On the Clinical Pharmacology of Reactive Oxygen Species.

Reactive oxygen species (ROS) have been correlated with almost every human disease. Yet clinical exploitation of these hypotheses by pharmacological modulation of ROS has been scarce to nonexistent. Are ROS, thus, irrelevant for disease? No. One key misconception in the ROS field has been its consideration as a rather detrimental metabolic by-product of cell metabolism, and thus, any approach eliminating ROS to a certain tolerable level would be beneficial. We now know, instead, that ROS at every concentration, low or high, can serve many essential signaling and metabolic functions. This likely explains why systemic, nonspecific antioxidants have failed in the clinic, often with neutral and sometimes even detrimental outcomes. Recently, drug development has focused, instead, on identifying and selectively modulating ROS enzymatic sources that in a given constellation cause disease while leaving ROS physiologic signaling and metabolic functions intact. As sources, the family of NADPH oxidases stands out as the only enzyme family solely dedicated to ROS formation. Selectively targeting disease-relevant ROS-related proteins is already quite advanced, as evidenced by several phase II/III clinical trials and the first drugs having passed registration. The ROS field is expanding by including target enzymes and maturing to resemble more and more modern, big data-enhanced drug discovery and development, including network pharmacology. By defining a disease based on a distinct mechanism, in this case ROS dysregulation, and not by a symptom or phenotype anymore, ROS pharmacology is leaping forward from a clinical underperformer to a proof of concept within the new era of mechanism-based precision medicine. SIGNIFICANCE STATEMENT: Despite being correlated to almost every human disease, nearly no ROS modulator has been translated to the clinics yet. Here, we move far beyond the old-fashioned misconception of ROS as detrimental metabolic by-products and suggest 1) novel pharmacological targeting focused on selective modulation of ROS enzymatic sources, 2) mechanism-based redefinition of diseases, and 3) network pharmacology within the ROS field, altogether toward the new era of ROS pharmacology in precision medicine.

What patents tell us about drug repurposing for cancer: A landscape analysis.

Intellectual property documents (patents and their published applications) are not only collections of legal exclusivity claims but also repositories of scientific and technical information, even though they are not peer reviewed. We have identified and analyzed international disclosures concerning drug repurposing for cancer that were published under the Patent Convention Treaty during the past five years, and show this burgeoning field from an angle that is not routinely captured in review papers of the field. We find that patenting activity for cancer-related new uses for known compounds has been quite constant recently and has targeted mainly small molecule active ingredients that are currently marketed as drugs. Universities contributed most applications, closely followed by corporations. The strong representation of non-academic research institutes from the public and private sector and foundations was surprising and indicates that drug repurposing for cancer has transcended the classical corporate-academia dichotomy. Many of the identified patent documents report findings that are not reflected in the peer review literature (e.g., sumatriptan for mycosis fungoides) or appear there only later (e.g., ibudilast for glioblastoma). Synergistic combinations of several repurposed compounds were also identified, as were two documents related to the repurposing of vaccines. Our findings underscore the necessity for drug repurposers as well as for oncologists to investigate patent documents in addition to the usual peer review literature search to obtain a comprehensive perspective of the state of the art.

Big data and data repurposing - using existing data to answer new questions in vascular dementia research.

INTRODUCTION: Traditional approaches to clinical research have, as yet, failed to provide effective treatments for vascular dementia (VaD). Novel approaches to collation and synthesis of data may allow for time and cost efficient hypothesis generating and testing. These approaches may have particular utility in helping us understand and treat a complex condition such as VaD. METHODS: We present an overview of new uses for existing data to progress VaD research. The overview is the result of consultation with various stakeholders, focused literature review and learning from the group's experience of successful approaches to data repurposing. In particular, we benefitted from the expert discussion and input of delegates at the 9th International Congress on Vascular Dementia (Ljubljana, 16-18th October 2015). RESULTS: We agreed on key areas that could be of relevance to VaD research: systematic review of existing studies; individual patient level analyses of existing trials and cohorts and linking electronic health record data to other datasets. We illustrated each theme with a case-study of an existing project that has utilised this approach. CONCLUSIONS: There are many opportunities for the VaD research community to make better use of existing data. The volume of potentially available data is increasing and the opportunities for using these resources to progress the VaD research agenda are exciting. Of course, these approaches come with inherent limitations and biases, as bigger datasets are not necessarily better datasets and maintaining rigour and critical analysis will be key to optimising data use.

Pulmonary arterial hypertension: on the way to a manageable disease.

Pulmonary arterial hypertension (PAH) is an orphan disease for which no specific pharmacological therapy was available until 1996. Pharmacotherapy for PAH is currently dominated by three endothelin receptor antagonists, bosentan, ambrisentan and sitaxentan (which is not yet approved in the US), and the PDE5 inhibitor sildenafil. Drug candidates undergoing phase III clinical trials for PAH include inhalable and oral treprostinil, aviptadil (an inhalable vasoactive intestinal peptide), and the PDE5 inhibitor tadalafil. Riociguat, a soluble guanylate cyclase stimulator, is scheduled to enter phase III clinical trials in 2008. By approximately 2010, the role of infusable or injectable PGs as treatment for PAH will likely diminish significantly, while inhalable nitric oxide will remain as mainstay therapy in neonatal PAH. Benefits in survival and quality-of-life will decide if any of the more experimental approaches that utilize newly discovered molecular pathways in PAH will ultimately result in marketed drugs.

Cardiovascular developments: patent highlights July to December 2006.

This overview provides a follow-up to a previously published paper on patent highlights of cardiovascular developments for January to June 2006. A period of six months could not have altered the fundamental preliminaries of the developmental challenges which cardiovascular disorders present to the pharmaceutical and biotechnology industry, and it was not expected that scientific insight would make quantum leaps during this brief interval. What makes such a repeat analysis nevertheless highly meaningful, beyond providing just another set of recent patent references, is the objective of validation--investigating whether the patterns that were observed during the initial review of the first half of 2006 actually represent established modalities of innovative industry efforts in the cardiovascular field. This objective was met by replicating the previous search of Thomson Scientific's Investigational Drugs database, and by using the same categorization of identified intellectual property disclosures.

New ocular therapeutics: a view from the patenting perspective.

This feature article provides an overview of the newest therapeutic developments for ocular diseases, based on patents and patent applications that were published in the 12-month period from November 2005 to October 2006. In contrast to peer-reviewed literature covering breakthroughs in basic science research, the patenting perspective discloses the intentions of the pharmaceutical industry for imminent drug development. Selected documents describing drug delivery, dry eye syndrome, ocular infections and lesions, glaucoma and age-related macular degeneration are discussed. The role of RNA interference, which is of particular interest in ophthalmology research, is also highlighted.

Cardiovascular and renal developments: patent highlights January to June 2006.

Failure of the cardiovascular system is the main reason for mortality in industrialized countries, and is a major cause of chronic morbidity. As most of the numerous ways in which it can fail will manifest in the second half of life and are exacerbated by old age, this situation is not likely to change in the near future unless fundamentally new ways of treating or preventing hypertension, atherosclerosis, myocardial infarction, chronic heart failure and cardiac arrhythmia are found. This prospect keeps the pharmaceutical industry on a constant, intense search for new therapeutic targets, new drugs, and new ways to identify such targets and drugs, as well as monitoring patient responses to drugs. This summary highlights the most interesting developments seen in cardiovascular and renal patents (other than those claiming formulations or combinations of known drugs) published during the first half of 2006.

From Psychiatry to Flower Power and Back Again: The Amazing Story of Lysergic Acid Diethylamide.

Among the psychedelic drugs that enjoyed a period of popularity in psychiatric research during the 1950s and 1960s, lysergic acid diethylamide (LSD) is the most prominent one. Psychiatrists of that time had seen LSD not only as a tool for psychotherapy but also as a potential therapeutic for anxiety, depression, alcohol abuse, autism, and even schizophrenia. When it became a quasi-religious epitome of the Hippie counterculture in the mid 1960s, and cases of what we now call hallucinogen persisting perception disorder and acute psychotic "flashbacks" mounted, authorities moved to make LSD illegal. Although research was never actually forbidden, the field almost completely dried out until the early 2010s. Using today's tools of molecular pharmacology, functional imaging, and neuronal network theory, neuropsychiatry is now resurrecting LSD research-with implications that leave us with many medical and ethical questions. Few people are aware that this is a repurposed compound, originally developed in an effort to synthesize a new analeptic. On top of all potential LSD might have in psychiatry, it also serves as a reminder of the unexpected potential that discarded early-stage compounds can have.

Sources and Targets for Drug Repurposing: Landscaping Transitions in Therapeutic Space.

Patent applications provide unique opportunities for landscaping ongoing medical innovation. In this analysis of drug repurposing patent applications published under the international Patent Convention Treaty during the years 2011-2014, we discuss what categories in the World Health Organization's International Classification of Diseases provide drugs and drug candidates for potential second medical uses, and how these proposed repurposed uses relate to each other and the original ones. Also discussed are the geographic origin of the patent assignees and their type and size. Beyond the expected interactions within the field of neuropsychiatry, frequent secondary use claims for oncology compounds to treat noninfectious respiratory diseases, and for cardiovascular compounds to treat neurological conditions, were unexpected findings derived from the repurposing heatmap. The relative absence of repurposing claims to treat parasitic or tropical diseases contrasts sharply with the broad attention this segment receives in the peer-reviewed literature. Equally notable are the dominance of universities and small pharmaceutical companies; a focus of large multinational companies to repurpose their own compounds; and the leading role of European-centered entities among the assignees. We believe that this investigation represents the first comprehensive cross-sectional attempt at mapping drug repurposing patterns across therapeutic fields, and could provide important clues that complement those obtained from the peer-reviewed literature.

Frovatriptan Vernalis.

Vanguard (now Vernalis) has developed frovatriptan, a selective 5-HT1B/1D partial agonist licensed from GlaxoSmithKline as a potential treatment for migraine [188478], [194382], [377863].

Zotepine for behavioural and psychological symptoms in dementia: an open-label study.

OBJECTIVE: To provide initial information on the safety and efficacy of the atypical antipsychotic zotepine in the treatment of behavioural and psychological symptoms of dementia (BPSD). METHODS: This was an open-label, single-centre field study. Twenty-four patients with BPSD associated with Alzheimer's disease (n=12) or other forms of dementia (n=12) were included. During the 8-week observation period, the patients received zotepine (Nipolept) [12.5-150 mg/day] for the psychotic components of BPSD; no other treatment interventions for BPSD were allowed. At baseline, day 28 and day 56, patients were evaluated using the Clinical Global Impressions (CGI) scale; the Mini-Mental State Examination (MMSE), the Syndrome Brief Test (SKT) and the Age Concentration Test (AKT) to assess cognition; and the Neuropsychiatric Inventory (NPI) and the Cohen-Mansfield Agitation Inventory (CMAI) to assess BPSD. General adverse effects and, more specifically, the emergence of extrapyramidal symptoms were also assessed. RESULTS: There was no change from baseline to day 56 in the CGI score and the caregiver burden (as indicated by the caregiver-related section of the NPI). There was also no change in cognition (as assessed by the MMSE, SKT and AKT). The neuropsychiatric symptom score according to part 1 of the NPI (especially key psychotic symptoms, aggression and disinhibition) and the CMAI scores improved by 36% and 15%, respectively, between baseline and the end of the study in a highly statistically significant fashion. No significant differences in treatment response or adverse effect profile were noted between the 12 patients with Alzheimer's disease and the 12 patients with other types of dementia. Zotepine was well tolerated, with tiredness and sedation (five and four cases, respectively) being the most frequent complaints. No clinically significant emergence of extrapyramidal symptoms was seen. CONCLUSIONS: Zotepine appears to be well tolerated and effective in treating BPSD, consistent with the performance of other atypical antipsychotic drugs in this condition. Larger, controlled studies are warranted.