Drug repurposing from the perspective of pharmaceutical companies.

Drug repurposing holds the potential to bring medications with known safety profiles to new patient populations. Numerous examples exist for the identification of new indications for existing molecules, most stemming from serendipitous findings or focused recent efforts specifically limited to the mode of action of a specific drug. In recent years, the need for new approaches to drug research and development, combined with the advent of big data repositories and associated analytical methods, has generated interest in developing systematic approaches to drug repurposing. A variety of innovative computational methods to enable systematic repurposing screens, experimental as well as through in silico approaches, have emerged. An efficient drug repurposing pipeline requires the combination of access to molecular data, appropriate analytical expertise to enable robust insights, expertise and experimental set-up for validation and clinical development know-how. In this review, we describe some of the main approaches to systematic repurposing and discuss the various players in this field and the need for strategic collaborations to increase the likelihood of success in bringing existing molecules to new indications, as well as the current advantages, considerations and challenges in repurposing as a drug development strategy pursued by pharmaceutical companies. LINKED ARTICLES: This article is part of a themed section on Inventing New Therapies Without Reinventing the Wheel: The Power of Drug Repurposing. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v175.2/issuetoc.

Cyanobacterial neurotoxin BMAA in ALS and Alzheimer's disease.

OBJECTIVE: The aim of this study was to screen for and quantify the neurotoxic amino acid beta-N-methylamino-L-alanine (BMAA) in a cohort of autopsy specimens taken from Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), Huntington's disease (HD), and non-neurological controls. BMAA is produced by cyanobacteria found in a variety of freshwater, marine, and terrestrial habitats. The possibility of geographically broad human exposure to BMAA had been suggested by the discovery of BMAA in brain tissues of Chamorro patients with ALS/Parkinsonism dementia complex from Guam and more recently in AD patients from North America. These observations warranted an independent study of possible BMAA exposures outside of the Guam ecosystem. METHODS: Postmortem brain specimens were taken from neuropathologically confirmed cases of 13 ALS, 12 AD, 8 HD patients, and 12 age-matched non-neurological controls. BMAA was quantified using a validated fluorescent HPLC method previously used to detect BMAA in patients from Guam. Tandem mass spectrometric (MS) analysis was carried out to confirm the identification of BMAA in neurological specimens. RESULTS: We detected and quantified BMAA in neuroproteins from postmortem brain tissue of patients from the United States who died with sporadic AD and ALS but not HD. Incidental detections observed in two out of the 24 regions were analyzed from the controls. The concentrations of BMAA were below what had been reported previously in Chamarro ALS/ Parkinsonism dementia complex patients, but demonstrated a twofold range across disease and regional brain area comparisons. The presence of BMAA in these patients was confirmed by triple quadrupole liquid chromatography/mass spectrometry/mass spectrometry. CONCLUSIONS: The occurrence of BMAA in North American ALS and AD patients suggests the possibility of a gene/environment interaction, with BMAA triggering neurodegeneration in vulnerable individuals.

Co-occurrence of brain tumours and demyelination of the central nervous system: coincidence or interrelation?

The co-occurrence of a brain tumour and demyelinating disease of the central nervous system (CNS) constitutes a rare clinical entity. We herein report the incidence of meningioma and CNS non-specific demyelination in a patient with a 6-year history of operated brain tumour (meningioma). Our case bolsters the argument that in at least some cases, the occurrence of a brain tumour could predispose to CNS non-specific demyelination.

Objective monitoring of tremor and bradykinesia during DBS surgery for Parkinson disease.

OBJECTIVE: High-frequency subthalamic nucleus deep brain stimulation (STN-DBS) is an established treatment for patients with advanced Parkinson disease (PD). To date, intraoperative monitoring of parkinsonian symptoms, such as tremor and bradykinesia, is largely based on subjective strategies. We conducted a pilot study to evaluate short-term intraoperative outcomes of unilateral macrostimulation of the STN-DBS in PD patients using a neuromotor symptom registration device (CATSYS 2000 System). METHODS: We studied 12 consecutive PD patients who received staged unilateral STN-DBS implants and 10 male control subjects free of neurologic deficits using a simple portable system with two sensors: a tremor pen and a touch recording plate. Results revealed excellent test-retest reliability for postural tremor in control subjects. PD patients were evaluated preoperatively during "off" state and intraoperatively for rest, postural tremor intensity, and frequency of finger tapping. Comparisons between premacrostimulation and postmacrostimulation were made using analysis of variance for repeated measures. RESULTS: Electronic rest tremor registration revealed a mean improvement of x 12.5 in tremor intensity measurements in the stimulated/contralateral side (p = 0.002). An overall x 3.8 improvement was registered on the nonstimulated/ipsilateral side. Significant improvements after STN-DBS were also recorded for postural tremor and frequency of finger tapping. CONCLUSION: Using a noninvasive, simple, and sensitive electronic recording method of intraoperative motor symptom registration, we were able to supplement short-term clinical observation by objectively quantifying the characteristics of tremor and finger tapping in response to subthalamic nucleus deep brain macrostimulation.

Painful limbs/moving extremities.

Painful limbs/moving extremities (PLME) is a disorder characterized by spontaneous, complex, slow (1-2 Hz) involuntary toe or finger movements. The movements that can be bilateral or unilateral are usually accompanied by pain in the affected limbs. Painless variants are less common. PLME has been associated with peripheral and central nervous system disease although idiopathic cases have been reported. Its etiopathogenesis is unknown and treatment approaches remain largely empirical. Nerve blocks and botulinum toxin type A injections as well as oral medication have had some measure of success. Current theories suggest that central oscillator(s) at the spinal or supraspinal levels may be involved. Future research in PLME should include prospective electrophysiological and functional imaging studies as well as clinical trials with botulinum toxin injections and oral pharmacological agents.

Urinary and erectile dysfunction in multiple system atrophy (MSA).

Multiple system atrophy (MSA) is a neurodegenerative disease of undetermined etiology that occurs sporadically and manifests itself as a combination of parkinsonian, autonomic, cerebellar, and pyramidal signs. Despite the lack of effective therapies, some of the symptoms may be, at least temporarily, improved with adequate symptomatic therapies. Urinary and erectile dysfunction (ED) symptoms are prominent early features in male MSA patients. Lower urinary tract infections (UTIs) are a major cause of morbidity and mortality in this disorder. More than 50% of MSA patients suffer from recurrent lower UTIs and a significant number (approximately 25%) die of complications related to them. Urogenital symptoms in MSA are usually due to a complex mixture of central and peripheral nervous abnormalities, sometimes superimposed on previous local pathological conditions such as benign prostatic hyperplasia and perineal laxity. There have been instances were MSA-related urological symptoms were confused with symptoms of benign prostatic hyperplasia, leading to unnecessary urological surgery. In this review, we present the phenotypic range and therapeutic approaches for common storage and voiding urological symptoms and ED, in patients with MSA.

Motor fluctuations and dyskinesias in advanced/end stage Parkinson's disease: a study from a population of brain donors.

Treatment-related motor fluctuations (MFs) and dyskinesias are considered one of the most important problems in the long-term management of Parkinson's disease (PD). However, only a few studies have focused on their characteristics during advanced and end stages of the disease. We therefore assessed MFs and dyskinesias in a cohort of 61 late/end stage patients with a clinical and pathological diagnosis of PD and investigated the influence of disease- and treatment-related variables on their occurrence. A total of 62.3% of our patients experienced "wearing-off" phenomena, 68.9% "on-off" motor fluctuations and 60.7% dyskinesias at advanced/end stage disease. Age at disease onset and disease duration were significantly associated with dyskinesias. A substantial number of patients experienced spontaneous resolution of their motor complications during the last two years of their disease without treatment modifications. The clinical heterogeneity of treatment-related motor complications in PD points towards a complex mechanism for their etiopathogenesis. Although advanced disease and L-dopa administration are closely tied to their development, other mechanisms involving synaptic aging, altered neuronal plasticity and post-synaptic degeneration may be involved.

Headache characteristics and brain metastases prediction in cancer patients.

The aim of this study was to evaluate the headache and other neurological symptoms and signs as guide predictors for the occurrence of brain metastases in cancer patients. We prospectively studied 54 cancer patients with newly appeared headache or with a change in the pattern of an existing headache during the recent months. All patients completed a questionnaire regarding headache's clinical characteristics and existence of accompanying symptoms. They also underwent a detailed neurological, ophthalmologic examination and brain neuroimaging investigation. Brain metastases were diagnosed in 29 patients. Univariate regression analysis showed an association between occurrence of brain metastases and nine clinical symptoms or signs. Multivariate regression analyses emerged only four of them as significant independent predictors. These were: bilateral frontal-temporal headache, more pronounced on the side of metastasis in cases of single metastases, with duration > or =8 weeks, pulsating quality and moderate to severe intensity (OR: 11.9; 95% CI. 2.52-56.1), emesis (OR: 10.2; 95% CI. 2.1-55.8), gait instability (OR: 7.4; 95% CI. 1.75-33.9) and extensor plantar response (OR: 12.1; 95% CI. 2.2-120.7). In conclusion, all cancer patients who manifest the above independent clinical predictors should be highly suspected for appearance of brain metastases and therefore should be thoroughly investigated.

The impact of paclitaxel or cisplatin-based chemotherapy on sympathetic skin response: a prospective study.

The current study aimed to assess the viability of sympathetic sudomotor fibers in cancer patients treated with cisplatin or paclitaxel-based chemotherapy and to ascertain whether this method could contribute to the diagnostic sensitivity of conventional techniques. Sympathetic skin response (SSR) from the hand and sole of 23 cancer patients (nine females and 14 males, mean age 62.4 +/- 10.5 years) was recorded unilaterally before and after chemotherapy with six courses of cumulative cisplatin or paclitaxel containing regimens. Clinical and electrophysiological data were also collected and correlated with the SSR results. Twenty-three healthy subjects served as controls. SSR abnormalities were only present in patients with evidence of peripheral neuropathy assessed by conventional nerve conduction techniques. Three patients had absent SSR in the upper limb whilst six patients had absent SSR both in the upper and lower limbs. In the upper limb, the mean SSR latency was not significantly altered through time (P = 0.086). In the lower limb the mean delay from baseline to follow-up was significantly changed (P = 0.029). In patients, the mean SSR latency was significantly prolonged compared with controls in both upper limb (P = 0.001) and lower limb (P = 0.000). SSR abnormalities were strongly related to sensory conduction abnormalities as detected by conventional techniques (r = 0.39, P = 0.004). Our results showed that SSR does not seem to add to the diagnostic sensitivity of conventional techniques in chemotherapy-induced neuropathy. However, its role in the disclosure of small fibers neuropathy abnormalities is worth considering. Further studies are warranted to address this important issue.

Can Alzheimer's type pathology influence the clinical phenotype of Parkinson's disease?

OBJECTIVES: Patients with clinical and pathological diagnosis of Parkinson's disease (PD) may, at death, also be found to have the pathological changes of Alzheimer's disease (AD). With this study we aim to determine the influence of AD pathology on the clinical phenotype of PD. METHODS: We studied 64 patients who donated their brains to the University of Miami Brain Endowment Bank(TM) and fulfilled the clinical and pathological criteria for PD. For the evaluation of AD pathology we used the CERAD criteria. Dementia was diagnosed, in life, also using standard criteria. Case histories were abstracted and reviewed by one investigator (SP) who then made comparisons between patients. RESULTS: Patients with AD pathology (PD-AD) were older both at the time of diagnosis and death. The presence of AD pathology did not seem to influence disease duration in our cohort of PD patients. As expected there was a clear relation between AD pathology and dementia but not all PD-AD patients were demented. Psychosis and depression were also found to be more prevalent in the PD-AD patients. In the comparison between demented and non-demented PD-AD patients dementia was more likely to appear in patients with PD and definite criteria for AD. CONCLUSION: Apart from dementia AD pathology seems to be associated with a number of other clinical characteristics of PD.

Dementia in Parkinson's disease: a post-mortem study in a population of brain donors.

OBJECTIVE: To identify factors associated with dementia in a cohort of Parkinson's disease (PD) brain donors and determine whether its presence may influence the clinical phenotype of the disease. METHODS: We included 67 consecutive patients with a clinical and pathological diagnosis of PD, who while alive, consented to donate their brains to the University of Miami Brain Endowment Bank(TM). Dementia and psychiatric complications of PD were diagnosed according to established criteria. Case histories were abstracted and reviewed and comparisons between PD patients with (PD-D, n = 34) and without (PD, n = 33) dementia were made. RESULTS: Age at death, age at disease onset and disease duration did not differ significantly between PD-D and PD patients. Other symptoms were similar in both groups. Visual hallucinations and bilateral symptoms at diagnosis were significantly higher in PD-D patients. No association between dementia and overall survival duration was found. Although the frequency of depression and psychosis was higher in the PD patients with dementia no statistical significance was reached. The overall lifetime prevalence of dementia in our group was 50.7%. CONCLUSIONS: Visual hallucinations and bilateral symptoms were associated with dementia in our cohort of PD brain donors. No association between dementia and survival duration was found. Understanding the influence of dementia on the clinical phenotype of the disease and predicting its development is essential for the successful management of PD.