On the Discovery and Development of Pimavanserin: A Novel Drug Candidate for Parkinson’s Psychosis

Parkinson’s disease psychosis (PDP) is a condition that may develop in up to 60 % of Parkinson’s patients, and is a major reason for nursing home placement for those affected. There are no FDA approved drugs for PDP but low doses of atypical anti-psychotic drugs (APDs) are commonly prescribed off-label. Only low-dose clozapine has shown efficacy in randomized controlled trials, but all APDs have black box warnings related to the increased mortality and morbidity when used in elderly demented patients. Using molecular pharmacological profiling of a large collection of marketed drugs, we discovered that potent inverse agonist activity against 5-HT_2A serotonin receptors was a common feature of atypical APDs, especially the atypical APDs used to treat PDP. Since low-dose clozapine therapy selectively blocks this receptor, it was hypothesized that a highly selective 5-HT_2A receptor inverse agonist might provide good symptom control in patients suffering from PDP, with a greatly improved safety and tolerability profile. A high throughput screening and subsequent chemical lead optimization campaign to develop potent, selective 5-HT_2A receptor inverse agonists was launched, eventually resulting in the discovery of pimavanserin. Pimavanserin displays nanomolar potency as a 5-HT_2A receptor inverse agonist, selectivity for 5-HT_2A over 5-HT_2C receptors, and no meaningful activity at any other G-protein coupled receptor. It demonstrated robust activity in preclinical models of schizophrenia and PDP, and did not worsen motoric symptoms, in contrast to the APDs tested. In a Phase III clinical trial, pimavanserin showed highly significant benefits in the primary endpoint, the scale for assessment of positive symptoms-PD, a scale adapted for use in PDP. In addition, improvements in all other efficacy endpoints, including physician’s clinical global impression, caregiver burden, night-time sleep quality and daytime wakefulness, were seen. Pimavanserin demonstrated good safety and tolerability and did not worsen motoric symptoms as assessed by the unified Parkinson’s disease rating scale parts II and III. An open-label extension study has further demonstrated that pimavanserin is safe and well-tolerated with long-term use. Pimavanserin may therefore offer a viable treatment option for patients suffering from PDP.     

Repurposing the FDA-Approved Pinworm Drug Pyrvinium as a Novel Chemotherapeutic Agent for Intestinal Polyposis

Mutations in the WNT-pathway regulator ADENOMATOUS POLYPOSIS COLI (APC) promote aberrant activation of the WNT pathway that is responsible for APC-associated diseases such as Familial Adenomatous Polyposis (FAP) and 85% of spontaneous colorectal cancers (CRC). FAP is characterized by multiple intestinal adenomas, which inexorably result in CRC. Surprisingly, given their common occurrence, there are few effective chemotherapeutic drugs for FAP. Here we show that the FDA-approved, anti-helminthic drug Pyrvinium attenuates the growth of WNT-dependent CRC cells and does so via activation of CK1α. Furthermore, we show that Pyrvinium can function as an in vivo inhibitor of WNT-signaling and polyposis in a mouse model of FAP: APC^min mice. Oral administration of Pyrvinium, a CK1α agonist, attenuated the levels of WNT-driven biomarkers and inhibited adenoma formation in APC^min mice. Considering its well-documented safe use for treating enterobiasis in humans, our findings suggest that Pyrvinium could be repurposed for the clinical treatment of APC-associated polyposes.     

Wireless Monitoring of Liver Hemodynamics In Vivo

Liver transplants have their highest technical failure rate in the first two weeks following surgery. Currently, there are limited devices for continuous, real-time monitoring of the graft. In this work, a three wavelengths system is presented that combines near-infrared spectroscopy and photoplethysmography with a processing method that can uniquely measure and separate the venous and arterial oxygen contributions. This strategy allows for the quantification of tissue oxygen consumption used to study hepatic metabolic activity and to relate it to tissue stress. The sensor is battery operated and communicates wirelessly with a data acquisition computer which provides the possibility of implantation provided sufficient miniaturization. In two in vivo porcine studies, the sensor tracked perfusion changes in hepatic tissue during vascular occlusions with a root mean square error (RMSE) of 0.135 mL/min/g of tissue. We show the possibility of using the pulsatile wave to measure the arterial oxygen saturation similar to pulse oximetry. The signal is also used to extract the venous oxygen saturation from the direct current (DC) levels. Arterial and venous oxygen saturation changes were measured with an RMSE of 2.19% and 1.39% respectively when no vascular occlusions were induced. This error increased to 2.82% and 3.83% when vascular occlusions were induced during hypoxia. These errors are similar to the resolution of a commercial oximetry catheter used as a reference. This work is the first realization of a wireless optical sensor for continuous monitoring of hepatic hemodynamics.     

Non-viral adeno-associated virus-based platform for stable expression of antibody combination therapeutics: Non-viral adeno-associated virus-based platform for stable expression of antibody combination therapeutics

Antibody combination therapeutics (ACTs) are polyvalent biopharmaceuticals that are uniquely suited for the control of complex diseases, including antibiotic resistant infectious diseases, autoimmune disorders and cancers. However, ACTs also represent a distinct manufacturing challenge because the independent manufacture and subsequent mixing of monoclonal antibodies quickly becomes cost prohibitive as more complex mixtures are envisioned. We have developed a virus-free recombinant protein expression platform based on adeno-associated viral (AAV) elements that is capable of rapid and consistent production of complex antibody mixtures in a single batch format. Using both multiplexed immunoassays and cation exchange (CIEX) chromatography, cell culture supernatants generated using our system were assessed for stability of expression and ratios of the component antibodies over time. Cultures expressing combinations of three to ten antibodies maintained consistent expression levels and stable ratios of component antibodies for at least 60 days. Cultures showed remarkable reproducibility following cell banking, and AAV-based cultures showed higher stability and productivity than non-AAV based cultures. Therefore, this non-viral AAV-based expression platform represents a predictable, reproducible, quick and cost effective method to manufacture or quickly produce for preclinical testing recombinant antibody combination therapies and other recombinant protein mixtures.     

Endemic Seed Plants in the Bahamian Archipelago

The Bahamian archipelago consists of approximately 2,400 islands occurring in the Atlantic Ocean off the coasts of Florida, Cuba, and Hispaniola. In 1982 Donovan Correll and Helen Correll published the most current synopsis of the floristic diversity of this island chain. Their publication cited a total of 1,371 vascular plant species of which 114 seed plants were listed as endemic to the archipelago (~8 % of the native flora). In the last 30 years, additional herbarium collections and taxonomic studies have shown that a number of species previously indicated to be endemic to these islands also occur in other regions or have been taxonomically merged into other species. The current number of species considered endemic to the Bahamian archipelago is 89 (~6 % of the total flora). There are 50 endemic species that have a known distribution on one (31 species) or two island groupings (19 species). Biogeographical analyses of endemic plant distributions shows three distinct clusters of species: southern, central, and the northern islands, with a fourth cluster that includes islands with a small area and one medium size island that seems that has been underexplored (i.e., Little Inagua). We anticipate that understanding the conservation status of endemic species and their distributions will help to develop legislation to preserve this Bahamian natural heritage.     

Plant Conservation Challenges in the Bahama Archipelago

The Bahamian archipelago has a rich flora with 89 endemic species. An international symposium held at Nassau in October 2012 to celebrate the 30th anniversary of the publication of the “Flora of the Bahama Archipelago” provided a forum to discuss plant conservation issues on these islands. This article builds on conclusions from this symposium and results from joint plant conservation research projects among the authors. The two main conservation challenges for these islands are: (1) environmental uncertainties derived from global warming and associated sea level changes and (2) the need for increased plant conservation awareness among the predominant urban population of the archipelago. Legal tools and biodiversity international agreements in place for The Commonwealth of the Bahamas can facilitate mechanisms for effective plant conservation. Further legal developments need to be established in The United Kingdom Overseas Territory of The Turks and Caicos Islands. There is an urgent need to redevelop the Botanic Garden of Nassau and designate it as the national botanic garden of The Bahamas. Further research related to the taxonomy, biology, conservation status, and distribution of the endemic species is urgently needed. Research initiatives pertinent to the detrimental effect and biology of invasive species are also lacking. The heterogeneous environments and uneven distribution of human populations across the archipelago are major challenges for conservation. Finally because of the political and economic status of The Bahamas and The Turks and Caicos, conservation agencies from the archipelago do not have easy access to international or British/European Union funds for global conservation initiatives.     

Evolutionary approaches to cultural and linguistic diversity

Evolutionary approaches to cultural change are increasingly influential, and many scientists believe that a 'grand synthesis' is now in sight. The papers in this Theme Issue, which derives from a symposium held by the AHRC Centre for the Evolution of Cultural Diversity (University College London) in December 2008, focus on how the phylogenetic tree-building and network-based techniques used to estimate descent relationships in biology can be adapted to reconstruct cultural histories, where some degree of inter-societal diffusion will almost inevitably be superimposed on any deeper signal of a historical branching process. The disciplines represented include the three most purely 'cultural' fields from the four-field model of anthropology (cultural anthropology, archaeology and linguistic anthropology). In this short introduction, some context is provided from the history of anthropology, and key issues raised by the papers are highlighted.     

Accelerating high quality bioanalytical LC/MS/MS assays using fused-core columns

High quality, ultra-fast bioanalytical LC/MS/MS methods were developed using short columns packed with fused-core particles and high (1.0–3.0 mL/min) flow rates. For more than two years, at flow rates up to 3.0 mL/min, using 0.33 min non-ballistic gradients, these methods were shown to provide comparable or better performance than slower assays for accuracy, precision, sensitivity, specificity, and ruggedness, and met all criteria required by the bioanalytical regulatory guidance.