Animal house stock control based on bar-coded cage labels

In an animal house serving the needs of a large research institute, a regular inventory of the animals in stock is a considerable help towards effective management of the facility. In particular, advising the licence-holders of what animals are being held in their name and reminding them of the costs involved is a valuable exercise. The introduction of a computerized system of stock control, based on bar-coded cage labels, is described. The system has proved economical to operate, accurate, and can be run by persons without computer expertise.     

Juvenile animal studies and pediatric drug development retrospective review: use in regulatory decisions and labeling

Juvenile animal toxicity studies are conducted to support applications for drugs intended for use in children. They are designed to address specific questions of potential toxicity in the growing animal or provide data about long-term safety effects of drugs that cannot be obtained from clinical trials. Decisions to conduct a juvenile animal study are based on existing data, such as a safety signal already identified in adult studies, or previous knowledge of the drug or chemical class for its potential to impair growth or developmental milestones. In 2006, the FDA issued an industry guidance in which considerations for determining when a juvenile animal study is warranted were outlined. A retrospective study was conducted covering years both before and after the issued guideline to examine the contribution of juvenile animal toxicity studies to the risk/benefit assessment of pediatric drugs at the FDA. The initial findings were presented as part of the May 2010 HESI workshop on the value of juvenile animal studies. The objective of the review was to better understand the value that the juvenile animal study contributes to regulatory decision making for pediatric drug development by looking at when the studies have been included in the product assessment; what, if any, impact the studies had on the regulatory decisions made; and whether the data were incorporated into the label. The data described below represent a first look at impact of the juvenile animal study since the pediatric legislation and the juvenile animal guidance were issued in the US.     

Rules for the use of model organisms in anti-aging pharmacology

The use of animal models for initially screening anti-aging drugs is a promising approach for drug discovery. However, there a number of potential artifacts, confounds and errors that can arise in such research programs. The following rules are intended to minimize such problems: (1) since aging occupies an increasing proportion of human adulthood, data that conflate aging and late life should not be extrapolated to human aging; (2) the response to candidate medications should show a normal dose-response pattern, although not necessarily a linear response; (3) medicated animal models should not be hypometabolic; (4) medicated animal models should not show pronounced reductions in fertility; (5) medicated animal models should not exhibit general nervous system depression; (6) the effect of the medication should not be highly sensitive to the culture environment; (7) the effect of the medication should not be highly dependent on the genetic ancestry of the stock employed, leaving aside inbreeding, which should be avoided because humans are not generally inbred. While these rules do not guarantee successful extrapolation of successful drug results from the animal model to humans in a clinical setting, the failure to adhere to these rules should raise doubts about such extrapolation.     

Analysis of protein synthesis dynamic model in eukaryotic cells: Input control

This paper presents the analysis of initiation control model of protein synthesis via eukaryotic initiation factor (eIF)-2 unit, introduced by [N.S. Bar, D.R. Morris, Dynamic model of the process of protein synthesis in eukaryoric cells, Bulletin of Mathematical Biology 69 (2007) 361-393, doi:10.1007/s11538-006-9128-2.] and propose methods to control it.Linearization of the model is presented as a measure to simplify the analysis and control application. The properties of the linear model were investigated and compared to the non-linear model using simulations. It was shown that the linear model is (marginally) stable and the states converge to a finite value. Linear optimal control theory can then be applied to the model under the value range where the linearized model is accurate. The effect of the input signals GCN2·tRNA and eIF-2 on the non-linear system was investigated. A few characteristics known from in vitro experiments of the initiation process were proven from a mathematical aspect and some conclusions about the function of the initiation complexes such as eIF2B and the ternary complex were derived. Consistent with published experiments, it was shown that overexpression of eIF-2 increases the concentration of 48S initiation complex and promote initiation rate. A state feedback control was applied in order to manipulate the initiation rate and it was proven that the 48S initiation complex can be driven to a desired value by calculating an input control law using measurement techniques available today. If this strategy can be implemented de facto, then a genuine control on protein synthesis process can be obtained.     

The impact of natural infestations of ticks in Zambia on the productivity of cattle and implications for tick control strategies in central Africa

Studies were carried out in Zambia using a farming systems approach to quantify the effects of tick control on traditionally managed Sanga cattle. In the first trial to investigate the effect of tick control, significant improvements in liveweight gain (LWG) occurred only in periods of medium to high challenge with adult Amblyomma variegatum. However, during the first 18 months of the study when animals were young, the acaricide used caused a suppression in weight gains. A supplementary experimental study indicated that the adverse effects of ticks on weight gain may be delayed when animals are on a low plane of nutrition. In both studies on the effects of ticks on LWG, estimates of weight loss per female A. variegatum were in the range of 46 to 69 g. In the second long term trial to measure the impact of tick control on overall heard productivity, outputs of milk and weaner calf per livestock unit carrying capacity were about 25% higher in a tick-free herd. The annual cost of control in 1988 at ZK286.26/livestock unit was greater than the increase in value of the products at ZK175.48/livestock unit carrying capacity. It is concluded from these studies that intensive tick control in the multipurpose livestock system in Zambia is not justified in the absence of serious tick-borne disease. However, strategic seasonal tick control of adult ticks from November to April would probably be economically viable. Calves should not be treated until they are 3 months of age.     

当前我国畜牧业抗菌药应用与耐药性应对趋势

抗菌药在现代农业和医学中发挥了举足轻重的作用,然而,随着民众对食品安全和生态环保意识的逐渐增强,抗菌药物的使用愈发受关注。如何科学合理使用抗菌药,确保动物安全健康,防止药物残留超标,进而实现畜牧业绿色发展是当前研究的重要课题。本文结合当前畜牧业抗菌药使用现状,从四个方面分析了滥用抗菌药的危害,并归纳总结了耐药机制研究进展,最后提出抗菌药替代策略,旨在为畜牧业抗菌药安全使用和抗菌药替代技术研发提供参考。     

Single Cell Analysis of Drug Distribution by Intravital Imaging

Recent advances in the field of intravital imaging have for the first time allowed us to conduct pharmacokinetic and pharmacodynamic studies at the single cell level in live animal models. Due to these advances, there is now a critical need for automated analysis of pharmacokinetic data. To address this, we began by surveying common thresholding methods to determine which would be most appropriate for identifying fluorescently labeled drugs in intravital imaging. We then developed a segmentation algorithm that allows semi-automated analysis of pharmacokinetic data at the single cell level. Ultimately, we were able to show that drug concentrations can indeed be extracted from serial intravital imaging in an automated fashion. We believe that the application of this algorithm will be of value to the analysis of intravital microscopy imaging particularly when imaging drug action at the single cell level.     

Human hepatic cell cultures: in vitro and in vivo drug metabolism

Drug metabolism is the major determinant of drug clearance, and the factor most frequently responsible for inter-individual differences in drug pharmacokinetics. The expression of drug metabolising enzymes shows significant interspecies differences, and variability among human individuals (polymorphic or inducible enzymes) makes the accurate prediction of the metabolism of a new compound in humans difficult. Several key issues need to be addressed at the early stages of drug development to improve drug candidate selection: a) how fast the compound will be metabolised; b) what metabolites will be formed (metabolic profile); c) which enzymes are involved and to what extent; and d) whether drug metabolism will be affected directly (drug-drug interactions) or indirectly (enzyme induction) by the administered compound. Drug metabolism studies are routinely performed in laboratory animals, but they are not sufficiently accurate to predict the metabolic profiles of drugs in humans. Many of these issues can now be addressed by the use of relevant human in vitro models, which speed up the selection of new candidate drugs. Human hepatocytes are the closest in vitro model to the human liver, and they are the only model which can produce a metabolic profile of a drug which is very similar to that found in vivo. However, the use of human hepatocytes is restricted, because limited access to suitable tissue samples prevents their use in high throughput screening systems. The pharmaceutical industry has made great efforts to develop fast and reliable in vitro models to overcome these drawbacks. Comparative studies on liver microsomes and cells from animal species, including humans, are very useful for demonstrating species differences in the metabolic profile of given drug candidates, and are of great value in the judicious and justifiable selection of animal species for later pharmacokinetic and toxicological studies. Cytochrome P450 (CYP)-engineered cells (or microsomes from CYP-engineered cells, for example, Supersomes) have made the identification of the CYPs involved in the metabolism of a drug candidate more straightforward and much easier. However, the screening of compounds acting as potential CYP inducers can only be conducted in cellular systems fully capable of transcribing and translating CYP genes.     

Comparative epidemiology and control of trypanosomes

Tsetse-transmitted trypanosomiasis in man and domestic livestock is a major constraint to livestock and socio-economic development in Africa. Analysis of the limited number of databases on matching animal health and productivity available for cattle in tsetse-infested areas of Africa has provided new information about the value of current methods of controlling the disease. It was established that the trypanotolerant breeds of cattle, namely N'Dama and West African Shorthorn, were much more productive than originally believed, despite their small stature, and, as a result, could be considered for livestock development programmes in tsetse-infested regions. Moreover, in areas of low tsetse challenge, it was shown that the strategic use of therapeutic trypanocidal drugs allowed the maintenance of high levels of productivity in dairy cattle and demonstrated genotype and acquired differences in treatment requirements. On the other hand, the use of a prophylactic drug regime allowed beef cattle to be reared to an economically acceptable level of productivity in an area where tsetse challenge was high that animals rapidly succumbed if left untreated. These results show that the current methods available for the control of animal African trypanosomiasis can be effective if properly applied.     

海洋生态资本理论框架下海洋生物资源的存量评估

海洋生态资本是能够直接或间接作用于人类社会经济生产、提供有用的产品流或服务流的海洋生态资源。海洋生态资源包括海洋生物资源及其生境资源。海洋生态资源的存量价值由海洋生物资源存量价值和海洋生境资源存量价值构成。针对我国海洋生物资源的特征,在海洋生态资本理论框架下,提出了鱼类、贝类、甲壳类、头足类、大型海藻等主要海洋生物资源的存量价值评估技术方法,包括物质量评估和价值量评估。探讨了海洋生物资源单位价格确定、评估价值修正、评估方法的适用性、成本扣除等问题。     

Prediction of convection-enhanced drug delivery to the human brain

The treatment for many neurodegenerative diseases of the central nervous system (CNS) involves the delivery of large molecular weight drugs to the brain. The blood brain barrier, however, prevents many therapeutic molecules from entering the CNS. Despite much effort in studying drug dispersion with animal models, accurate drug targeting in humans remains a challenge. This article proposes an engineering approach for the systematic design of targeted drug delivery into the human brain. The proposed method predicts achievable volumes of distribution for therapeutic agents based on first principles transport and chemical kinetics models as well as accurate reconstruction of the brain geometry from patient-specific diffusion tensor magnetic resonance imaging. The predictive capabilities of the methodology will be demonstrated for invasive intraparenchymal drug administration. A systematic procedure to determine the optimal infusion and catheter design parameters to maximize penetration depth and volumes of distribution in the target area will be discussed. The computational results are validated with agarose gel phantom experiments. The methodology integrates interdisciplinary expertise from medical imaging and engineering. This approach will allow physicians and scientists to design and optimize drug administration in a systematic fashion.     

Regulatory alterations of daily energy expenditure induced by fasting or overfeeding in unrestrained rats

The consequences of fasting or overfeeding during 2 days on energy expenditure were investigated by continuously monitoring O2 consumption in unrestrained, unanesthetized rats. O2 consumption decreased by 15% on the 1st day of fasting and then by an additional 15% on the 2nd day. On the 3rd day, when rats were fed again, energy intake increased by 30% above control (prefasting) values, whereas energy expenditure rapidly increased but no more than control values. On the other hand, when ad libitum fed animals were offered a sucrose solution (32%) for 2 days, energy intake increased by 30% and energy expenditure by 9-12%. On the 3rd day, when the rats were fed with their normal diet, energy intake significantly decreased under control (preoverfeeding) values during one day, but energy expenditure rapidly returned to normal values. The results show that fasting decreases, whereas hyperphagia increases 24-h energy expenditure during the treatments. When the treatments are terminated, energy expenditure rapidly returns to normal values, but fasting induces a postfasting increase of energy intake (during 2 days), whereas hyperphagia, on the contrary, results in a transient decrease of appetite. This indicates that alterations of food intake induce compensatory changes of energy expenditure during the treatments, but that after the treatments, energy balance is normalized via regulatory adjustments in the ratio of energy expenditure over energy intake.     

Energy balance following sympathetic denervation of brown adipose tissue

The effects of sham, bilateral surgical denervation or excision of interscapular brown adipose tissue on body composition and energetic efficiency were studied in young CFLP mice kept at 25 degrees C and fed a laboratory stock diet. A preliminary experiment showed that 15 weeks following surgery, total body fat was increased by 42% in the denervated group and by 72% in the excised group while body protein was unchanged. In another 7-week energy balance experiment, body fat was also significantly higher by 15 and 18% in the denervated and excised group, respectively, but metabolizable energy intake was slightly lower than that of sham controls. Determination of energy expenditure both by the comparative carcass slaughter technique and by measurement of daily oxygen consumption showed that the metabolic rate was reduced in the denervated nd excised groups. The capacity for thermogenesis, as measured by an increase in oxygen consumption following injections of noradrenaline (600 micrograms/kg body weight) was similar in energetic efficiency, and indicates an important role of the sympathetic nervous system in the regulation of animal heat production by brown adipose tissue and in the overall control of thermogenesis.     

The effect of parasympathetic drugs on energy expenditure: relevance to the autonomic hypothesis

The influence of the parasympathetic nervous system in the control of energy expenditure was investigated in obese and lean rodents during chronic administration of drugs that alter parasympathetic transmission. In the genetically obese ob/ob mice and fa/fa rats and in monosodium glutamate induced hypothalamic obese mice, administration of the parasympathetic inhibitors hyoscine, benztropine, and mecamylamine either had no effect on energy balance or caused losses in body weight that could entirely be accounted for by a reduction in food intake; 24-h oxygen consumption in drug-treated animals was no different from that of the nontreated controls. In the lean animals, both the parasympathetic inhibitors (hyoscine, benztropine, and mecamylamine) and stimulators (bethanecol and neostigmine) had no influence on energy balance nor on body composition. These studies refute the concept that an overactive parasympathetic tone underlies the elevated energetic efficiency of obese models and suggests that the parasympathetic nervous system is unlikely to play an important role in the long-term control of energy expenditure.     

New chemical adaptor unit designed to release a drug from a tumor targeting device by enzymatic triggering

A new controlled drug delivery system for selective chemotherapy was developed. It is based on a chemical adaptor unit, that releases a drug by a spontaneous cyclization mechanism after cleavage of an enzymatic substrate. It also provides a generic linkage of a drug with a targeting device in a manner set to be triggered by defined enzymatic activity. The system is generic and allows using a variety of drugs, targeting devices, and enzymes by introducing the corresponding substrate as a trigger for drug release in the chemical adaptor.     

Use of Computer-assisted Model in Diagnosis of Drug Hypersensitivity Jaundice

Of 374 patients with jaundice seen in the liver unit over a four-year period 21 were finally thought to be hypersensitive to one of seven different drugs. The clinical, laboratory, and histological features were often difficult to distinguish from those of viral hepatitis, tumour of the extrahepatic biliary tree, or primary biliary cirrhosis. A computer-assisted diagnostic model made use of minor differences, and made a correct diagnosis in all patients. Even when information about drug ingestion was left out it was still correct in 81% of patients. Sixty-four other patients gave a history of ingestion of potentially hepatotoxic drugs of whom 62 were correctly diagnosed by the computer. In the complete series of 374 patients only two were incorrectly computed to have drug jaundice when there was no history of drug ingestion.Two additional patients became jaundiced after exposure to drugs, but were found to have primary biliary cirrhosis.     

The impact of pharmaceutical innovation on longevity and medical expenditure in France, 2000–2009

Longitudinal, disease-level data are used to analyze the impact of pharmaceutical innovation on longevity (mean age at death) and medical expenditure in France during the period 2000–2009. The estimates imply that pharmaceutical innovation increased mean age at death by 0.29 years (3.43 months) during this period—about one-fifth of the total increase in longevity. This estimate is smaller than those obtained in previous studies of Germany and the U.S., but the rate of adoption of new drugs was lower in France. Longevity is much more strongly related to the number of drugs than it is to the number of drug classes.Pharmaceutical innovation during 2000–2009 is estimated to have increased per capita pharmaceutical expenditure by $125 (26%) in 2009, but most (87%) of this increase was offset by a reduction in hospital expenditure. The baseline estimate of the cost per life-year gained from pharmaceutical innovation in France during 2000–2009 is about $8100. This estimate is fairly close to the mean of estimates obtained ($10,800) from U.S., German, and Australian studies.     

Translating clinical findings into knowledge in drug safety evaluation--drug induced liver injury prediction system (DILIps)

Drug-induced liver injury (DILI) is a significant concern in drug development due to the poor concordance between preclinical and clinical findings of liver toxicity. We hypothesized that the DILI types (hepatotoxic side effects) seen in the clinic can be translated into the development of predictive in silico models for use in the drug discovery phase. We identified 13 hepatotoxic side effects with high accuracy for classifying marketed drugs for their DILI potential. We then developed in silico predictive models for each of these 13 side effects, which were further combined to construct a DILI prediction system (DILIps). The DILIps yielded 60-70% prediction accuracy for three independent validation sets. To enhance the confidence for identification of drugs that cause severe DILI in humans, the "Rule of Three" was developed in DILIps by using a consensus strategy based on 13 models. This gave high positive predictive value (91%) when applied to an external dataset containing 206 drugs from three independent literature datasets. Using the DILIps, we screened all the drugs in DrugBank and investigated their DILI potential in terms of protein targets and therapeutic categories through network modeling. We demonstrated that two therapeutic categories, anti-infectives for systemic use and musculoskeletal system drugs, were enriched for DILI, which is consistent with current knowledge. We also identified protein targets and pathways that are related to drugs that cause DILI by using pathway analysis and co-occurrence text mining. While marketed drugs were the focus of this study, the DILIps has a potential as an evaluation tool to screen and prioritize new drug candidates or chemicals, such as environmental chemicals, to avoid those that might cause liver toxicity. We expect that the methodology can be also applied to other drug safety endpoints, such as renal or cardiovascular toxicity.     

A novel device for the automated administration of test compounds to laboratory animals

A prototype instrument is described that permits efficient administration of test compounds to laboratory animals by intubation. The system integrates a balance, a computer and a volumetric dispenser. Complete animal identification, weight and dose records are kept and may be interfaced with mainframe computers. A range of doses may be delivered from a single stock solution. No carryover is evident between doses. The system is accurate, precise and rugged. The system is cost effective relative to current manual gavage techniques and offers added safety for investigators handling toxic materials.