Should We Be Using the Poisoning Severity Score?

Introduction

Despite the existence of a number of severity-of-illness classifications for other areas of medicine, toxicology research lacks a well-accepted method for assessing the severity of poisoning. The Poisoning Severity Score (PSS) was developed in the 1990s in Europe as a scoring system for poisonings reported to a poison center in order to describe a patient’s most severe symptomatology. We reviewed the literature to describe how the PSS is utilized and describe its limitations.

Discussion

We searched the medical literature in all languages using PUBMED, EMBASE, and SCOPUS from inception through August 2013 using predefined search terms. Out of 204 eligible publications, 40 met our criteria for inclusion in this review. There has been a paucity of published studies from North America that used the PSS. In some cases,  the PSS was misapplied or modified from standard scoring, making a bottom line appraisal of the validity or reliability of the original version of the instrument challenging. The PSS has several subjective criteria, is time consuming to score, and is likely to be of little use with some types of poisonings, limiting its clinical utility.

Conclusion

The PSS was developed as a tool to document encounters with poisoned patients. However, it is used infrequently and, when applied, has been misused or modified from its original form. In its current form, it has limited clinical utility and likely cannot be broadly applied to many exposures due to their unique clinical circumstances. With better global collaboration among medical toxicologists, it is possible that a modified score could be developed for use clinically or as a research instrument.

     

ADME of Biologics—What Have We Learned from Small Molecules?

Thorough characterization and in-depth understanding of absorption, distribution, metabolism, and elimination (ADME) properties of a drug candidate have been well recognized as an important element in small molecule (SM) drug discovery and development. This has been the area of focus for drug metabolism and pharmacokinetics (DMPK) scientists, whose role has been evolving over the past few decades from primarily being involved in the development space after a preclinical candidate was selected to extending their involvement into the discovery stage prior to candidate selection. This paradigm shift has ensured the entry into development of the best candidates with optimal ADME properties, and thus has greatly impacted SM drug development through significant reduction of the failure rate for pharmacokinetics related reasons. In contrast, the sciences of ADME and DMPK have not been fully integrated into the discovery and development processes for large molecule (LM) drugs. In this mini-review, we reflect on the journey of DMPK support of SM drug discovery and development and highlight the key enablers that have allowed DMPK scientists to make such impacts, with the aim to provide a perspective on relevant lessons learned from SM drugs that are applicable to DMPK support strategies for LMs.     

Should we explore the clinical utility of hormesis?

The idea that low-dose adaptive effects as described in hormesis can be used clinically has been discussed for hundreds if not thousands of years. Paracelsus famous adage that ;the dose makes the poison' and the common folk saying that one can be cured by ;the hair of the dog that bit you' speak to this idea. So why has so little research been done on the possible clinical utility of hormesis? What areas of clinical hormesis seem to be the most promising to explore? This article examines these concepts and proposes some initial areas or research where the possible utility of hormeiss might be investigated.     

The Measurement of the β/α Anomer Composition Within Amorphous Lactose Prepared by Spray and Freeze Drying Using a Simple 1H-NMR Method

Purpose  

Reports of the anomeric composition of amorphous lactose are rare and state a highly variable range of composition (between 0% and 60% w/w β content). We aimed to develop a quantitative measurement by ¹H-NMR of α and β anomer content in amorphous lactose produced by different production methods.     

Can the concept of hormesis Be generalized to carcinogenesis?

The concept of hormesis (i.e., low-dose stimulation/high-dose inhibition) has been shown to be widely generalizable with respect to chemical class, animal model, gender, and biological end point. The public health implication of this lack of linearity in the low-dose area of the dose-response curve raises the question of whether low doses of carcinogens will reduce cancer risk. Articles relating to the process of carcinogenesis (i.e., initiation, promotion, tumor development, and progression) were obtained from a recently developed chemical hormesis database and evaluated for their evidence of hormesis. Numerous examples in well-designed studies indicate that U- or J-shaped dose-response relationships exist with respect to various biomarkers of carcinogenesis in different animal models of both sexes. Examples of such J-shaped dose-response relationships in each stage of the process of carcinogenesis were selected for detailed toxicological examination. These results have important implications for both the hazard assessment of carcinogens and cancer risk assessment procedures.     

Roll Compaction/Dry Granulation of Dibasic Calcium Phosphate Anhydrous—Does the Morphology of the Raw Material Influence the Tabletability of Dry Granules?

The influence of raw material particle morphology on the tabletabilty of dry granules was investigated. Therefore, dibasic calcium phosphate anhydrous was used as a model material. One milled grade, 2 agglomerated grades with different porosities, and a functionalized structure, that is, an agglomerate formed by very small primary particles, were included. Particle size, density, and specific surface area of raw materials were measured. The starting materials and 2 fractions of dry granules were compressed to tablets. The tabletability of granules was compared to that of the powders and the influence of specific compaction force, granule size, and lubrication on tablet tensile strength was evaluated. All materials showed a loss in tabletability induced by a previous compaction step but to a varying extent. Only in case of the functionalized calcium phosphate morphology, this effect depended on the specific compaction force. In contrast to the other materials, the tabletability of functionalized calcium phosphate was influenced by the granule size. This effect was not related to an overlubrication as internal and external lubrication resulted in similar tensile strengths. A clear influence of the particle morphology on tablet strength was demonstrated by the study. The functionalized structure showed aspects of a more plastic deformation behavior. The functionalized dibasic calcium phosphate and the more porous agglomerate performed as potential filler/binder in the field of roll compaction/dry granulation.     

The Future of Hormesis: Where Do We Go from Here?

Although the occurrence of U-shaped dose responses in toxicology (i.e., hormetic effects) have been known for more than a century, the concept of hormesis has long been marginalized under the belief that such observations could be explained by a combination of poor study designs and normal variability. However, recent efforts have established that numerous highly reliable studies demonstrating hormetic effects exist and that such findings appear to be highly generalizable across species, endpoint measures, and class of agents assessed. In light of such a long and complicated history, and its significant biomedical/toxicological implications, this article explores the unique challenges that the concept of hormesis confronts in both the experimental and institutional domains with respect to assessing its scientific foundations and validity and the impediments to its intstitutional acceptance and use with society. This perspective is then immediately critiqued by five authors in subsequent articles.     

Evaluation of Dosing Strategies of N-acetylcysteine for Acetaminophen Toxicity in Patients Greater than 100 Kilograms: Should the Dosage Cap Be Used?

IntroductionAcetaminophen is a commonly used analgesic and antipyretic, with the potential to cause significant injury when ingested in toxic amounts. Although the antidote n-acetylcysteine (NAC) is available, evidence supporting dose recommendations for patients weighing over 100 kg are lacking. We performed a retrospective, multi-center analysis to determine if a capped NAC dosing scheme is similar to a non-capped dosing scheme in patients weighing over 100 kg.MethodsBetween January 2009 and January 2016, we identified patients presenting to 12 different centers who were evaluated for acetaminophen poisoning treatment. Patients must have weighed greater than 100 kg and were evaluated and identified as needing treatment for acetaminophen-related poisoning with NAC. The primary outcome was occurrence of hepatic injury, defined as an AST or ALT ≥ 100 IU/L. Secondary endpoints included number of drug-related adverse events, occurrence of hepatotoxicity, cumulative NAC dose, regimen cost, length of hospital and intensive care unit stays, and in-hospital mortality.ResultsThere were 83 patients identified as meeting the pre-specified inclusion and exclusion criteria. A capped NAC dosing scheme resulted in no difference in hepatic injury when compared to a non-capped regimen (49.4% vs 50%, p = 1.000). The capped dosage regimen was associated with a lower cumulative dose (285.2 mg/kg vs 304.6 mg/kg, p < 0.001) and cost. No other statistically significant differences were identified among the secondary endpoints.ConclusionA capped NAC dosing scheme was not associated with higher rates of hepatic injury or hepatotoxicity in obese patients in the setting of acetaminophen poisoning when compared to a non-capped regimen. Further research is needed to verify these results.     

Betaine—The dark knight of the brain

The role of betaine in the liver and kidney has been well documented, even from the cellular and molecular point of view. Despite literature reporting positive effects of betaine supplementation in Alzheimer's, Parkinson's and schizophrenia, the role and function of betaine in the brain are little studied and reviewed. Beneficial effects of betaine in neurodegeneration, excitatory and inhibitory imbalance and against oxidative stress in the central nervous system (CNS) have been collected and analysed to understand the main role of betaine in the brain. There are many ‘dark’ aspects needed to complete the picture. The understanding of how this osmolyte is transported across neuron and glial cells is also controversial, as the expression levels and functioning of the known protein capable to transport betaine expressed in the brain, betaine-GABA transporter 1 (BGT-1), is itself not well clarified. The reported actions of betaine beyond BGT-1 related to neuronal degeneration and memory impairment are the focus of this work. With this review, we underline the scarcity of detailed molecular and cellular information about betaine action. Consequently, the requirement of detailed focus on and study of the interaction of this molecule with CNS components to sustain the therapeutic use of betaine.     

Immunotoxins: The Role of the Toxin ?

Immunotoxins are antibody-toxin bifunctional molecules that rely on intracellular toxin action to kill target cells. Target specificity is determined via the binding attributes of the chosen antibody. Mostly, but not exclusively, immunotoxins are purpose-built to kill cancer cells as part of novel treatment approaches. Other applications for immunotoxins include immune regulation and the treatment of viral or parasitic diseases. Here we discuss the utility of protein toxins, of both bacterial and plant origin, joined to antibodies for targeting cancer cells. Finally, while clinical goals are focused on the development of novel cancer treatments, much has been learned about toxin action and intracellular pathways. Thus toxins are considered both medicines for treating human disease and probes of cellular function.