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Unexpected adverse preclinical findings (APFs) are not infrequently encountered during drug development. Such APFs can be functional disturbances such as QT prolongation, morphological toxicity or carcinogenicity. The latter is of particular concern in conjunction with equivocal genotoxicity results. The toxicologic pathologist plays an important role in recognizing these effects, in helping to characterize them, to evaluate their risk for man, and in proposing measures to mitigate the risk particularly in early clinical trials. A careful scientific evaluation is crucial while termination of the development of a potentially useful drug must be avoided. This first part of the review discusses processes to address unexpected APFs and provides an overview over typical APFs in particular classes of drugs. If the mode of action (MoA) by which a drug candidate produces an APF is known, this supports evaluation of its relevance for humans. Tailor-made mechanistic studies, when needed, must be planned carefully to test one or several hypotheses regarding the potential MoA and to provide further data for risk evaluation. Safety considerations are based on exposure at no-observed-adverse-effect levels (NOAEL) of the most sensitive and relevant animal species and guide dose escalation in clinical trials. The availability of early markers of toxicity for monitoring of humans adds further safety to clinical studies. Risk evaluation is concluded by a weight of evidence analysis (WoE) with an array of parameters including drug use, medical need and alternatives on the market. In the second part of this review relevant examples of APFs will be discussed in more detail. 相似文献
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Reasons for performing the study: Dynamic laryngeal collapse (DLC) associated with poll flexion is a performance limiting dynamic upper airway disorder commonly diagnosed in Coldblooded trotters. An inspiratory obstruction occurs when affected horses are driven with tension on the reins, inducing poll flexion. To date, surgical treatment and conservative management have failed to improve racing performance in affected horses. Objectives: To test the efficacy of an external device, the modified checkrein, in limiting poll flexion, diminishing laryngeal collapse and improving airway mechanics when horses are driven on a treadmill with tension on the reins and test the hypothesis that the modified checkrein will limit poll flexion thereby improving endoscopic appearance of the larynx and reduce airway obstruction in harness racehorses affected with DLC. Methods: Fourteen Norwegian Coldblooded trotter (NCT) racehorses previously diagnosed with DLC associated with poll flexion exercised on a high‐speed treadmill at speeds that resulted in heart rate >200 beats/min. Upper airway videoendoscopy recordings, tracheal pressures and video recordings of the head and neck position were collected while horses exercised with the conventional checkrein on Day 1 and the modified checkrein on Day 2. Results: The modified checkrein successfully limited poll flexion as measured by no change in head position parameters between phases of no rein tension and phases of rein tension. Endoscopic scores were significantly improved (arytenoids cartilage collapse P<0.0001; vocal fold collapse P<0.0001) and tracheal peak inspiratory pressures were significantly less negative (P = 0.0162) when horses were fitted with the modified checkrein compared to the conventional checkrein. Conclusions and potential relevance: The modified checkrein successfully limited poll flexion and also prevented upper airway obstruction in NCT horses affected with DLC associated with poll flexion. The modified checkrein seems promising in offering a method of conservative management in harness racehorses affected with this disorder. 相似文献
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DM Leathwick TS Waghorn CM Miller DS Atkinson NA Haack A-M Oliver 《New Zealand veterinary journal》2013,61(6):305-312
AIM: To determine whether drenching regimes for lambs by which a proportion (10%) of the heaviest animals was selectively left untreated, or animals are only drenched ‘on demand’ when faecal nematode egg counts (FEC) exceeded a threshold level, would result in measurable increases in parasite larval challenge in the autumn and/or decreases in the performance of lambs. METHODS: A replicated study compared three drenching strategies in which mobs of lambs (n=360 in total) received either: a five-drench preventive programme, administered to all animals (Treatment 1); a five-drench preventive programme, but the 10% heaviest animals left untreated each time (Treatment 2); or drench treatments administered only when FEC exceeded 500 eggs per gram of faeces (epg) (Treatment 3). After the five-drench programme, animals in Treatments 1 and 2 were treated according to FEC as for Treatment 3. A triple-combination drench containing ivermectin, oxfendazole and levamisole, administered orally, was used for all treatments. There were nine farmlets, allowing three replicates of each treatment, in a completely randomised design. Parasite infestations on pasture were measured in autumn by pasture plucks, and worm burdens were monitored in tracer lambs, while the performance of lambs was assessed by liveweight gains, fleece weights, and body condition and dag scores. RESULTS: Increased numbers of Haemonchus contortus and Trichostrongylus colubriformis larvae on pasture were found in the autumn on farmlets treating selectively or on-demand (Treatments 2 and 3). No differences were detected in other parasite species. Mean liveweight gains did not differ between treatments but some differences were detected between drenched and undrenched lambs in Treatment 2. Mean body condition and mean dag scores of lambs in Treatment 3 tended to be lower and higher, respectively, than those of lambs in Treatment 1; Treatment 2 was generally intermediate. CONCLUSIONS: Drenching strategies for lambs designed to slow the development of anthelmintic resistance, by increasing the pool of susceptible worms available to dilute resistant survivors after treatment, resulted in increased numbers of H. contortus and T. colubriformis but not other species of parasite on pasture. The increased parasite challenge to lambs in the autumn was associated with small production losses, which may be acceptable to farmers wishing to implement such strategies. It is clear that further work is required on the interaction between management practices and the population dynamics of parasites, especially with regard to creating pools of susceptible genotypes to slow the development of drench resistance. 相似文献
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CS Pinares-Patiño GC Waghorn RS Hegarty SO Hoskin 《New Zealand veterinary journal》2013,61(5):252-261
AbstractAIMS: The aims of this cross-sectional study were to investigate the herd and cow-level prevalence of bovine digital dermatitis (BDD) in dairy farms in the northern Taranaki region of New Zealand, and to identify whether there was any spatial clustering of herds with the disease.METHODS: A survey of 224 dairy farms in the northern Taranaki region of New Zealand was undertaken from September 2014 to February 2015. Following training in robust criteria to confirm BDD visually, a technician inspected the rear feet of every milking cow on the farms during milking. The identity of cows with lesions and the feet involved were recorded. The proportion of cows affected among the inspected population (cow-level prevalence), the proportion of a herd affected (farm-level prevalence), and proportion of farms with ≥1 cow with lesions, were calculated. A bivariate K function analysis was then used to assess whether farms with ≥1 cow with lesions were clustered, after accounting for the distribution of the farms involved in the study.RESULTS: Bovine digital dermatitis lesions were observed on 143/224 (63.8 (95% CI=57.5–70.1)%) farms. Within-farm prevalence was 0% on 81 (36.2%) farms, between >0 and <3% on 120 (53.5%) farms, with a maximum prevalence of 12.7% on one farm. Overall, cow-level prevalence was 707/60,455 (1.2 (95% CI=0.9–3.0)%), and on affected farms was 707/41,116 (1.7 (95% CI=1.4–2.1)%). In affected cows, 268/707 (37.9%) had a lesion on left foot only, 262/707 (37.1%) on the right foot only and 177/707 (25.0%) on both feet. The K function analysis showed no evidence of clustering of farms with BDD.CONCLUSIONS: Bovine digital dermatitis was widespread among the survey farms, but there was no evidence that there was any clustering of herds with BDD. The cow-level prevalence on affected farms was much lower than reported elsewhere.CLINICAL RELEVANCE: Although the prevalence at the cow level was low, if these data are representative of other regions of New Zealand, BDD could easily become a major problem on dairy farms in New Zealand, as has been observed in other countries. 相似文献
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Indicators of success for smart law enforcement in protected areas: A case study for Russian Amur tiger (Panthera tigris altaica) reserves 下载免费PDF全文
Michiel H. H. HÖTTE Igor A. KOLODIN Sergei L. BEREZNUK Jonathan C. SLAGHT Linda L. KERLEY Svetlana V. SOUTYRINA Galina P. SALKINA Olga Y. ZAUMYSLOVA Emma J. STOKES Dale G. MIQUELLE 《Integrative zoology》2016,11(1):2-15
Although considerable conservation resources have been committed to develop and use law enforcement monitoring and management tools such as SMART, measures of success are ill‐defined and, to date, few reports detail results post‐implementation. Here, we present 4 case studies from protected areas with Amur tigers (Panthera tigris altaica) in Russia, in which indicators of success were defined and evaluated at each. The ultimate goal was an increase in tiger numbers to 1 individual/100 km2 at each site. We predicted that improvements in law enforcement effectiveness would be followed by increases in prey numbers and, subsequently, tiger numbers. We used short‐term and long‐term indicators of success, including: (i) patrol team effort and effectiveness; (ii) catch per unit effort indicators (to measure reductions in threats); and (iii) changes in target species numbers. In addition to implementing a monitoring system, we focused on improving law enforcement management using an adaptive management process. Over 4 years, we noted clear increases in patrol effort and a partial reduction in threats. Although we did not detect clear trends in ungulate numbers, tiger populations remained stable or increased, suggesting that poaching of tigers may be more limiting than prey depletion. Increased effectiveness is needed before a clear reduction in threats can be noted, and more time is needed before detecting responses in target populations. Nonetheless, delineation of concrete goals and indicators of success provide a means of evaluating progress and weaknesses. Such monitoring should be a central component of law enforcement strategies for protected areas. 相似文献