A critique of the European Commission Document, “State of the Art Assessment of Endocrine Disrupters”

In this commentary, we critique a recently finalized document titled “State of the Art Assessment of Endocrine Disrupters” (SOA Assessment). The SOA Assessment was commissioned by the European Union Directorate-General for the Environment to provide a basis for developing scientific criteria for identifying endocrine disruptors and reviewing and possibly revising the European Community Strategy on Endocrine Disrupters. In our view, the SOA Assessment takes an anecdotal approach rather than attempting a comprehensive assessment of the state of the art or synthesis of current knowledge. To do the latter, the document would have had to (i) distinguish between apparent associations of outcomes with exposure and the inference of an endocrine-disruption (ED) basis for those outcomes; (ii) constitute a complete and unbiased survey of new literature since 2002 (when the WHO/IPCS document, “Global Assessment of the State-of-the-Science of Endocrine Disruptors” was published); (iii) consider strengths and weaknesses and issues in interpretation of the cited literature; (iv) follow a weight-of-evidence methodology to evaluate evidence of ED; (v) document the evidence for its conclusions or the reasoning behind them; and (vi) present the evidence for or reasoning behind why conclusions that differ from those drawn in the 2002 WHO/IPCS document need to be changed. In its present form, the SOA Assessment fails to provide a balanced and critical assessment or synthesis of literature relevant to ED. We urge further evidence-based evaluations to develop the needed scientific basis to support future policy decisions.     

Report on the 10th Anniversary of International Drug Discovery Science and Technology Conference, 8 – 10 November 2012, Nanjing,China

The 10th Anniversary of International Drug Discovery Science and Technology (IDDST) Conference was held in Nanjing, China from 8 to 10 November 2012. The conference ran in parallel with the 2nd Annual Symposium of Drug Delivery Systems. Over 400 delegates from both conferences came together for the Opening Ceremony and Keynote Addresses but otherwise pursued separate paths in the huge facilities of the Nanjing International Expo Centre. The IDDST was arranged into 19 separate Chapters covering drug discovery biology, target validation, chemistry, rational drug design, pharmacology and toxicology, drug screening technology, ‘omics' technologies, analytical, automation and enabling technologies, informatics, stem cells and regenerative medicine, bioprocessing, generics, biosimilars and biologicals and seven disease areas: cancer, CNS, respiratory and inflammation, autoimmune, emerging infectious, bone and orphan diseases. There were also two sessions of a ‘Bench to Bedside to Business' Program and a Chinese Scientist programme. In each period of the IDDST conference, up to seven sessions were running in parallel. This Meeting Highlight samples just a fraction of the content of this large meeting. The talks included have as a link, the use of new approaches to drug discovery. Many other excellent talks could have been highlighted and the author has necessarily had to be selective.     

Influence of Processing Conditions on the Physical State of Mannitol—Implications in Freeze-Drying

Purpose To study the effect of processing conditions on the physical state of mannitol during various stages of the lyophilization cycle of a protein formulation. Materials and Methods Mannitol and trehalose were used as the bulking agent and lyoprotectant, respectively. The physical state of mannitol during various stages of freeze-drying cycle, in the absence and presence of a model protein, was characterized using low temperature X-ray powder diffractometry (XRD) and differential scanning calorimetry (DSC). Results Mannitol did not crystallize even when the solution for lyophilization was cooled to −45°C at a slow cooling rate of 1°C/min. Annealing facilitated mannitol crystallization, and in the absence of the protein, a mixture of δ-mannitol and mannitol hemihydrate was obtained at both low (−18°C) and high (−8°C) annealing temperatures. However, in the presence of protein, the high annealing temperature promoted δ-mannitol crystallization and inhibited formation of mannitol hemihydrate, while the low annealing temperature facilitated the formation of mannitol hemihydrate. Interestingly, the hemihydrate in the frozen solution was retained in the final lyophile, even when the primary and secondary drying temperatures were as high as −5 and 65°C, respectively. Conclusions The presence of protein as well as the processing conditions (annealing temperature and time, primary and secondary drying temperatures) influenced the physical form of mannitol in the final lyophile. The protein promoted formation of δ-mannitol while inhibiting the formation of mannitol hemihydrate. Since the physical form of mannitol was greatly influenced by the presence of protein, it will be prudent to conduct the preliminary lyophilization cycle development studies in the presence of the protein. If mannitol hemihydrate is formed during annealing, its dehydration may require high secondary drying temperature.     

Influence of the Active Pharmaceutical Ingredient Concentration on the Physical State of Mannitol—Implications in Freeze-Drying

Purpose The aim of this study was to investigate the effect of the concentration of the active pharmaceutical ingredient on the physical state of mannitol in frozen aqueous systems. Methods A human monoclonal antibody was used as the model protein. Mannitol and sucrose were used as the bulking agent and the lyoprotectant, respectively. The thermal behavior of frozen mannitol–sucrose solutions during and after annealing, in the absence and presence of the protein, were characterized by low-temperature powder X-ray diffractometry and differential scanning calorimetry. The influence of the protein on the crystallization behavior of mannitol was also evaluated. Results The excipient concentration had a pronounced effect on the glass transition temperature of maximally freeze-concentrated amorphous phase (T_g′). At fixed excipient compositions, the protein had no effect on the T_g′ if the protein concentration was ≤20 mg/ml. However, at higher protein concentrations, there was a marked increase in T_g′ as a function of protein concentration. The inhibitory effect of the protein on mannitol crystallization was concentration dependent and was directly evident from X-ray diffractometry experiments. Annealing facilitated both mannitol nucleation and crystal growth even in the presence of the protein. Conclusions The ratio of mannitol to sucrose and the protein concentration have an impact on the T_g′ and may therefore influence the primary drying temperature. The protein inhibits both the nucleation and growth of mannitol crystals and this effect seems to be concentration dependent. The presence of the protein and the protein concentration dictate the processing conditions, i.e., annealing time, annealing temperature, and primary drying temperature.     

Computer Simulation of Skin Permeability of Hydrophobic and Hydrophilic Chemicals – Influence of Follicular Pathway

A recently published mechanistic skin permeability model (Kasting et al., 2019. J Pharm Sci 108:337-349) that included a follicular diffusion pathway has been extended to describe transient diffusion and finite dose applications. The model follows the disposition of two components, solute and solvent, so that solvent deposition processes can be explicitly represented. Experimentally-calibrated permeability characteristics of the follicular pathway leading to the permeation of highly hydrophilic permeants are further refined. Details of the refinements and a comparison with the earlier model using two large experimental datasets are presented. An example calculation shows the marked difference between the time scales for achievement of near steady-state diffusion for large hydrophilic and lipophilic compounds, with the former being more than 100-fold faster than the latter. However, the true steady state for the hydrophilic compound is not reached until much later due to the very slow filling of the corneocyte phase.     

Opinion of the Scientific Committee on Consumer safety (SCCS) – Opinion on the safety of the use of deoxyarbutin in cosmetic products

Conclusion of the opinionAlthough on the basis of the provided scientific data the use of deoxyarbutin as such can be considered safe for consumers in cosmetic products in a concentration up to 3% in face creams, hydroquinone will be formed at levels which raise concerns with regard to the safety of such products during life-cycle of the product (e.g. storage conditions and stability under in-use conditions).Therefore, the overall conclusion of the SCCS is that the use of deoxyarbutin up to 3% in face creams is not safe.     

Opinion of the Scientific Committee on Consumer safety (SCCS) – Opinion on the safety of the use of α-arbutin in cosmetic products

Conclusion of the opinionThe SCCS considers the use of α-Arbutin safe for consumers in cosmetic products in a concentration up to 2% in face creams and up to 0.5% in body lotions.A potential combined use of α-Arbutin and other hydroquinone releasing substances in cosmetic products has not been evaluated in this Opinion.     

Managing Complex Mixtures of Chemicals – A Forward Look From The Regulators’ Perspective

The key findings to emerge from the successful Direct Toxicity Assessment Demonstration Programme are reviewed. At present, whole sample toxicity tests can identify and help control releases of complex mixtures that are likely to cause short-term toxic effects. Protection of aquatic organisms from the many hazardous chemicals that enter the environment, usually as complex mixtures, will require the introduction of new and improved techniques that are affordable and provide rapid turnaround of information. A number of bioassays were rigorously tested during the DTA programme. Further developments are suggested and other methods, including biosensors, biomarkers, and biological survey are briefly reviewed.     

Pleiotropic effects of statins on the treatment of chronic periodontitis – a systematic review

Aim

Statins are inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A reductase and are an important group of hypolipidaemic drugs, widely used in the treatment of hypercholesterolaemia and cardiovascular disease. Some studies have shown that statins are able to modulate inflammation and alveolar bone loss.

Methods

In order to evaluate whether statins could influence periodontal treatment, improving the clinical and radiographic parameters in chronic periodontitis, a systematic review was conducted in the databases PUBMED and BIREME, searching for articles in English and Portuguese, published between the years 2004 and 2014, using the combined keywords statin, periodontal disease, periodontitis and alveolar bone. Studies regarding the treatment of chronic periodontitis in humans, blind or double-blind, retrospective cohort or randomized controlled trials that used statins topically or systemically were selected.

Results

Statins have important anti-inflammatory and immune effects, reducing levels of C-reactive protein and matrix metalloproteinases and their intermediate products, such as tumour necrosis factor-α, and are also able to inhibit the adhesion and extravasation of leukocytes, which block the co-stimulation of T cells. Statins reduce bone resorption by inhibiting osteoclast formation and lead to increased apoptosis of these cells. The effect of statins on bone formation is related to the increased gene expression of bone morphogenetic protein in osteoblasts.

Conclusion

Although we found biological mechanisms and clinical results that show lower alveolar bone loss and reduction of clinical signs of inflammation, further studies are needed to evaluate the clinical applicability of statins in the routine treatment of chronic periodontitis.     

Increasing the Robustness of Biopharmaceutical Precipitation Assays – Part II: Recommendations on the use of FaSSIF

Biopharmaceutical precipitation assays are an important in vitro tool to characterize the precipitation behavior of weakly basic drugs during their transit from the stomach into the small intestine. To mimic the intestinal fluids more closely, biorelevant media like Fasted State Simulated Intestinal Fluid (FaSSIF) and versions thereof are often applied. When applying UV analytics to measure the drug concentration during the transfer experiments, changes in the UV spectrum of the medium have been observed when FaSSIF was stored over a longer period of time or under accelerated conditions. Therefore, this study aimed at evaluating the stability of FaSSIF under various storage conditions. Furthermore, the impact of stressed FaSSIF on the supersaturation and precipitation behavior of ketoconazole was investigated. As a result of this study, it was demonstrated that the FaSSIF powder composition changes during storage, which, in turn, impacts the supersaturation and precipitation behavior of ketoconazole in in vitro transfer studies. Based on the results of this study, we provide recommendations on the application of FaSSIF in biopharmaceutical precipitation assays with the aim to increase reproducibility and enhance data reliability for those compounds where changing FaSSIF composition may impact the supersaturation and precipitation behavior.     

Managing community acquired pneumonia in the elderly – the next generation of pharmacotherapy on the horizon

Introduction: Community acquired pneumonia (CAP) is associated with high rates of morbidity and mortality, especially among the elderly. Antibiotic treatment for CAP in the elderly is particularly challenging for many reasons, including compliance issues, immunosuppression, polypharmacy and antimicrobial resistance. There are few available antibiotics that are able to address these concerns.

Areas covered: After a systematic review of the current literature, we describe seven novel antibiotics that are currently in advanced stages of development (phase 3 and beyond) and show promise for the treatment of CAP in those over the age of 65. These antibiotics are: Solithromycin, Pristinamycin, Nemonaxacin, Lefamulin, Omadacycline, Ceftobiprole and Delafloxacin. Using a novel conceptual framework designed by the present authors, known as the ‘San Antonio NIPS model’, we evaluate their strengths and weaknesses based on their ability to address the unique challenges that face the elderly.

Expert opinion: All seven antibiotics have potential value for effective utilization in the elderly, but to varying degrees based on their NIPS model score. The goal of this model is to reorganize a clinician’s focus on antibiotic choices in the elderly and bring attention to a seldom discussed topic that may potentially become a health-care crisis in the next decade.     

Potential Involvement of μ-Opioid Receptor Dysregulation on the Reduced Antinociception of Morphine in the Inflammatory Pain State in Mice

The antinociceptive effect of morphine in the inflammatory pain state was described in the von Frey filament test using the complete Freund’s adjuvant (CFA)-induced mouse inflammatory pain model. After an i.pl. injection of CFA, mechanical allodynia was observed in the ipsilateral paw. The antinociceptive effect of morphine injected s.c. and i.t. against mechanical allodynia was reduced bilaterally at 1 day and 4 days after the CFA pretreatment. The expression level of mRNA for μ-opioid receptors at 1 day after the CFA pretreatment was reduced bilaterally in the lumbar spinal cord and dorsal root ganglion (DRG). In contrast, the protein level of μ-opioid receptors at 1 day after CFA pretreatment was decreased in the ipsilateral side in the DRG but not the lumbar spinal cord. Single or repeated i.t. pretreatment with the protein kinase Cα (PKCα) inhibitor Ro-32-0432 completely restored the reduced morphine antinociception in the contralateral paw but only partially restored it in the ipsilateral paw in the inflammatory pain state. In conclusion, reduced morphine antinociception against mechanical allodynia in the inflammatory pain state is mainly mediated via a decrease in μ-opioid receptors in the ipsilateral side and via the desensitization of μ-opioid receptors in the contralateral side by PKCα-induced phosphorylation.     

Failure Mode Identification of Insulin Drug Products – Impact of Relevant Stress Conditions on the Quality of the Drug

Fast-acting insulin drug products (DPs) are carried and administered by diabetic patients to maintain their blood glucose level throughout the day, exposing the DPs to stress conditions. Apidra, Novolog, and Humalog insulin DPs were tested under various stress conditions. Dynamic light scattering (DLS), and size exclusion chromatography (SEC) were used to monitor the stability and aggregation. Thermal stress alone did not influence the stability. However, 24 hr exposure to vigorous mechanical stress shifted the DLS size peaks of Novolog and Humalog from 5 ± 1 nm to > 50.9 ± 25.6 nm, and the SEC native protein peak areas decreased 52% for Novolog and 18.4% for Humalog. Combined stress accelerated protein aggregation more drastically. Novolog and Humalog size shifted (>75 nm) after 3 hr and the peak area decreased > 97.9% after 6 hr exposure, indicating that high temperature accelerated the aggregation triggered by agitation. Soluble aggregates were captured by DLS early on compared to SEC. Apidra was comparably stable indicating DP formulation plays a critical role in stability. Our study provides a greater understanding of potential failure modes patients and care givers may encounter while handling insulin DPs.     

Current State of the Art of Allogeneic CAR Approaches – Pile ‘Em High and Sell ’Em Cheap

The advent and rapid propagation of Chimeric Antigen Receptor (CAR)-based therapeutics in recent years has taken the oncology field by storm and delivered considerable benefit to cancer patients, many of whom previously had no other treatment options available to them. CAR-based therapies are now a bona fide therapeutic modality in the fight against cancer, along with more “traditional” treatments, such as small molecule and antibody drugs. For the technology to take the next step and reach much larger numbers of patients in need, it will be necessary for those treatments to become “off-the-shelf” offering patients a standardised, consistent, and cost-effective product. This article offers an overview of the evolution and development options for off-the-shelf CAR-based treatments, the advantages and disadvantages of the various approaches, along with key optimisation parameters that must be considered.     

Opinion of the Scientific Committee on Consumer Safety (SCCS) – Final version of the opinion on Phenoxyethanol in cosmetic products

The SCCS considers 2-phenoxyethanol safe for use as a preservative with a maximum concentration of 1.0%, taking into account the information provided.The toxicokinetics default factor of 4.0 can be reduced to 1.0 yielding a minimum Margin of Safety (MoS) of 25 instead of 100 for the safety assessment of 2-phenoxyethanol.Therefore, the MoS of about 50 for children also covers this specific age group who might be higher exposed to 2-phenoxyethanol than adults.This Opinion does not take into account exposure from sources other than cosmetics.