Drug discovery strategies for acute radiation syndrome

Introduction: There are at the minimum two major, quite different approaches to advance drug discovery. The first being the target-based drug discovery (TBDD) approach that is commonly referred to as the molecular approach. The second approach is the phenotype-based drug discovery (PBDD), also known as physiology-based drug discovery or empirical approach.

Area covered: The authors discuss, herein, the need for developing radiation countermeasure agents for various sub-syndromes of acute radiation syndromes (ARS) following TBDD and PBDD approaches. With time and continuous advances in radiation countermeasure drug development research, the expectation is to have multiple radiation countermeasure agents for each sub-syndrome made available to radiation exposed victims.

Expert opinion: The majority of the countermeasures currently being developed for ARS employ the PBDD approach, while the TBDD approach is clearly under-utilized. In the future, an improved drug development strategy might be a ‘hybrid’ strategy that is more reliant on TBDD for the initial drug discovery via large-scale screening of potential candidate agents, while utilizing PBDD for secondary screening of those candidates, followed by tertiary analytics phase in order to pinpoint efficacious candidates that target the specific sub-syndromes of ARS.     

Incidence of postoperative pain after use of calcium hydroxide mixed with normal saline or 0.2% chlorhexidine digluconate as intracanal medicament in the treatment of apical periodontitis

Objective

To compare the incidence of postoperative pain after the use of calcium hydroxide powder mixed with normal saline or 0.2% chlorhexidine digluconate as intracanal medicament.

Participants

Fifty-five subjects aged 17–60 years with teeth diagnosed to have apical periodontitis.

Intervention

Two-visit conventional root canal treatment of seventy teeth. The teeth were divided by randomization (balloting) into two groups: control group and experimental group, each with thirty-five teeth treated with calcium hydroxide mixed with normal saline or with 0.2% chlorhexidine digluconate as intracanal medicament respectively. Incidence of postoperative pain was assessed using the universal pain assessment tool and whether or not analgesic was taken.

Main outcome measured

Incidence of post-operative pain.

Result

Postoperative pain occurred only at 1-day and 1-week reviews. In the control group, the overall incidence of pain was the same at both review periods (5.7%), while the experimental group showed a slight decrease in incidence between 1-day (17.2%) and 1-week (11.4%) reviews. Incidence of flare-ups was more in the experimental group (11.4%) than in the control group (5.7%). No significant statistical differences between the two groups were observed (p > 0.05).

Conclusion

The incidence of postoperative pain was lower in the normal saline treatment group, but the difference was not statistically significant.     

Nonhuman primates as models for the discovery and development of radiation countermeasures

Introduction: Despite significant scientific advances over the past six decades toward the development of safe and effective radiation countermeasures for humans using animal models, only two pharmaceutical agents have been approved by United States Food and Drug Administration (US FDA) for hematopoietic acute radiation syndrome (H-ARS). Additional research efforts are needed to further develop large animal models for improving the prediction of clinical safety and effectiveness of radiation countermeasures for ARS and delayed effects of acute radiation exposure (DEARE) in humans.

Area covered: The authors review the suitability of animal models for the development of radiation countermeasures for ARS following the FDA Animal Rule with a special focus on nonhuman primate (NHP) models of ARS. There are seven centers in the United States currently conducting studies with irradiated NHPs, with the majority of studies being conducted with rhesus monkeys.

Expert opinion: The NHP model is considered the gold standard animal model for drug development and approval by the FDA. The lack of suitable substitutes for NHP models for predicting response in humans serves as a bottleneck for the development of radiation countermeasures. Additional large animal models need to be characterized to support the development and FDA-approval of new radiation countermeasures.     

Epidemiologic evidence linking oxidative stress and pulmonary function in healthy populations

Respiratory health in the general population declines regardless of the presence of pulmonary diseases. Oxidative stress has been implicated as one of the mechanisms involved in respiratory dysfunction. This review was to evaluate studies that relate oxidative stress factors with pulmonary function among the general population without prior respiratory illnesses. The search yielded 54 citations. Twenty-one studies qualified for incorporation in this review. Owing to the heterogeneity of the review, studies were discussed based on identified oxidative stress factors responsible for pulmonary dysfunction. Oxidative stress biomarkers, including gene polymorphisms of nuclear factor erythroid 2-related factor 2, heme oxygenase 1, glutathione S transferase, superoxide dismutase, and lipid peroxidation products were involved in lung function decline. In addition, the antioxidant status of individuals in reference to dietary antioxidant intake and exposure to environmental pollutants affected oxidative stress and pulmonary function, as indicated by forced expired volume in one second, forced vital capacity, and forced expiratory flow at 25%–75%_. This review indicated that oxidative stress is implicated in the gradual decline of lung function among the general population, and gene polymorphism along the antioxidant defense line and/or their interaction with air pollutants reduce lung function. Different polymorphic forms among individuals explain why the rate of lung function decline differs among people. Dietary antioxidants have respiratory health benefits in antioxidant gene polymorphic forms. Therefore, the genetic composition of an individual may be considered for monitoring and identifying people at risk of respiratory illnesses.     

Biological responses in rats exposed to cigarette smoke and Middle East sand (dust)

Respiratory symptoms are frequently reported in personnel deployed to the Middle East. This project characterized the respiratory toxicity of inhaled Iraqi sand (IS). Adult rats underwent a 6-wk inhalation to air or mainstream cigarette smoke (MSCS) (3?h/d, 5?d/wk) that included exposure to IS or crystalline silica (1?mg/m(3), 19?h/d, 7?d/wk) or air during the last 2 weeks. Assessments included motor activity, whole-body plethysmography, cytological and biochemical analysis of bronchoalveolar lavage fluid, lung metal burden, nasal and lung pathology, and changes in lung protein and gene expression. A number of metals including nickel, manganese, vanadium, and chromium were detected in IS. Elevated lung parenchyma aluminum, silica, barium, manganese, and vanadium concentrations were seen in IS-exposed rats, suggesting that several metals present in IS are bioavailable. Rats exposed to IS only developed mild inflammation in the anterior nose and lung. Silica inhalation was associated with some pulmonary responses that were not seen in IS-exposed rats, such as mild laryngeal and tracheal inflammation, mild tracheal epithelial hyperplasia, and elevated lung silica concentrations. MSCS inhalation with or without co-exposure to either IS or silica resulted in changes consistent with pulmonary inflammation and stress response. Rats exposed to MSCS and silica had more widespread airway lesions when compared with rats exposed to MSCS only. Silica-exposed rats had more robust pulmonary gene expression and proteomic responses than that seen in IS-exposed rat. Our studies show that the respiratory toxicity of IS is qualitatively similar to or less than that seen following short-term silica exposure.     

The Effects of botulinum toxin A on muscle histology during distraction osteogenesis

Distraction osteogenesis is a highly successful method of bone formation, yet muscle fibrosis and contractures can result in significant morbidity. In the current study, we investigate the efficacy of botulinum toxin A in preventing fibrosis and potentially increasing muscle development in distracted muscles. Fifteen New Zealand White rabbits underwent tibial distraction at 1.5 mm/day until a 20% gain was achieved. Treatment groups were divided by drug (saline or botulinum toxin) and target muscle (gastrocnemius or tibialis anterior). Two additional control animals received no treatment. Bromeodeoxyuridine was delivered continuously throughout the 8‐week experiment, and following muscle harvest. Tissues were stained for BrdU, Pax‐7, vimentin, and haematoxylin and eosin staining. Mitotic activity increased in all distracted animals; however, in the animals receiving botulinum toxin A injections into the gastrocnemius, the antagonist tibialis anterior suffered up to 9% less fibrosis than distraction alone (p = 0.024). Use of botulinum A toxin did not appear to promote or improve neogenesis of muscle fibers, nor did it decrease fibrosis in the injected muscles. It appears from this study, and a previously published study on the effects of this toxin on muscle function, that botulinum A toxin maybe of some benefit in decreasing morbidity in the antagonist muscle but not the muscle injected with the toxin. © 2008 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 27:310–317, 2009     

Effects of botulinum toxin A on functional outcome during distraction osteogenesis.

Distraction osteogenesis is useful for correcting limb length inequality, deformities, or short stature. Despite success with bone formation, soft tissue maladaptations including muscle and joint contracture may lead to undesirable results. Botulinum toxin A has been useful in treating spasticity in cerebral palsy, and has been used clinically in select cases to allay contracture in distraction osteogenesis. This study examines the toxin's efficacy in preventing distraction-induced loss of muscle strength and range of motion. The left tibias of 15 New Zealand White rabbits were distracted 1.5 mm/day until approximately a 20% gain was achieved. Each treatment group was divided into animals injected with saline or botulinum toxin in either the gastrocnemius or tibialis anterior muscles. A control group of two additional animals underwent no surgical procedure. Strength and range of motion were assessed prior to, and following, the experiment. At the study's end, animals were euthanized and muscles were harvested, when lengths and weights were recorded. All muscles injected with botulinum toxin showed decreased wet weight and persistent weakness upon completion of the study. Range of motion decreased in all distracted animals. When the gastrocnemius was injected, its strength was reduced but the tibialis anterior strength was preserved, and the limb achieved 22% greater dorsiflexion than saline controls (p = 0.016). When the tibialis anterior received the toxin, plantarflexion was increased by 23% (p = 0.049). Botulinum toxin injection prior to limb distraction increases the "post-lengthened" excursion of the injected muscle and this increased length may have a protective effect on its antagonist. In toxin-injected gastrocnemius muscles, the level of equinus contracture is reduced due to length gains in the Achilles tendon while the anterior tibialis maintains its ability to generate torque. Injection of botulinum toxin in the gastrocnemius may minimize equinus contracture and protect the anterior tibialis from damage during human tibial lengthening. Longer follow-up studies are needed to ensure that toxin-induced muscle weakness resolves with time.     

Recurrent hypertrophy of the labia minora: a hormonally related lesion possibly related to fibroepithelial stromal polyps of the vulva

The literature on hypertrophy of the labia minora has focused predominantly on surgical procedures, with little attention to etiology. We present a case of recurrent labial hypertrophy and postulate that this is a hormonally related lesion, similar to fibroepithelial stromal polyps.