Demonstrating bioequivalence using clinical endpoint studies

For drug products not amenable to blood level studies, clinical endpoint studies have been used as an indirect measure of formulation difference in bioavailability between test and reference products. However, clinical endpoint studies are not as sensitive in detecting formulation differences as blood level studies and offer numerous challenges to both regulatory authorities and sponsors. The objective of this article is not to suggest new regulatory policies, but to explore new methodologies and alternative solutions to clinical endpoint bioequivalence (BE) studies, which are used when a blood level study is not considered to be appropriate. To achieve this objective, this article identifies situations where a clinical endpoint study might be appropriate, lists the advantages and disadvantages of this type of study design, and discusses possible alternative solutions. It is concluded that future evidence-based research is needed to explore new methodologies such as clinical trial simulations of various study designs, new statistical methods, and new in vitro methods to demonstrate BE.     

Considerations for extrapolating in vivo bioequivalence data across species and routes

The purpose of this article is to discuss the numerous species-specific and route-specific factors that can influence the peak and extent of exposure of an active pharmaceutical ingredient as they relate to the demonstration of bioequivalence between veterinary drug products (test and reference formulations). Evaluation of potential circumstances when species-to-species or route-to-route extrapolations of bioequivalence data could be considered is provided, together with suggestions for alternative statistical analysis. It is concluded that further research is much needed in this area to establish an appropriate scientific basis for across-species and across-route comparisons.     

Acute and Chronic Effects of a Contraceptive Compound RTI‐4587‐073(l) on Testicular Histology and Endocrine Function in Miniature Horse Stallions

The objective of this study was to evaluate acute endocrine effects as well as histological changes in testicular parenchyma induced by the contraceptive compound RTI‐4587‐073(l). Six miniature stallions were used in this experiment. The treatment group (n = 3) received one oral dose of 12.5 mg/kg of RTI‐4587‐073(l), and the control group (n = 3) received placebo only. The stallions' baseline parameters (semen, testicular dimensions, endocrine values) were collected and recorded for 5 weeks before treatment and for 6 weeks after treatment. Multiple blood samples were collected for endocrine analysis. Testicular biopsies were obtained before treatment, 1 day after treatment and every other week after treatment. Ultrasound exams were performed to monitor the dimensions of the stallions' testes. All stallions were castrated 6 weeks after treatment. Sperm numbers, motility and percentage of morphologically normal sperm decreased (p < 0.05), while the number of immature germ cells increased in ejaculates from treated animals (p < 0.05). Serum concentrations of inhibin and follicle‐stimulating hormone did not change. Testosterone concentrations initially transiently decreased (p < 0.05) after administration of RTI‐4587‐073(l), and increased several days later (p < 0.05). Testicular content of testosterone and estradiol 17‐β was lower in treated stallions than in control stallions on Day 1 after treatment (p < 0.05). Severe disorganization of the seminiferous tubules, significant loss of immature germ cells and complete depletion of elongated spermatids were observed in testicular biopsies obtained from treated stallions 1 day, 2 and 4 weeks after treatment. These changes were still present in the testicular samples taken from treated stallions after castration. The results of this study confirmed that RTI‐4587‐073(l) has antispermatogenic effects in stallions. Furthermore, we concluded that this compound causes acute sloughing of immature germ cells from the seminiferous tubules. RTI‐4587‐073(l) has significant but transient effects on Leydig cell function in stallions.     

Epidemiological Description of Cystic Ovarian Disease in Argentine Dairy Herds: Risk Factors and Effects on the Reproductive Performance of Lactating Cows

To describe the epidemiology of cystic ovarian disease (COD), to find possible risk factors associated with the incidence of cysts and to analyse the impact of COD on the reproductive performance of dairy cows, databases from 22 dairy herds from the main dairy region in Argentina were retrospectively evaluated throughout a 3‐year period (2009–2011). A total of 248 COD cases over 9156 parturitions were recorded, resulting in a cumulative incidence rate of 2.7%. Cystic ovarian disease incidence density was lower during the first 100 days post‐partum (DPP) than during later stages of lactation. Seasonality had a significant influence on the disease presentation with higher incidence rates during winter and spring. Cows with a previous diagnosis of clinical mastitis showed 2.72 times more chances of developing ovarian cysts. Cystic cows had longer calving to first service and calving to conception intervals and lower conception rate than controls.     

Pyloric outflow obstruction secondary to sclerosing encapsulating peritonitis in a dog

A 6-year-old, male neutered mixed breed dog was presented emergently with a three-week history of hyporexia, vomiting, diarrhoea and weight loss. Upon examination, the patient was dull, had generalised muscle atrophy, moderate abdominal pain and a mild amount of peritoneal effusion. A fluid-filled, distended, corrugated small bowel with marked gastroparesis and moderate peritoneal effusion was noted on abdominal ultrasonography. Endoscopy revealed hyperaemic and friable mucosa and a subjectively narrowed pylorus. Emergency exploratory celiotomy was performed due to worsening patient condition and revealed thick, diffuse, fibrous adhesions of the abdominal cavity. Based on these findings, sclerosing encapsulating peritonitis (SEP) was suspected. A large mass of omentum adjacent to the greater curvature of the stomach had caused a pyloric outflow obstruction. Adhesiolysis was attempted but was unsuccessful due to the friability of the small intestines. The dog was humanely euthanased under anaesthesia. A diagnosis of SEP was confirmed via necropsy. No underlying cause was identified. This is the first known case of a pyloric outflow obstruction secondary to SEP in a dog. Although rare, this condition should be considered as a differential for dogs with signs of a pyloric outflow obstruction with concurrent ascites and abdominal pain, hyporexia, vomiting and diarrhoea.     

Pleistocene extinction of genyornis newtoni: human impact on australian megafauna

More than 85 percent of Australian terrestrial genera with a body mass exceeding 44 kilograms became extinct in the Late Pleistocene. Although most were marsupials, the list includes the large, flightless mihirung Genyornis newtoni. More than 700 dates onGenyornis eggshells from three different climate regions document the continuous presence of Genyornis from more than 100,000 years ago until their sudden disappearance 50,000 years ago, about the same time that humans arrived in Australia. Simultaneous extinction of Genyornis at all sites during an interval of modest climate change implies that human impact, not climate, was responsible.     

辽宁省棉铃虫虫情划区的调查研究

研究表明,北方特早熟棉区的辽宁省各地棉铃虫的发生程度与气温（年均等温线８～９℃）、降水（年平均降水量５００～７００ｍｍ）及寄主植物的分布三个条件重合程度呈明显的正相关。据此,将本省棉铃虫的发生区域划分为：重发生区、轻发生区、可发生区、偶发生区、不发生区,并绘制出棉铃虫区域划分图。