decreased from 33.7 to 30.3 at the end of the study. The physician’s global assessment rated the drug as effective in 61.3% of patients.

Conclusions: This PMS provides useful safety and effectiveness data for long-term treatment with istradefylline in a real-world setting for patients with PD exhibiting the wearing-off phenomenon with L-DOPA.     

Clinical trials in neuroprotection

Many common neurological and psychiatric disorders are accompanied by extensive neuronal loss, either acutely or chronically. These include stroke, head trauma, spinal cord injury, epilepsy, perinatal and perioperative hypoxia–ischaemia, Alzheimer’s and Parkinson’s diseases, amyotrophic lateral sclerosis (ALS) and even some aspects of schizophrenia and depression. Despite considerable research effort, no agent has been found that can protect the brain from any of these neurodegenerative conditions. ‘Clinical Trials in Neuroprotection,’ sponsored by the University of Pennsylvania, was held to address this situation in a unique way. Rather than focus on one neurodegenerative condition, the conference brought together researchers from a variety of neuroprotection areas. They reviewed basic mechanisms of neuronal injury, the animal models used in a variety of paradigms and the design and results of clinical trials in many neuroprotection areas. The presentations and extensive discussions focused on common issues encountered and lessons learned, and on developing innovative strategies for clinical evaluation of potential neuroprotective agents. Conference participants came to a general consensus that some mechanisms were the same for all conditions, models need to be improved, new clinical trial paradigms should consider drug combinations and/or sequential administration of neuroprotective agents, new biomarkers should be developed and a ‘proof-of-principle’ trial would be widely valuable and should be developed.     

Contact sensitivity in Behçet’s disease

Context: Behçet’s disease (BD) is a multisystemic inflammatory disorder with unknown etiology. Many immunological changes were reported in BD previously and these changes may affect the frequency of contact sensitivity in these patients.

Objective: We aimed to identify whether there is an interaction between contact sensitivity and BD.

Methods: The ‘European standard series’ with 27 allergens were performed on the upper backs of patients and healthy volunteers according to international standards using the IQ-Chamber. The test-units which contain these allergens were removed after 2 days. According to International Contact Dermatitis Research Group Recommendations test areas were evaluated on days 2, 3 and 7 to detect any delayed allergic reactions. The results of both groups were compared by using chi-square test.

Results: One hundred adult persons (50 BDs and 50 healthy controls) were tested. Positive patch test reaction to 1 or more allergens was observed in 7 (14%) patients in BD group and in 12 (24%) persons in control group. There was no statistically significant difference between these two groups.

Conclusions: The frequency of contact sensitivity in BD is not different from healthy persons.     

The pharmacology of donepezil: a new treatment for Alzheimer’s disease

Donepezil (donepezil hydrochloride, E-2020, Aricept?, Eisai), launched in March 1997, was the first drug to be marketed for the symptomatic treatment of Alzheimer’s disease (AD) in the UK. It had been launched a year earlier in the US where clinicians had already had experience of tacrine (THA). Donepezil is a piperidine based, potent, specific, non-competitive and reversible inhibitor of acetylcholinesterase (AChE). It is structurally dissimilar from other established cholinesterase inhibitors, namely THA (an acridine compound) and the carbamates, physostigmine and rivastigmine and has a pharmacokinetic and tolerability profile distinct from these agents. Experimentally, donepezil inhibits AChE activity in human erythrocytes and increases extracellular acetylcholine levels in the cerebral cortex and the hippocampus of the rat. Pharmacologically, donepezil has a half-life of approximately 70 h lending itself to once daily administration. The most common adverse events reported in clinical trials have been gastrointestinal, typically nausea, vomiting, diarrhoea and constipation. Headache, dizziness and sleep disturbance have also been reported; there has been no evidence of hepatotoxicity. Clinically a number of placebo-controlled trials have shown that donepezil 5 or 10 mg daily was associated with significant improvements in cognitive function, as assessed by the Alzheimer’s disease Assessment Scale-cognitive subscale (ADAS cog) after 12 or 24 weeks treatment. Significant improvements in global function and activities of daily living have also been demonstrated after 24 weeks treatment compared with placebo in patients with mild to moderate AD. Donepezil was the first rational treatment available in the UK for this disabling condition and as such received considerable attention. Much of the original attention was negative, ostensibly based on the scientific view that there was not enough published evidence to justify widespread use, but this was driven by concerns about the potentially high drug costs if all patients with AD were eligible to receive it. Considerable data have now been produced from Phase II, III and post-marketing surveillance. This drug evaluation will review the basic pharmacology of donepezil and place it in context with the trial data and the author’s clinical experience with the drug.