Could rusalatide acetate be the future drug of choice for diabetic foot ulcers and fracture repair?

Rusalatide acetate (Chrysalin^®) is an investigational drug being evaluated for treatment of chronic wounds and fractures. Rusalatide acetate interacts with cell surface receptors to stimulate a cascade of cellular and molecular wound healing events, including activation of nitric oxide signaling. Rusalatide acetate significantly accelerated healing of diabetic foot ulcers and distal radius fractures in Phase I/II clinical trials. Subsequently, in one of the largest Phase III fracture studies to date, rusalatide acetate showed significant acceleration of distal radius fracture healing radiographically but failed to meet its primary clinical endpoint – time to removal of immobilization – within the intent-to-treat population. Subset analysis showed that rusalatide acetate met this primary clinical endpoint and significantly accelerated radiographic healing in osteopenic women. Rusalatide acetate may therefore show its greatest efficacy in healing-impaired patients.     

Could rusalatide acetate be the future drug of choice for diabetic foot ulcers and fracture repair?

Rusalatide acetate (Chrysalin) is an investigational drug being evaluated for treatment of chronic wounds and fractures. Rusalatide acetate interacts with cell surface receptors to stimulate a cascade of cellular and molecular wound healing events, including activation of nitric oxide signaling. Rusalatide acetate significantly accelerated healing of diabetic foot ulcers and distal radius fractures in Phase I/II clinical trials. Subsequently, in one of the largest Phase III fracture studies to date, rusalatide acetate showed significant acceleration of distal radius fracture healing radiographically but failed to meet its primary clinical endpoint - time to removal of immobilization - within the intent-to-treat population. Subset analysis showed that rusalatide acetate met this primary clinical endpoint and significantly accelerated radiographic healing in osteopenic women. Rusalatide acetate may therefore show its greatest efficacy in healing-impaired patients.     

Could the Ebola virus matrix protein VP40 be a drug target?

Filoviruses are filamentous lipid-enveloped viruses and include Ebola (EBOV) and Marburg, which are morphologically identical but antigenically distinct. These viruses can be very deadly with outbreaks of EBOV having clinical fatality as high as 90%. In 2012 there were two separate Ebola outbreaks in the Democratic Republic of Congo and Uganda that resulted in 25 and 4 fatalities, respectively. The lack of preventive vaccines and FDA-approved therapeutics has struck fear that the EBOV could become a pandemic threat. The Ebola genome encodes only seven genes, which mediate the entry, replication, and egress of the virus from the host cell. The EBOV matrix protein is VP40, which is found localized under the lipid envelope of the virus where it bridges the viral lipid envelope and nucleocapsid. VP40 is effectively a peripheral protein that mediates the plasma membrane binding and budding of the virus prior to egress. A number of studies have demonstrated specific deletions or mutations of VP40 to abrogate viral egress but to date pharmacological inhibition of VP40 has not been demonstrated. This editorial highlights VP40, which is the most abundantly expressed protein of the virus and discusses VP40 as a potential therapeutic target.     

Big gene banks: nuggets for drug discovery or fool's gold?

Gene-mapping studies that look for complex traits among human populations have deepened our understanding of disease causes, but do they hold promise for identifying drug targets?     

How can drug discovery for psychiatric disorders be improved?

Psychiatric disorders such as depression, anxiety and schizophrenia are leading causes of disability worldwide, and have a huge societal impact. However, despite the clear need for better therapies, and major advances in the understanding of the molecular basis of these disorders in recent years, efforts to discover and develop new drugs for neuropsychiatric disorders, particularly those that might revolutionize disease treatment, have been relatively unsuccessful. A multidisciplinary approach will be crucial in addressing this problem, and in the first Advances in Neuroscience for Medical Innovation symposium, experts in multiple areas of neuroscience considered key questions in the field, in particular those related to the importance of neuronal plasticity. The discussions were used as a basis to propose steps that can be taken to improve the effectiveness of drug discovery for psychiatric disorders.     

Could nanoparticle systems have a role in the treatment of cerebral gliomas?

Malignant brain tumors are difficult to manage clinically and are associated with high rates of morbidity and mortality. Late diagnosis and the limitations of conventional therapies that may result from inefficient delivery of the therapeutic or contrast agent to brain tumors due to the blood-brain barrier and nonspecificity of the agents, are major reasons for this unsolved clinical problem. Nanotechnology involves the design, synthesis, and characterization of materials and devices that have a functional organization in at least one dimension on the nanometer scale. The nanoparticle has emerged as a potential vector for brain delivery, able to overcome the difficulties of modern strategies. Moreover, multifunctionality can be engineered into a single nanoplatform so that it can provide tumor-specific detection, treatment, and follow-up monitoring. This review reports the latest research in nanoparticle-based glioma treatment. FROM THE CLINICAL EDITOR: In recent years, nanoparticles have emerged as potential delivery vectors targeting brain tumors, including multifunctional NP-s allowing tumor-specific detection, treatment, and follow-up monitoring. This review summarizes the latest research in nanoparticle-based glioma treatment.     

The cell biology of parasitism in Trypanosoma brucei: insights and drug targets from genomic approaches?

The African trypanosome, Trypanosoma brucei exhibits a complex, digenetic life cycle that alternates between the tsetse fly vector and the mammalian host. The life cycle is characterised by a complex series of cell type differentiations and variations in metabolism. In addition the trypanosome exhibits a particular cell biology that has become adapted for its role as a parasite. This article places some of these areas in a frame-work that considers the role of cellular processes in parasitism. I rehearse some conclusions from recent studies and provide hyphotheses and suggestions for future work. Areas debated include: cell surface protein expression, cell differentiation, endomembrane trafficking and protein targeting, the cytoskeleton,flagellum functions in motility, attachment and plasma membrane differentiation, organelle specialisations, control of cell cycle, parasite/host, parasite/parasite and parasite/vector interactions. The review also focuses on the likely impact of the genome project and reverse genetics in providing greater insight to these cellular processes and how, if coordinated with some alan by scientists and funding agencies, this may provide novel targets for future drug development.     

Functional versus chemical diversity: is biodiversity important for drug discovery?

Prospecting the full biodiversity of nature to find leads for new drugs is not necessary. Because finding leads is aimed at identifying biological activity, structure is of secondary importance. Furthermore, although natural chemical diversity might be unrivalled, functional diversity is bound to be considerably less. It is likely that many millions of chemically distinct molecules exist in nature but it is inconceivable that the number of different biological functions is near this number. This is corroborated by knowledge obtained from the genome sequences of an increasing number of species. It is unlikely that ligands for specific molecular targets are restricted to one species and even individual compounds are often found in more than one species. Important molecular mechanisms are likely to be ubiquitous and there are no a priori reasons to assume that some are restricted to, for example, tropical rainforests. Thus, there are no obvious advantages of "biodiversity prospecting", which will, possibly, endanger fragile ecosystems in the search for rare species.     

How can statistical approaches enhance transdisciplinary study of drug misuse prevention?

Application of statistical techniques in transdisciplinary research includes statistical model selection and model specification. This paper presents statistical models used in drug misuse prevention research. The historical roots of these models are discussed to illustrate the numerous disciplines from which different techniques originated. Single and multilevel approaches are described to illustrate methods of synthesizing perspectives from different scientific arenas. Using single-level approaches in transdisciplinary research, these models can easily incorporate broader theoretical considerations and more integrated hypotheses by representing each discipline with a set of variables. Simultaneous testing of every set of variables obtained from different disciplines may provide more comparable results to identify critical factors associated with substance-use behavior. Using multilevel approaches, more powerful syntheses across disciplines can be achieved by representing each discipline at a different level.     

What can be inferred from bacterium–nanoparticle interactions about the potential consequences of environmental exposure to nanoparticles?

This article collates published information regarding the in vitro antibacterial activity of both metal and carbon nanoparticles. The aims are to establish a consensus regarding modes of antibacterial activity, and to evaluate the applicability of current knowledge to prediction of likely effects of nanoparticles upon important microbial processes in environmental exposures. The majority of studies suggest that nanoparticles cause disruption to bacterial membranes, probably by production of reactive oxygen species. Contact between the nanoparticle and bacterial membrane appears necessary for this activity to be manifested. Interfacial forces such as electrostatic interactions are probably important in this respect. However, the toxicity of free metal ions originating from the nanoparticles cannot be discounted. Passage of nanoparticles across intact membranes appears to be unlikely, although accumulation within the cytoplasm, probably after membrane disruption, is often observed. To date, published studies have not been designed to mimic natural systems and therefore provide poor understanding of the likely consequences of intentional or unintentional environmental release. The limited studies currently available fail to identify any significant effects at the microbial level of nanoparticles in more complex systems.     

Can fluconazole concentrations in saliva be used for therapeutic drug monitoring?

The saliva/plasma concentration ratio of fluconazole was investigated in 22 HIV-1-infected individuals with an oropharyngeal Candida infection to determine whether saliva fluconazole concentrations could provide useful information for therapeutic drug monitoring in this population. Steady-state paired plasma and saliva samples were obtained after approximately 1 week of treatment with 50-or 100-mg fluconazole as capsules. A significant correlation between plasma and salivary levels of fluconazole was observed. The median saliva/plasma concentration ratio was 1.3 and was independent of the ingested dose and the plasma fluconazole concentration. The prediction of fluconazole concentrations in plasma from the concentrations in saliva was, although unbiased, not precise. From these findings, the authors conclude that although stimulated salivary fluconazole concentrations are significantly correlated with plasma concentrations, it is not possible to predict plasma fluconazole levels from the salivary concentrations with adequate precision. However, saliva fluconazole concentrations have sufficient value to test for compliance and even semiquantitative prediction of plasma concentrations.     

Effect of γ-cyclodextrin on the in vitro skin permeation of a steroidal drug from nanoemulsions: impact of experimental setup

Numerous reports on the enhancement effect of cyclodextrins (CDs) on the skin permeation of dermally applied drugs exist, the majority of which is based on in vitro diffusion cell studies. The specific experimental setup of such studies may skew the obtained results, which is rarely discussed in the context of CD studies. Thus, the aim of this work was to conduct a systematic in vitro investigation of the permeation enhancement potential of γ-CD on a steroidal drug from a nanoemulsion. The role of critical diffusion cell parameters such as the dose of application, occlusive conditions, the nature of the receptor medium and the skin thickness were investigated. The results showed that significantly enhanced skin permeation rates of fludrocortisone acetate were indeed caused by 1% (w/w) of γ-CD at both finite and infinite dose conditions. At 0.5% (w/w) of γ-CD, significant enhancement was only achieved at infinite dose application. Additional in vitro tape stripping experiments confirmed these tendencies, but the observed effects did not reach statistical significance. It may be concluded that the full permeation enhancement potential of the CD as observed in the franz-cell setup can only be realised at infinite dose conditions while preserving the formulation structure.     

Cost-effectiveness analysis: should it be required for drug registration and beyond?

Cost-effectiveness analysis (CEA) is applied in situations where trade-offs exist, typically, greater benefit for an increased cost over an alternative therapy or strategic option versus usual care. CEA is useful where a new strategy is more costly but expected to be more effective or where a new strategy is less costly but less effective. A good example for the relevance of CEA is the unanimous recommendation of a US federal vaccine advisory panel to vaccinate 11-year-old girls against cervical cancer. This recommendation was at least partly because of data showing the relative cost-effectiveness of HPV vaccine. In this era of finite budgets, CEA may facilitate drug development, drug approval, patient segmentation and pricing model development throughout the drug lifecycle continuum.     

Could endogenous substrates of drug-metabolizing enzymes influence constitutive physiology and drug target responsiveness?

Integration of genomic data from pharmacokinetic pathways and drug targets is an emerging trend in bioinformatics, but is there a clear separation of pharmacokinetic pathways and drug targets? Should we also consider the potential interactions of endogenous substrates of drug-metabolizing enzymes with receptors and other molecular drug targets as we combine pharmacogenomic datasets? We discuss these overarching questions through a specific pharmacogenomic case study of the cytochrome P450 (CYP)2D6, serotonin and dopamine triad. Importantly, CYP2D6 may contribute to the regeneration of serotonin from 5-methoxytryptamine by virtue of its catalytic function as a 5-methoxyindolethylamine O-demethylase. Furthermore, serotonergic neurons provide a regulatory feedback on dopaminergic neurotransmission. Hence, we hypothesize that independent of its role as a pharmacokinetic gene, CYP2D6 may nuance the regulation of serotonergic and dopaminergic neurophysiology. Additionally, we reflect upon the contribution of hyperspecialization in biomedicine to the present disconnect between research on pharmacokinetics and drug targets, and the potential for remedying this important gap through informed dialogue among clinical pharmacologists, human geneticists, bioethicists and applied social scientists.     

Which Xenobiotic(s) Could be Responsible for the Radiologic Findings Below?

Background

The proconvulsive properties of tramadol, bupropion, and nortriptyline have been well documented. Spinal fractures secondary to drug-induced seizures have been rarely reported.

Case Report

A 39-year-old female presented with a chief complaint of back pain. She went to bed feeling well in a separate room from her husband. During the previous night, he heard a noise and went into her room, finding her confused and twisted in an awkward position on her bed. Later she complained to him of severe back pain, prompting transport to a hospital. Shortly after arrival in the emergency department, staff witnessed a generalized convulsion. Following a one-hour post-ictal period, she complained of worsened back pain. Lab studies were normal, including a urine tox screen for drugs of abuse. No alcohol was implicated. ECG showed sinus rhythm, HR 113 beats/min, QRS 108 ms, QTc 389 ms. Brain magnetic resonance imaging (MRI) was normal. X-ray and an MRI of the thoracic spine confirmed four contiguous vertebral compression fractures, from T2 through T5. EEG showed diffuse changes consistent with a metabolic or toxicologic process. She denied taking any drugs other than prescribed doses of her medications, which included tramadol, bupropion, and nortriptyline. She had no previous history of seizures, head injury, or CVA. Bupropion and tramadol were discontinued, and seizures did not recur.

Case Discussion

This patient's history, EEG findings, and brain imaging all point to a metabolic or toxic cause. It is likely that her three proconvulsant medications—even at therapeutic doses—synergistically lowered her seizure threshold or even precipitated her seizures. Retrospective studies and case reports portray these drugs as potentially offending agents.

Conclusions

Sudden onset of back pain during sleep can be an important clue to a seizure complicated by vertebral compression fractures, even in the absence of trauma. Toxicology consultation in seizures of unclear etiology can help discern drugs that offend even in therapeutic doses.