Toxicologic pathology in a multicultural world--India.

The global practice of drug development is expanding into many different continents and countries. India, in particular, is rapidly emerging as an economic force in this arena by offering ever-expanding opportunities for pharmaceutical market expansion as well as productive drug development partnerships. The key to the country's current socioeconomic success appears to be education, particularly the development of higher and professional education. Also, recent modifications to India's patent laws offer greater protections and incentives for international investment. Increasing numbers of competent contract research organizations create attractive opportunities for large Western pharmaceutical companies with a desire to gain access to burgeoning markets as well as mitigate the rising cost of drug development with less costly services. Well-trained veterinary pathologists are available, appropriate facilities are being constructed, and laboratory capabilities are expanding. Developing a productive partnership with a credible laboratory service in India, as with any new provider, requires due diligence and knowledgeable scrutiny of key elements of the work stream, such as facilities, education and training of laboratory personnel, Good Laboratory Practices, animal care, timelines, and data management. Ultimately and with appropriate management, mutually beneficial drug development partnerships are available in India.

Cardiac valvular pathology: comparative pathology and animal models of acquired cardiac valvular diseases.

Recent voluntary withdrawal of the ergoline-derivative Alzheimers' drug Pergolide (Permax) resulting from demonstrated risk of cardiac valve injury illustrates the increased importance of valve injury in pharmaceutical toxicology. Following the 2001 landmark discovery of cardiac valve injury associated with the widely prescribed anti-obesity drug combination fenfluramine-phentermine, and subsequent withdrawal, the need to understand and assess cardiac valve biology and pathology both preclinically and clinically has been accentuated. Unique aspects of the developmental biology, anatomy, and physiology of cardiac valves compared to main cardiac tissue have been discovered, and key elements of the pathophysiology of various valvular injury mechanisms have been described. Although general clinical cardiac valvular disease in humans has been well characterized, animal modeling of valvular injury has proved to be difficult and undersubscribed. Additionally, both the preclinical, pharmaceutical, toxicologic assessment of valvular injury and the understanding of species-comparative valvular pathology have been limited. As discoveries and awareness grows, the purpose of this paper is to review the structure and function of cardiac valves, mechanisms, and outcomes of the common acquired human cardiac valve diseases, including those that are drug-related; to summarize comparative laboratory animal valvular pathology; and to review the literature of contemporary animal models of valvular injury.

A new selective estrogen receptor modulator with potent uterine antagonist activity, agonist activity in bone, and minimal ovarian stimulation.

The use of selective estrogen receptor modulators for the treatment of estrogen-dependent diseases in premenopausal women has been hindered by undesirable ovarian stimulation and associated risks of ovarian cysts. We have identified a selective estrogen receptor modulator compound (LY2066948) that is a strong estrogen antagonist in the uterus yet has minimal effects on the ovaries of rats. LY2066948 binds with high affinity to both estrogen receptors and has potent estrogen antagonist activity in human uterine and breast cancer cells. Oral administration of LY2066948 to immature rats blocked uterine weight gain induced by ethynyl estradiol with an ED50 of 0.07 mg/kg. Studies in mature rats demonstrated that LY2066948 decreases uterine weight by 51% after 35 d treatment, confirming potent uterine antagonist activity over several estrous cycles. This strong uterine response contrasted with the minimal effects on the ovaries: serum estradiol levels remained within the normal range, whereas histologic evaluation showed granulosa cell hyperplasia in few of the rats. Bone studies demonstrated that LY2066948 prevented ovariectomy-induced bone loss and treatment of ovary-intact rats caused no bone loss, confirming estrogen receptor agonist skeletal effects. Collectively, these data show that LY2066948 exhibits a tissue-specific profile consistent with strong antagonist activity in the uterus, agonist activity in bone, and minimal effects in the ovaries.

Gastric mucosal damage following repeat administration of melanocortin subtype-4 receptor ligands to Fischer 344 rats.

Since the melanocortin system plays a role in the central control of feeding, melanocortin receptor ligands may be efficacious in treating human obesity. Ten structurally similar melanocortin subtype-4 receptor (MC4R) ligands from an aryl piperazine chemical platform were evaluated in female Fischer 344 rats to assess the toxicity of this class of compounds. Rats were orally gavaged with 100, 250, or 500 mg/kg of each compound in 10% acacia and purified water daily for 4 days. In treated rats, notable clinical observations included a dose-dependent decrease in mean body weight and food consumption. A morphologically unique compound-related histologic lesion occurred in the nonglandular gastric mucosa. The lesions consisted of multiple, raised, sometimes ulcerated, white foci which, microscopically, were discrete, intraepithelial vesicles containing dense accumulations of neutrophils continuous with inflammation in the submucosa. Ruptured vesicles resulted in ulcers and occasionally gastric perforation. The morphologic characteristics of this acute lesion were described and concluded to be a direct toxicity of the compounds unrelated to melanocortin-mediated pharmacology.