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.     

Exploitation of receptor tyrosine kinases by viral-encoded growth factors

Receptor tyrosine kinases (RTKs) are essential components of cell communication pathways utilized from the embryonic to adult stages of life. These transmembrane receptors bind polypeptide ligands, such as growth factors, inducing signalling cascades that control cellular processes such as proliferation, survival, differentiation, motility and inflammation. Many viruses have acquired homologs of growth factors encoded by the hosts that they infect. Production of growth factors during infection allows viruses to exploit RTKs for entry and replication in cells, as well as for host and environmental dissemination. This review describes the genetic diversity amongst virus-derived growth factors and the mechanisms by which RTK exploitation enhances virus survival, then highlights how viral ligands can be used to further understanding of RTK signalling and function during embryogenesis, homeostasis and disease scenarios.     

The possible antianginal effect of allopurinol in vasopressin-induced ischemic model in rats

The anti-anginal effects of allopurinol were assessed in experimental model rats of angina and their effects were evaluated with amlodipine. In the vasopressin-induced angina model, oral administration of allopurinol in dose of 10 mg/kg revealed remarkably analogous effects in comparison with amlodipine such as dose-dependent suppression of vasopressin-triggered time, duration and severity of ST depression. In addition, allopurinol produced dose dependent suppression of plasma Malondialdehyde (MDA) level, systolic blood pressure, cardiac contractility and cardiac oxygen consumption; while in contrast, amlodipine minimally suppressed the elevation of plasma MDA level. Endothelial NO synthase (eNOS) expression, serum nitrate were strikingly increased, however lipid profile was significantly reduced. Seemingly, allopurinol was found to be more potent than amlodipine – a calcium channel antagonist. To conclude, it was explicitly observed and verified that on the ischemic electrocardiography (ECG) changes in angina pectoris model in rats, allopurinol exerts a significant protective effects, reminiscent of enhancement of vascular oxidative stress, function of endothelial cells, improved coronary blood flow in addition to the potential enhancement in myocardial stress. Moreover, our findings were in conformity with several human studies.     

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.     

Mortality Pattern in Surgical Wards of a University Teaching Hospital in Southwest Nigeria: A Review

Background

There are many reports from different parts of the world addressing different aspects of surgical mortality. There are few reports from our country, however, and most of them have dealt with mortality in the emergency room. The aim of this study was to determine the prevalence of mortality associated with surgical care and the trends in prevalence of surgical mortality. We used our results as benchmarks to identify areas of improvement.

Methods

The records of all patients who died during admission for surgical care in Olabisi Onabanjo Teaching Hospital Sagamu between January 2006 and December 2010 were studied retrospectively. Relevant data were extracted, including demographics, surgical diagnosis, co-morbid conditions, length of hospital stay, surgical procedure performed, outcome of treatment, and date of death. Results were analyzed with Statistical Package for Social Sciences version 15.

Results

The total admission in the surgical wards for 2005–2010 was 5,444, with a total of 2,217 surgical operations carried out during the same period. There were 277 (5.09 %) deaths (165 male and 112 female patients). Of 277 deaths, only 170 case notes (61 %) were available for review. Primary causes of death were classified as cancer (50 deaths, 29.4 %), trauma (66, 38.8 %), infection/inflammatory (16, 9.4 %), and other (38, 22.4 %). Surgical operations were performed in 60 (35.3 %) of the patients who died. No surgery was done in 110 (64.7 %) of those who died.

Conclusions

The pattern of surgical mortality is not directly related to surgical procedures as most of the deaths occurred in the nonoperative care group. Trauma-associated deaths topped the list.     

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.     

SARS changes the ED paradigm

Severe acute respiratory syndrome (SARS) is an emerging viral infectious disease. The SARS outbreak in Singapore started in mid-March 2003. Emergency departments, being the primary portal of entry into the hospitals, had to come up with rapid strategic changes and modifications to accommodate and manage this public health problem effectively. This report discusses the changes in the Department of Emergency Medicine at Singapore General Hospital, the largest public, teaching and tertiary hospital in Singapore, during this outbreak. It will highlight the safety aspects and universal precautions undertaken, the changes to the triage system, working hours, admission policies, as well as the fluctuations in the patient load.     

Characterization of 17B-hydroxysteroid dehydrogenase isoenzyme expression in benign and malignant human prostate

In the present study, expressions of 17B-hydroxysteroid dehydrogenase (17HSD) types 1, 2 and 3, 5α-reductase type 2 and human androgen receptor mRNAs were determined in 12 benign prostatic hyperplasia and 17 prostatic carcinoma specimens. 17HSD type 2 was found to be the principal isoenzyme expressed in the prostate. Significantly higher expressions of 17HSD type 2 and 5α-reductase type 2 were detected in benign prostatic hyperplasia compared with the carcinoma specimens. Expression of the androgen receptor in the 2 groups was not significantly different. 17HSD type 3 mRNA was not detected in any of the specimens investigated. Only low constitutive expression of the 2.3 kb mRNA of 17HSD type I was seen. Immunohistochemical analyses indicated that this did not lead to significant enzyme expression, only faint staining for the enzyme protein being detected, mainly in uroepithelial cells. No significant correlation was found between any of the mRNAs analyzed, but the data on 5α-reductase type 2 mRNA support the presence of an increased proportion of 5α-dihydrotesterone in the hyperplastic prostate. In cultured PC-3 prostatic cancer cells and in transiently transfected human embryonic kidney 293 cells, 17HSD type 2 was found exclusively to convert 5α-dihydrotestosterone and testosterone into the less potent 17-keto compounds 5α-androstanedione and 4-androstenedione, respectively. We suggest that the 17HSD type 2 isoenzyme plays a part in the metabolic pathway, resulting in the inactivation of testosterone and 5α-dihydrotestosterone locally in the prostate. The enzyme expressed in the prostate could, therefore, protect cells from excessive androgen action. © 1996 Wiley-Liss, Inc.