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.     

Evaluation of mucoadhesive property and the effect of Boswellia carteri gum on intranasal vaccination against small ruminant morbillivirus infection (PPR)

ABSTRACT

A study was conducted to evaluate mucoadhesive property and immunomodulatory effect of phytogenic gums from Boswellia frereana, Boswellia carteri andCommiphora myrrha on intranasal Peste des petits ruminants (PPR) vaccination in goats and sheep in an ex-vivo and in-vivo situations. Plant gums were purified, dried and compressed into 500gm tablets. Modified shear stress measurement technique was used on freshly excised trachea and intestine tissues of goat to measure peak adhesion time. Forty eight animals (24 goats and 24 sheep) were divided into eight groups (of 3 goats and 3 sheep) and immunized intranasally with gum-vaccine combinations in two ratios (1:1, 1:2). Antibody against PPR virus was measured on day 14, 28, 42 and 56 post vaccination using H-based PPR bELISA. The peak adhesion time of the different gums was transient. PPR virus antibodies were detected in all immunized goats and sheep but not in unvaccinated control. The best percentage inhibition was recorded for Boswellia carteri-vaccine combination group at a ratio of 1:1. Administration of Boswellia carteri-PPR vaccine combination through intranasal or subcutaneous route, elicited similar antibody titre, implying that the intranasal route may be used as a non-invasive alternative delivery in PPR vaccination of small ruminants.     

Antireproductive effect of calcium channel blockers on male rats

Introduction  Drugs have been shown to adversely affect male fertility and recently anti-hypertensive drugs were added to the list. The anti-fertility effects of nifedipine and similar calcium channel blockers are well-illustrated in in vitro experiments but not in vivo. Purpose  The present study was designed to experimentally elucidate the sub-chronic effect of nifedipine, verapamil and diltiazem on sperm functions and reproductive hormone levels in vivo. Methods  Male rats (150–200 g) were divided into four groups of ten rats each. Group 1 (control) received distilled water; Group 2 received nifedipine 0.57 mg/kg BW; Group 3 were given verapamil 3.40 mg/kg BW and Group 4 were given diltiazem 2.57 mg/kg BW. Each drug-treated group had its own recovery group from which treatment was discontinued for 30 days before the animals were sacrificed. Blood samples were collected for hormonal assay of FSH, LH and testosterone. Semen evaluation was done and the testes, seminal vesicle, epididymis and prostate were removed, and weighed immediately. Results  Nifedipine, verapamil and diltiazem significantly decreased (P < 0.05) sperm count and motility in drug treated groups. The weight of the epididymis was significantly reduced (P < 0.05) in the drug treated rats. Semen parameters and other associated changes were restored after 30 days of drug withdrawal. Conclusion  Calcium channel blockers appear to have a reversible anti-fertility effect on male rats which does not occur through inhibition of the pituitary-gonadal axis.     

Risk of Colorectal Adenomas in Women with Prior Breast Cancer

Background and Aims

Longer life expectancy in patients with prior breast cancer may increase their risk of developing other primary cancers, including colorectal cancer (CRC). Whether the risk of developing CRC in this patient population is higher in comparison to those with no prior cancer remains unclear. The purpose of this study was to compare the prevalence of colorectal adenomas and any CRC in breast cancer survivors with those who have no history of prior cancer and assess any difference with use of antiestrogen therapy.

Methods

We compared the prevalence of colorectal cancer and adenomas in breast cancer survivors with that of a group of matched controls. Eligible survivors were ??85?years of age; had initially been diagnosed with stage 0, I, II, or III breast cancer; had completed all cancer treatments with the exception of adjuvant antiestrogen therapy; and had no evidence of recurrence on follow-up. We used the screening colonoscopy database at our institution to identify age-, sex-, and race-matched controls with no history of cancer.

Results

We identified 302 study-eligible breast cancer survivors and 302 matched controls. No colorectal cancers were found in either group. Forty-one breast cancer survivors and 30 controls had tubular adenomas; four survivors and three controls had villous adenoma; and eight survivors and ten controls had advanced adenoma. Multivariate regression analysis revealed that adjuvant antiestrogen therapy was not significantly associated with an increased risk of advanced adenoma.

Conclusions

The prevalence of colorectal adenomas in breast cancer survivors and controls was similar. Breast cancer survivors, including those receiving adjuvant antiestrogen therapies may follow the colorectal screening guidelines used for average-risk population.     

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.     

An in vitro study into the corrosion of intra-oral magnets in the presence of dental amalgam

The aim of this investigation was to study the corrosion behaviour and products of uncoated neodymium-iron-boron magnets in the presence of dental amalgam. Microcosm plaques were grown on discs of neodymium-iron-boron magnets or amalgam in a constant depth film fermentor. The biofilms were supplied with artificial saliva and growth was determined by viable counting. The results showed that the neodymium-iron-boron magnets corroded with an average daily weight loss of 0.115 +/- 0.032 per cent. However, when the magnets were in close proximity to the amalgam the amount of corrosion was reduced to a daily loss of 0.066 +/- 0.023 per cent. The highest loss of constituent elements from the corrosion products of the magnets was observed for iron. The composition of the microcosm plaques altered markedly between the two materials with less streptococci and more Veillonella spp. present in the biofilms grown on magnets in the presence of amalgam. The corrosion of neodymium-iron-boron magnets is limited and in the presence of amalgam is reduced further. This suggests that amalgam present in the mouth will not cause an increased clinical risk in terms of biocompatibility with neodymium-iron-boron magnets.     

Use of the regression analysis technique to determine the true phosphorus digestibility and the endogenous phosphorus output associated with corn in growing pigs

The objectives of this study were to determine true phosphorus (P) digestibility and the endogenous P output associated with corn for growing pigs using the regression analysis technique. Four barrows, average initial body weight of 25 kg, were fitted with a T-cannula and fed four diets according to a 4 x 4 Latin square design. Four cornstarch-based diets, containing four levels of P at 0.7, 1.5, 2.2 and 2.8 g/kg dry matter intake (DMI), were formulated from corn. Each experimental period comprised 8 d with 4-d adaptation and 4-d collection of ileal digesta and fecal samples. The apparent ileal and fecal P digestibility values in corn were affected (P < 0.05) by P contents in the assay diets. The apparent ileal and fecal P digestibility values increased from -51.0 to 33.3% and from -41.4 to 39.1%, respectively, as P content increased from 0.7 to 2.8 g/kg DMI. Linear relationships (P < 0.05), expressed as g/kg DMI, between the apparent ileal and fecal digestible P and the total intake of dietary P, suggested that true P digestibility and the endogenous P outputs associated with corn can be determined by the regression analysis technique. There were no differences (P > 0.05) in true P digestibility values (54.0 +/- 6.5 vs. 59.8 +/- 8.5%) and the endogenous P outputs (0.693 +/- 0.128 vs. 0.670 +/- 0.160 g/kg DMI) between the ileal and the fecal determinations. The endogenous fecal P output represented 12.3% and 25.8% of the daily total and available P requirements in growing pigs recommended by the National Research Council in 1998. The present literature data of apparent digestibility and availability underestimate the true digestive utilization of P in corn for growing pigs by approximately 35%. Current diet formulation on the bases of total, apparent P digestibility and availability values in corn inevitably leads to P overfeeding and excessive P excretion in pigs.