Pharmacokinetic and pharmacodynamic characterization of an oral lysophosphatidic acid type 1 receptor-selective antagonist.

Lysophosphatidic acid (LPA) is a bioactive phospholipid that signals through a family of at least six G protein-coupled receptors designated LPA1₋6. LPA type 1 receptor (LPA1) exhibits widespread tissue distribution and regulates a variety of physiological and pathological cellular functions. Here, we evaluated the in vitro pharmacology, pharmacokinetic, and pharmacodynamic properties of the LPA1-selective antagonist AM095 (sodium, {4'-[3-methyl-4-((R)-1-phenyl-ethoxycarbonylamino)-isoxazol-5-yl]-biphenyl-4-yl}-acetate) and assessed the effects of AM095 in rodent models of lung and kidney fibrosis and dermal wound healing. In vitro, AM095 was a potent LPA1 receptor antagonist because it inhibited GTPγS binding to Chinese hamster ovary (CHO) cell membranes overexpressing recombinant human or mouse LPA1 with IC50 values of 0.98 and 0.73 µM, respectively, and exhibited no LPA1 agonism. In functional assays, AM095 inhibited LPA-driven chemotaxis of CHO cells overexpressing mouse LPA1 (IC50= 778 nM) and human A2058 melanoma cells (IC50 = 233 nM). In vivo, we demonstrated that AM095: 1) had high oral bioavailability and a moderate half-life and was well tolerated at the doses tested in rats and dogs after oral and intravenous dosing, 2) dose-dependently reduced LPA-stimulated histamine release, 3) attenuated bleomycin-induced increases in collagen, protein, and inflammatory cell infiltration in bronchalveolar lavage fluid, and 4) decreased kidney fibrosis in a mouse unilateral ureteral obstruction model. Despite its antifibrotic activity, AM095 had no effect on normal wound healing after incisional and excisional wounding in rats. These data demonstrate that AM095 is an LPA1 receptor antagonist with good oral exposure and antifibrotic activity in rodent models.

A novel, orally active LPA(1) receptor antagonist inhibits lung fibrosis in the mouse bleomycin model.

BACKGROUND AND PURPOSE: The aim of this study was to assess the potential of an antagonist selective for the lysophosphatidic acid receptor, LPA(1), in treating lung fibrosis We evaluated the in vitro and in vivo pharmacological properties of the high affinity, selective, oral LPA(1)-antagonist (4'-{4-[(R)-1-(2-chloro-phenyl)-ethoxycarbonylamino]-3-methyl-isoxazol-5-yl}-biphenyl-4-yl)-acetic acid (AM966). EXPERIMENTAL APPROACH: The potency and selectivity of AM966 for LPA(1) receptors was determined in vitro by calcium flux and cell chemotaxis assays using recombinant and native cell cultures. The in vivo efficacy of AM966 to reduce tissue injury, vascular leakage, inflammation and fibrosis was assessed at several time points in the mouse bleomycin model. KEY RESULTS: AM966 was a potent antagonist of LPA(1) receptors, with selectivity for this receptor over the other LPA receptors. In vitro, AM966 inhibited LPA-stimulated intracellular calcium release (IC(50)= 17 nM) from Chinese hamster ovary cells stably expressing human LPA(1) receptors and inhibited LPA-induced chemotaxis (IC(50)= 181 nM) of human IMR-90 lung fibroblasts expressing LPA(1) receptors. AM966 demonstrated a good pharmacokinetic profile following oral dosing in mice. In the mouse, AM966 reduced lung injury, vascular leakage, inflammation and fibrosis at multiple time points following intratracheal bleomycin instillation. AM966 also decreased lactate dehydrogenase activity and tissue inhibitor of metalloproteinase-1, transforming growth factor beta1, hyaluronan and matrix metalloproteinase-7, in bronchoalveolar lavage fluid. CONCLUSIONS AND IMPLICATIONS: These findings demonstrate that AM966 is a potent, selective, orally bioavailable LPA(1) receptor antagonist that may be beneficial in treating lung injury and fibrosis, as well as other diseases that are characterized by pathological inflammation, oedema and fibrosis.

Nitrapyrin: a scientific advisory group review of the mode of action and carcinogenicity in B6C3F1 mice.

Nitrapyrin has been registered as a nitrogen stabilizer in the United States for many years based on a robust set of regulatory data. These data demonstrated that nitrapyrin was not genotoxic and that there were no tumors elicited in rats or mice that were relevant for human risk assessment. A repeat carcinogenicity study in B6C3F1 mice, conducted at two substantially higher-dose levels (0, 125 or 250 mg/kg/day) than the original study (0, 5, 25 or 75 mg/kg/day) identified liver, stomach, epididymal and Harderian gland tumors. In order to assess the relevance of these findings for human risk assessment, a Scientific Advisory Group (SAG) examined relevant microscopic changes in these tissues and also evaluated genotoxicity and mechanistic data. The SAG determined that the maximum tolerated dose had been exceeded in mice given 125 or 250 mg/kg/day, based on 26-33% decreased body weight gains (males-250 mg/kg/day), hepatocellular necrosis and compensatory hepatocellular proliferation (males and females-125 and 250 mg/kg/day). The SAG believed that the increased incidences of hepatocellular foci of alteration and hepatocellular neoplasms represented an epigenetic response to hepatocellular necrosis and increased mitogenesis. Increased incidences of proliferative lesions in the forestomach mucosa were likely secondary to the irritant effects of nitrapyrin. Neither the liver nor forestomach effects were interpreted to be a direct carcinogenic effect. Higher incidences of Harderian gland adenomas (females) and undifferentiated sarcomas in the epididymis represented normal biological variations in incidence and were unrelated to nitrapyrin. Therefore, it was the SAG's opinion that nitrapyrin exposure that does not produce target organ toxicity in exposed individuals would not be expected to increase the risk of cancer.

Dosimetry considerations in the enhanced sensitivity of male Wistar rats to chronic ethylene glycol-induced nephrotoxicity.

Male Wistar rats have been shown to be the most sensitive sex, strain and species to ethylene glycol-induced nephrotoxicity in subchronic studies. A chronic toxicity and dosimetry study was therefore conducted in male Wistar rats administered ethylene glycol via the diet at 0, 50, 150, 300, or 400 mg/kg/day for up to twelve months. Subgroups of animals were included for metabolite analysis and renal clearance studies to provide a quantitative basis for extrapolating dose-response relationships from this sensitive animal model in human health risk assessments. Mortality occurred in 5 of 20 rats at 300 mg/kg/day (days 111-221) and 4 of 20 rats at 400 mg/kg/day (days 43-193), with remaining rats at this dose euthanized early (day 203) due to excessive weight loss. Increased water consumption and urine volume with decreased specific gravity occurred at 300 mg/kg/day presumably due to osmotic diuresis. Calculi (calcium oxalate crystals) occurred in the bladder or renal pelvis at > or =300 mg/kg/day. Rats dying early at > or =300 mg/kg/day had transitional cell hyperplasia with inflammation and hemorrhage of the bladder wall. Crystal nephropathy (basophilic foci, tubule or pelvic dilatation, birefringent crystals in the pelvic fornix, or transitional cell hyperplasia) affected most rats at 300 mg/kg/day, all at 400 mg/kg/day, but none at < or =150 mg/kg/day. No significant differences in kidney oxalate levels, the metabolite responsible for renal toxicity, were observed among control, 50 and 150 mg/kg/day groups. At 300 and 400 mg/kg/day, oxalate levels increased proportionally with the nephrotoxicity score supporting the oxalate crystal-induced nephrotoxicity mode of action. No treatment-related effects on the renal clearance of intravenously infused (3)H-inulin, a marker for glomerular filtration, and (14)C-oxalic acid were observed in rats surviving 12 months of exposure to ethylene glycol up to 300 mg/kg/day. In studies with naïve male Wistar and F344 rats (a less sensitive strain), a significant difference was observed in oxalate clearances between young rats (i.e. Wistar clearance < F344) but not in age-matched old rats. Regardless, the ratios of oxalate:inulin clearances in these two strains of rats, including those exposed to ethylene glycol, were all < 1, suggesting that a fraction of the filtered oxalate is reabsorbed. Other species, including humans, typically have clearance ratios >1 and are more effective at clearing oxalic acid by both glomerular filtration and active secretion. Thus, the lower renal clearance and kidney accumulation of oxalates in male Wistar rats enhances their sensitivity, which will be a factor in human risk assessments. The benchmark dose values (BMD05, BMDL05) were 170 mg/kg/day and 150 mg/kg/day for nephropathy, and 170 mg/kg/day and 160 mg/kg/day for birefringent crystals, using incidence times severity data in each case. The NOAEL of 150 mg/kg/day is the same as that reported after 16-week exposure and appears to be a threshold dose below which no renal toxicity occurs, regardless of exposure duration.

Spinosad insecticide: subchronic and chronic toxicity and lack of carcinogenicity in CD-1 mice.

The potential toxicologic and oncogenic effects of spinosad, a natural fermentation product with insecticidal properties, were investigated. The 13-week toxicity study consisted of groups of 10 CD-1 mice/sex provided diets containing 0, 0.005, 0.015, 0.045, or 0.12% spinosad (Study 1). The 0.12% group was terminated on Test Day 44 due to mortality and overt clinical signs of toxicity. An 18-month chronic oncogenicity study consisted of groups of 50 CD-1 mice/sex provided diets containing 0, 0.0025, 0.008, or 0.036% spinosad (Study 2). Two interim groups of 10 mice/sex/group were terminated after 3 and 12 months. Females given 0.036% were terminated on Day 455 due to markedly lower body weights and feed consumption, as well as excessive mortality. Because of the early termination of the female high-dose group, additional groups of 10 male and female mice (12-month interim necrospy) and 50 male and female mice (18-month necropsy) were provided diets containing 0, 0.0008, or 0.024% spinosad (Study 3) to fully assess potential chronic toxicity and oncogenicity. Standard toxicologic parameters were evaluated consistent with existing regulatory guidelines. The primary effect in the 13-week and 18-month studies was intracellular vacuolation of histiocytic and epithelial cells in numerous tissues and organs at doses of > or = 0.015%. The histological vacuolation corresponded to ultrastructural lysosomal lamellar inclusion bodies. This alteration was consistent with phospholipidosis, a condition that results from accumulation of polar lipids in lysosomes. Lesions with no apparent direct relation to vacuolation were hyperplasia of the glandular mucosa of the stomach, skeletal muscle myopathy, bone marrow necrosis, and anemia with associated splenic hematopoiesis. The incidence of tumors in mice given spinosad was not increased relative to controls at any dose level. The no observed effect level for the 13-week study was 0.005% (6 mg/kg/day) spinosad, and for the chronic toxicity/oncogenicity study was 0.008% (11 mg/kg/day) spinosad for male and female CD-1 mice.

Going like gangbusters: transnational tobacco companies "making a killing" in South America.

This article reports on the recent growth of transnational tobacco companies (TTCs) in South America. Although some scholarly attention has been directed toward such growth in Asia and eastern Europe, South America has also been targeted by the TTCs' aggressive expansionist practices in recent years. Fighting "Big Tobacco" is entirely different from combating most public health problems. Unlike cigarettes, most infectious diseases and maternal and child health problems never provide profits to transnational corporations and governments. Also, most public health problems (with alcohol being another notable exception) are not exacerbated by extensive advertising campaigns that promote the cause of the health problems. Supported by data gathered during three months of fieldwork in Ecuador, Peru, Chile, and Argentina in 1997, this article suggests that the TTCs' marketing strategies override cultural differences in the choices people make regarding smoking and health. Combining critical medical anthropology and public health, this article concludes that unless dramatic actions are taken, an avoidable outbreak of tobacco-related diseases will eventually reach epidemic proportions on the South American continent. It is also a "call to arms" for more medical anthropologists to investigate tobacco-related matters around the world.

Chronic toxicity and oncogenicity studies of ingested 1, 3-dichloropropene in rats and mice.

Fischer 344 rats and B6C3F1 mice were administered 1, 3-dichloropropene (1,3-D) via their diets for up to 2 years, at dose levels of 0, 2.5, 12.5, or 25 mg 1,3-D/kg body wt/day for rats and 0, 2.5, 25, or 50 mg 1,3-D/kg body wt/day for mice. The test material was stabilized in the feed by microencapsulation in a starch/sucrose matrix (80/20%). Rats given 12.5 or 25 mg/kg/day, and mice given 25 or 50 mg/kg/day, had decreased body weights and body weight gains. There were no effects on survival or clinical pathology parameters for rats or mice. Histopathologic effects attributed to treatment in rats consisted of basal cell hyperplasia of the nonglandular mucosa of the stomach in males and females given 12.5 or 25 mg/kg/day for 12 and 24 months and an increased number of hepatocellular adenomas in males given 12.5 or 25 mg/kg/day and females given 25 mg/kg/day for 24 months. The increase in hepatocellular adenomas was statistically identified by pairwise comparison only in males given 25 mg/kg/day. An increased incidence of eosinophilic foci of altered cells in the liver was also noted in all treated groups of rats at 24 months. The latter observation, however, was considered of equivocal toxicological significance because of the common spontaneous occurrence of liver foci in aged Fischer 344 rats. The only histologic change attributed to treatment in mice was decreased size of hepatocytes in males given 50 mg/kg/day for 12 months. The decreased size of hepatocytes was consistent with decreased cytoplasmic glycogen content and corresponded to decreased liver weights. This effect was not present at 24 months. There was no oncogenic response observed in mice. The low-dose level of 2.5 mg/kg/day was interpreted as the no-observed-adverse-effect level (NOAEL) for systemic chronic toxicity of 1,3-D in the Fischer 344 rat. The no-observed-effect level (NOEL) for chronic systemic toxicity was 2.5 mg/kg/day in the B6C3F1 mouse.

Structure-based design of an osteoclast-selective, nonpeptide src homology 2 inhibitor with in vivo antiresorptive activity.

Targeted disruption of the pp60(src) (Src) gene has implicated this tyrosine kinase in osteoclast-mediated bone resorption and as a therapeutic target for the treatment of osteoporosis and other bone-related diseases. Herein we describe the discovery of a nonpeptide inhibitor (AP22408) of Src that demonstrates in vivo antiresorptive activity. Based on a cocrystal structure of the noncatalytic Src homology 2 (SH2) domain of Src complexed with citrate [in the phosphotyrosine (pTyr) binding pocket], we designed 3',4'-diphosphonophenylalanine (Dpp) as a pTyr mimic. In addition to its design to bind Src SH2, the Dpp moiety exhibits bone-targeting properties that confer osteoclast selectivity, hence minimizing possible undesired effects on other cells that have Src-dependent activities. The chemical structure AP22408 also illustrates a bicyclic template to replace the post-pTyr sequence of cognate Src SH2 phosphopeptides such as Ac-pTyr-Glu-Glu-Ile (1). An x-ray structure of AP22408 complexed with Lck (S164C) SH2 confirmed molecular interactions of both the Dpp and bicyclic template of AP22408 as predicted from molecular modeling. Relative to the cognate phosphopeptide, AP22408 exhibits significantly increased Src SH2 binding affinity (IC(50) = 0.30 microM for AP22408 and 5.5 microM for 1). Furthermore, AP22408 inhibits rabbit osteoclast-mediated resorption of dentine in a cellular assay, exhibits bone-targeting properties based on a hydroxyapatite adsorption assay, and demonstrates in vivo antiresorptive activity in a parathyroid hormone-induced rat model.

Subchronic and chronic toxicity of ingested 1,3-dichloropropene in dogs.

The potential toxicologic effects to dogs of 1,3-dichloropropene (1, 3-D), a soil fumigant used for the control of nematodes, were investigated. The 13-week subchronic toxicity study consisted of male and female beagle dogs (4/sex/dose group) given approximately 0, 5, 15, or 41 mg 1,3-D/kg body wt/day (approximately equivalent amounts of cis and trans isomers) via their diets. The 1-year chronic toxicity study consisted of male and female beagle dogs (4/sex/dose group) provided diets delivering approximately 0, 0.5, 2. 5, or 15 mg/kg body wt/day. The test material was stabilized in the feed by microencapsulation in a starch/sucrose matrix (80/20). In both the 13-week and the 1-year studies, the primary effect of 1,3-D in male and female dogs ingesting a dosage of >/=15 mg/kg/day was hypochromic, microcytic anemia. The anemia was regenerative, with increased erythropoietic activity characterized by polychromasia of erythrocytes and increased numbers of reticulocytes in peripheral blood. In the 13-week study, the anemia in dogs given 41 mg/kg/day progressively worsened over time, while the anemia in dogs given 15 mg/kg/day remained relatively constant between 42 and 90 days of dosing. Partial reversal of the anemia of high-dose animals occurred during a 5-week recovery period following the 13-week dosing regimen. In the 13-week study, terminal fasted body weights of males given 15 or 41 mg/kg/day were decreased 3 and 28%, respectively, and body weights of females given 5, 15, or 41 mg/kg/day were decreased 4.5, 12, and 24%, respectively, relative to controls. Males given 5 mg/kg/day for 13 weeks had no change in body weights relative to controls. In the 1-year study, the hypochromic microcytic anemia in dogs given 15 mg/kg/day remained relatively constant in severity between 3 and 12 months of treatment. Histopathologic alterations associated with anemia in the 1-year study consisted of increased hematopoiesis of the bone marrow and increased extramedullary hematopoiesis of the spleen. Body weights of males given 15 mg/kg/day were 5-12% lower than controls during the first 13 weeks of the study and 13-19% lower than controls during the remaining 9 months. Body weights of females given 15 mg/kg/day were 5-14% lower than controls over the majority of the dosing period. Males and females given 0.5 or 2.5 mg/kg/day for 1 year had no change in body weights relative to controls. A no-observed-effect level of 2.5 mg/kg/day was established for male and female dogs from the 1-year study.

Congenital infantile fibrosarcoma: a case study.

Congenital infantile fibrosarcoma (CIFS) is a rare soft-tissue malignancy most commonly involving the extremities. Metastases are rare; however, local recurrence is common. Because the tumor is so rare and clinical experience is lacking, both diagnosis and treatment are difficult. The complex planning and implementation of neonatal and oncologic care require ongoing collaboration between both nursing specialties. This case study discusses the pathophysiology, diagnosis, and management of an infant with CIFS, with emphasis on the nursing care of the patient and family.

Clearing the air: challenges to introducing smoking restrictions in West Virginia.

One of the most fundamental rights, the right to breathe air free of unhealthy carcinogens, is continuously threatened by powerful corporate tobacco interests, which spend enormous amounts of money not only to promote smoking, but also to stifle local, state, and national efforts to control smoking in the United States. From the perspective of a "committed participant" this paper discusses recent difficulties encountered in attempting to introduce West Virginia's first comprehensive smoking control legislation, and the strategies used to overcome them. The primary message reported here is that, given the overwhelming financial, emotional, and human-potential costs involved in ongoing tobacco abuse in the United States, it is essential that citizens unite to protect the health of all children and the vast majority of adults who do not smoke, and to discourage the consumption of cigarettes, the single biggest cause of disease and death in our society. The example reported here from West Virginia demonstrates that persistent citizen activism can make a critical difference in promoting laws that protect human health from unhealthy environmental tobacco smoke.

Dichloroacetylene: effects on the rat trigeminal nerve somatosensory evoked potential.

Humans overexposed to trichloroethylene (TCE), under specific conditions, were reported to develop trigeminal nerve dysfunction. A degradation byproduct dichloroacetylene (DCA), however, has been suggested as the probable neurotoxicant rather than TCE. Studies in mice, rats, and rabbits support the hypothesis of DCA-induced trigeminal neurotoxicity. This study, therefore, was conducted to characterize DCA-induced trigeminal nerve dysfunction in rats using the electrodiagnostic procedure trigeminal nerve-stimulated somatosensory evoked potential (TSEP). A group of six rats was exposed once to DCA (approximately 300 ppm) or room air for 2.25 h and a separate group of six rats was not exposed and served as controls. Trigeminal nerve somatosensory evoked potentials (TSEPs) were collected before exposure and 2, 4, and 7 days postexposure. Because DCA was manufactured from TCE with acetylene added as a stabilizer, another group of rats was exposed to TCE and acetylene without generation of DCA. TSEPs from DCA-exposed rats were smaller and slower compared to their baseline recordings and to the concurrent negative controls. TSEPs from the controls and the TCE/acetylene-exposed rats were unchanged. Neuropathology did not reveal treatment-related lesions. It was concluded that the rat is mildly to markedly susceptible to DCA-induced trigeminal nerve dysfunction as assessed by TSEP, but that the kidney was the likely target organ based on gross observations and the DCA literature.

Subchronic toxicity of ingested 1,3-dichloropropene in rats and mice.

Male and female Fischer 344 rats and B6C3F1 mice (10/sex/ dose group) were given 0, 5, 15, 50, or 100 mg/kg/day (rats) or 0, 15, 50, 100, or 175 (mice) mg/kg/day racemic 1,3-dichloropropene (1,3-D), respectively, via their diets for 13 weeks. Satellite groups of rats (recovery = 10 rats/sex/group) ingesting 0 or 100 mg/kg/ day 1,3-D were provided control feed for an additional 4 weeks to examine recovery. The test material was stabilized in the feed by microencapsulation in a starch/sucrose matrix (80/20). The body weights of male and female rats ingesting > or = 5 and > or = 15 mg/kg/ day, respectively, and of all treatment groups of mice were decreased relative to controls. The terminal body weights of high dose group rats and mice were decreased approximately 13-16%. A number of changes in serum biochemical parameters and decreases in organ weights accompanied the depressed body weights of these animals. Histologically, the only treatment-related change observed was a slight degree of basal cell hyperplasia and hyperkeratosis in the nonglandular portion of the stomachs of a majority of male and female rats ingesting > or = mg/kg/day. After the 4-week recovery period, most treatment-related changes were noted to be reversible in nature. No treatment-related histopathological changes were observed in the tissues of treated mice. Based upon relatively slight depressions in body weights at the lowest dosages tested, the no-observed-adverse-effect levels for male rats and both sexes of mice were determined to be 5 mg/kg/day and 15 mg/kg/ day, respectively. A no-observed-effect level of 5 mg/kg/day was established for female rats.

Making a killing south of the border: transnational cigarette companies in Mexico and Guatemala.

Cigarette smoking is the most unnecessary of modern epidemics in the world today, according to the World Health Organization. In response to declining sales at home, multinational cigarette companies are increasingly targeting allegedly developing countries with their deadly products, often with the strong support of the U.S. government. While Asian countries have been most heavily targeted in recent years, Latin American countries have not been overlooked. This paper discusses macro-level and micro-level implications of the tobacco companies' promotions, based on data gathered in Mexico and Guatemala during 1990. Recommendations for combating the corporations' efforts are also discussed.

Garbage imperialism: health implications of dumping hazardous wastes in Third World countries.

This paper calls for studies of the potential health implications of today's hazardous waste disposal practices, and suggests that such studies are urgently needed in Third World countries where industrial nations are increasingly dumping their unwanted waste materials. The United States produces enormous quantities of hazardous waste each year, and approximately 1,200 "priority hazardous waste sites" presently threaten the nation's health. Because of environmental regulations, landfill closings, and citizen opposition to local waste facilities, industrialized countries are increasingly disposing of their problematic materials by shipping them to the Third World, where they pose substantial threats to human health and the environment. From a political economy perspective, this paper suggests that global health would be better served by reducing hazardous waste production, encouraging reusing and recycling, and restricting or banning international shipment of toxic wastes.

Cutaneous plasmacytomas with amyloid in six dogs.

Cutaneous plasmacytomas associated with local deposition of amyloid were diagnosed by light microscopy in a series of six older dogs (mean age 10.7 years) consisting of two Cocker Spaniels, a Poodle, a Weimeraner, and two mixed-breed dogs. The neoplasms occurred on the digits (2 dogs), forelimb (2 dogs), lip (1 dog), and ear (1 dog). In most cases, groups of neoplastic plasma cells were widely separated by large homogeneous islands of amyloid. The neoplastic cells had characteristic plasmacytoid features, but the degree of pleomorphism varied greatly between different neoplasms. In four of the six tumors, the diagnosis of plasmacytoma was confirmed by the demonstration of a monoclonal plasma cell population using immunofluorescent staining for anti-canine immunoglobulins. In these tumors, the neoplastic cells reacted with only one class of immunoglobulins (IgG). The amyloid did not react with any of the reagents used. The suspicion that the amyloid was of immunoglobulin origin (primary amyloid) was supported by its retention of birefringence under polarized light after treatment with potassium permanganate and staining with Congo red.

Tobacco, politics and economics: implications for global health.

This paper examines the expanding presence of multinational cigarette companies into almost every country in the world, and discusses the health implications of this global penetration. Cigarettes deserve special attention because tobacco is the only legally available consumer product that is harmful to one's health when used as intended. A temptation exists to blame governments for the existence of health-threatening products within their borders. However, this paper illustrates the extent to which extra-national forces influence domestic policies and circumstances. Cigarette smokers are often blamed for their lethal habit, despite billion-dollar promotional schemes which attract people to smoking, obscuring the harmful consequences of consuming a highly addictive drug. Multinational cigarette companies are increasingly targeting Asian and Third World populations. To facilitate this market penetration, political avenues are often pursued with considerable success, disregarding the health implications associated with cigarette tobacco. The use of tobacco in development programs (e.g. the U.S. 'Food for Peace' program) has political and economic implications for donor and recipient countries, and lucrative advantages for the tobacco companies. However, this paper recommends that corporate profits and foreign policy should not be pursued at the expense of tobacco-related diseases and premature deaths among Third World peoples.

Transnational tobacco companies and health in underdeveloped countries: recommendations for avoiding a smoking epidemic.

This paper examines the impact of transnational tobacco companies on health in underdeveloped countries and makes recommendations for avoiding a coming smoking epidemic. Although tobacco is generally seen as primarily a health problem, tobacco's future in the Third World depends upon a number of nonhealth related considerations, especially political and economic factors. Unfortunately, there is very little relationship between what the World Health Organization and others have recommended, and what most Third World countries are doing today. Although the controversy concerning cigarette smoking and health has only become a 'burning issue' in recent decades, tobacco products have been used around the world for hundreds of years. The public outcry against cigarette smoking has become increasingly widespread since the 1964 U.S. Surgeon General's report on smoking and health. The ill effects of cigarette smoking are now widely considered collectively as the number one preventable health problem in the world, responsible for an estimated 2.5 million deaths per year. In response to declining sales in developed countries, the tobacco transnational corporations have begun focusing their attention on Third World markets, where tobacco consumption has increased dramatically in recent years. Cigarettes not only take precious limited resources away from desperately needed basic human needs, but they also inflict future health problems on vast numbers of Third World people who have only a vague understanding of the risks involved in cigarette smoking. Until Third World governments address the long-term consequences of their short-term lust for cash, the probabilities of a smoking epidemic in the Third World grow increasingly likely.(ABSTRACT TRUNCATED AT 250 WORDS)

Hypertrophic osteopathy in a pony with a pituitary adenoma.

Hypertrophic osteopathy was diagnosed in a pony that had no antemortem or postmortem evidence of an intrathoracic lesion. With a history of hirsutism in an aged pony, a pituitary adenoma was suspected, and evaluation of plasma cortisol and insulin values and their response to thyrotropin-releasing hormone supported the diagnosis.

Polycystic disease of the kidney and liver in an adult Persian cat.

Polycystic disease of the kidney and liver was diagnosed in a 10-year-old spayed female Persian cat. Previous reports of renal and hepatic polycystic disease in dogs and cats have described only juvenile forms, with death at an early age. The cat of this report had large, fluid-filled kidney and liver cysts, compared with the relatively small, spongiform cysts of puppies and kittens. The clinicopathological findings in this adult Persian cat are comparable to the adult form of renal and hepatic polycystic disease of man.