Pharmacokinetics of ibuprofen after intravenous and oral administration and assessment of safety of administration to healthy foals.

OBJECTIVE: To determine pharmacokinetics of ibuprofen in healthy foals and to determine clinical effects after oral administration for 6 days. ANIMALS: 7 healthy 5- to 10-week-old foals. PROCEDURE: Serum concentrations of ibuprofen were measured after IV and oral (nasogastric tube) administration at dosages of 10 and 25 mg/kg of body weight. Foals were given ibuprofen (25 mg/kg, PO, q 8 h) as a paste for 6 days. Serum and urine were obtained before and after the 6-day period. RESULTS: Half-life of elimination (Kel t1/2) of IV-administered ibuprofen (ie, 10 and 25 mg/kg), was 79 and 108 minutes, maximal serum concentration (C(MAX)) was 82 and 160 microg/ml, and clearance was 0.003 and 0.002 L/kg/min, respectively. At the higher dosage, clearance was significantly lower and C(MAX) was significantly higher. Ibuprofen given via nasogastric tube resulted in Kel t1/2 of 81 and 100 minutes and C(MAX) of 22 and 52 microg/ml for 10 and 25 mg/kg, respectively. The absorption half-life was 13 minutes, and bioavailability ranged from 71 to 100%. Foals remained healthy during oral administration of ibuprofen. Serum urea nitrogen, creatinine, and L-iditol dehydrogenase values increased significantly, and gamma-glutamyltransferase (GGT) activity and osmolality decreased, but all measurements remained within reference ranges. Urine GGT activity doubled. Necropsy did not reveal gross or histologic renal lesions attributable to ibuprofen. Acute gastric ulcers were evident in 1 foal, although clinical signs of ulcers were not observed. CONCLUSIONS AND CLINICAL RELEVANCE: Ibuprofen can be given safely to healthy foals at dosages < or = 25 mg/kg every 8 hours for up to 6 days.

Coadministration of nomegestrol acetate does not diminish the beneficial effects of estradiol on coronary artery dilator responses in nonhuman primates (Macaca fascicularis).

OBJECTIVE: Our purpose was to examine the effect of coadministered nomegestrol acetate on estradiol-induced dilator responses of coronary arteries. STUDY DESIGN: In this prospective randomized trial, ovariectomized monkeys were fed a moderately atherogenic diet for 3 months while being treated with (1) no hormone replacement (control, n = 12), (2) estradiol (1.5 mg/d equivalent) added to the diet (n = 12), or (3) estradiol (1.5 mg/d equivalent) plus nomegestrol acetate (3.75 mg/d equivalent) (n = 12) added to the diet. Effects of treatment were measured with analysis of variance. Post hoc analyses were done by multiple comparison tests with Bonferroni corrections. RESULTS: Constrictor responses of epicardial coronary arteries (measured with quantitative angiography) and decreased coronary blood velocity (measured with Doppler ultrasonography) to acetylcholine (10(-6) mol/L) were less in the estradiol-treated monkeys (with or without cotreatment with nomegestrol acetate) than in the untreated monkeys (P <.05). Typical estrogenic responses were induced by estradiol in the endometrium (ie, increased proliferation [Ki-67 expression] [P <.04] and increased hormone receptor expression). These effects were antagonized by nomegestrol acetate. CONCLUSIONS: Although nomegestrol acetate has typical progestin-like effects on the uterus, it does not diminish the beneficial effects of estrogen on acetylcholine-induced dilator responses of coronary arteries.

The potential of soybean phytoestrogens for postmenopausal hormone replacement therapy.

Hormone replacement therapy for postmenopausal women greatly reduces their risk of coronary heart disease. However, current pharmaceutical regimens have a low acceptance rate among postmenopausal women. We have sought to identify an alternative treatment that would retain the beneficial health effects of current standard therapy without its negative aspects. We have concentrated our research on naturally occurring estrogens (called phytoestrogens) found in soybeans, in the belief that delivery of phytoestrogens via the diet would be more acceptable than pharmaceutical regimens. Using a well-established nonhuman primate model of postmenopausal women, we have investigated the effects of soy phytoestrogens on cardiovascular risk factors and the reproductive system. In this review, we summarize the results of our ongoing research.

Oral contraceptives and hormone replacement therapy do not increase the incidence of arterial thrombosis in a nonhuman primate model.

Older oral contraceptive (OC) formulations containing high doses of potent synthetic estrogens and progestins are associated with increased risk of thrombosis. To examine the effects of current low-dose OC and hormone replacement therapy (HRT) regimens on arterial thrombosis, premenopausal and surgically postmenopausal cynomolgus monkeys were divided into four treatment groups. Premenopausal monkeys were given either no OCs or ethinyl estradiol and levonorgestrel as an OC at a dose equivalent to that currently given to women. Postmenopausal monkeys were given either no HRT or conjugated equine estrogens and medroxyprogesterone as an HRT at a dose equivalent to that currently given to women. The monkeys were fed an atherogenic diet containing these treatments for 27 to 30 months. At the end of this time, arterial thrombosis was evaluated with a standardized stenosis/injury procedure in the left carotid artery. Blood flow velocity was monitored for cyclic or permanent occlusive thrombosis. The current OC and HRT regimens did not increase the susceptibility of the artery wall to develop an occlusive thrombus following injury and stenosis. In fact, there was a reduction in the incidence of thrombosis in the OC animals compared with untreated controls. Increased amounts of atherosclerosis were associated with an increased incidence of occlusive arterial thrombosis. Several selected coagulation parameters [von Willebrand factor, protein C, lipoprotein(a), and platelet aggregation] did not appear to be associated with either the amount of atherosclerosis or incidence of arterial thrombosis.

Contrasting effects of conjugated estrogens and tamoxifen on dilator responses of atherosclerotic epicardial coronary arteries in nonhuman primates.

BACKGROUND: Estrogens have been shown to improve dilator responses of atherosclerotic coronary arteries. Tamoxifen is a mixed estrogen agonist/antagonist with as yet unexplored effects on vascular function. Therefore, the goal of this study was to compare the effects of conjugated equine estrogens (CEEs) with those of tamoxifen on epicardial coronary artery dilator responses in atherosclerotic, ovariectomized monkeys. METHODS AND RESULTS: Fifty ovariectomized cynomolgus monkeys were fed an atherogenic diet for 34 months. During this time, monkeys were assigned to one of three treatment groups: (1) control, no hormone replacement (n=15); (2) CEEs mixed in the diet at a dose of 0.043 mg x kg(-1) x d(-1) (n=14); or (3) tamoxifen mixed in the diet at a dose of 1.3 mg x kg(-1) x d(-1) (n=21). Quantitative angiography was used to measure coronary artery dilator responses to intracoronary infusions of acetylcholine (10(-8), 10(-7), and 10(-6) mol/L) and nitroglycerin (15 microg/min). Coronary arteries of the tamoxifen-treated group constricted in response to high-dose acetylcholine (-5.4+/-2.3%, P<.05 versus control), whereas those of the CEE group did not (P>.05 versus control). Conversely, arteries from the CEE group dilated in response to nitroglycerin (9.1+/-2.1%, P<.05 versus control), whereas those from the tamoxifen group did not (P>.05 versus control). Statistical adjustments for variations in plaque extent (determined subsequently after necropsy) and plasma lipoproteins did not alter the results. CONCLUSIONS: Tamoxifen has primarily estrogen-antagonistic effects on epicardial coronary artery dilator responses in atherosclerotic monkeys. Results implicate the estrogen receptor as a modulator of coronary artery dilator responses in ovariectomized, atherosclerotic monkeys.

Soy isoflavones enhance coronary vascular reactivity in atherosclerotic female macaques.

OBJECTIVE: To examine the effects of soy phytoestrogens on coronary vascular reactivity in atherosclerotic male and female rhesus monkeys. DESIGN: A prospective, randomized, blinded, controlled study. SETTING: Comparative Medicine Clinical Research Center of an academic medical center. PATIENT(S): Twenty-two young adult rhesus monkeys with pre-existing diet-induced atherosclerosis. INTERVENTION(S): Monkeys were fed soy-based diets for 6 months identical in composition, except that the isoflavones were extracted from one flow-isoflavone) and intact in the other (high-isoflavone). Quantitative coronary angiography was performed at the end of the study period. Females in the low-isoflavone group under went a second angiography after an acute IV dose of genistein. MAIN OUTCOME MEASURE(S): Percent change in diameter of the proximal left circumflex coronary artery in response to intracoronary acetylcholine and nitroglycerin, compared with control diameter. RESULT(S): Arteries from males constricted in response to acetylcholine. Arteries from females in the low-isoflavone group constricted (-6.2% +/- 2.8%, mean +/- SEM), whereas arteries from females in the high-isoflavone group dilated (6.4% +/- 1.2%, mean +/- SEM). Intravenous administration of genistein caused dilation in the previously constricting low-isoflavone females (3.3% +/- 2.8%). CONCLUSION(S): Like mammalian estrogens, dietary soy isoflavones enhance the dilator response to acetylcholine of atherosclerotic arteries in female monkeys.

Effects of 17 alpha-dihydroequilenin sulfate on atherosclerotic male and female rhesus monkeys.

OBJECTIVES: Our purpose was to determine the effects of 17 alpha-dihydroequilenin on plasma lipid and lipoprotein, glucose, and insulin concentrations; coronary artery vasomotor function; and reproductive organ and mammary gland proliferation in atherosclerotic male and female rhesus macaques. STUDY DESIGN: Fifty adult female and 33 adult male rhesus macaques were randomized to treatment by lifetime dietary cholesterol exposure and ratio of total plasma cholesterol to high-density lipoprotein cholesterol. The female treatment groups were intact female controls (n = 9), ovariectomized controls (n = 16), ovariectomized plus 0.3 mg/kg/day 17 alpha-dihydroequilenin (n = 17) and ovariectomized plus subcutaneous estradiol (n = 7). The male treatment groups were control (n = 16) and 1.25 mg/kg/day 17 alpha-dihydroequilenin (n = 17). Treatment lasted 5 weeks. Longitudinal assessments of plasma lipid and lipoprotein and glucose and insulin concentrations were performed. Coronary artery vasomotor function was assessed by quantitative coronary angiography 1 week after initiation of treatment. Morphologic and immunohistochemical assessments of proliferation index values of reproductive organs and mammary glands were done at necropsy. RESULTS: 17 alpha-Dihydroequilenin prevented endothelium-dependent vasoconstriction in males (p < 0.05) and ovariectomized females (p < 0.08). 17 alpha-Dihydroequilenin treatment increased plasma apolipoprotein A-1 concentrations (p < 0.05) and lowered fasting insulin concentrations (p < 0.05) without changing fasting plasma glucose concentrations in males. 17 alpha-Dihydroequilenin had no other effects on plasma lipid and lipoprotein concentrations in either males or females. It had no trophic effects on uterus, endometrium, or breast. There was no effect on either prostatic or testicular weight. CONCLUSION: 17 alpha-Dihydroequilenin may represent a single-agent hormone therapy for reduction of ischemic hear disease risk for both menopausal women and men. It has no apparent trophic effects on reproductive organs or mammary glands of female and male rhesus macaques.

The effects of disease severity and sex on coronary endothelium-dependent vasomotor function in an atherosclerotic primate model.

BACKGROUND: The relationship between the extent of atherosclerosis and vascular reactivity is not known, since studies of humans have used indirect measures of the extent of atherosclerosis (angiography and ultrasound), and most patients studied had only minimal-to-moderate atherosclerosis. It is known that atherosclerosis impairs coronary vasodilatation in response to acetylcholine, and that estrogen improves vascular reactivity of atherosclerotic coronary arteries in women and perhaps in men. However, the effects of estrogen and sex on arteries with advanced, complicated plaques are not known. METHODS: We used quantitative coronary angiography to measure vascular reactivity to infusions of 10(-6) mol/l acetylcholine and 15 micrograms/min nitroglycerin in 70 segments of coronary arteries in 16 rhesus monkeys (12 males, five intact females, nine ovariectomized females) with a wide range of extents of atherosclerosis. The extent and severity of atherosclerotic plaque in each segment was quantified by histologic and histomorphometric methods. Effects of sex and ovariectomy on vascular reactivity were examined at low and high levels of plaque severity. RESULTS: Vascular responses ranged from constriction (by 18%) to dilatation (by 14%) compared with the control diameter. The magnitude of the vascular response to acetylcholine, either dilatation or constriction, decreased with increasing plaque severity (P < 0.01). At low severity, arteries of intact females dilated (by 7.2 +/- 2.1%), whereas those of males and ovariectomized females constricted (by 4.5 +/- 1.5% and 5.0 +/- 1.2%, respectively; P < 0.001, versus intact females). When lesions were severe, vascular responses did not differ among groups. CONCLUSIONS: Our results indicate that arteries became unresponsive to acetylcholine as atherosclerotic lesions progressed in size and complexity, and that sex and estrogen status affected vascular reactivity only when lesions were small. These findings may imply a limited range of lesion development within which vascular reactivity can be influenced by sex and estrogen status.

Regression of atherosclerosis in female monkeys.

The objective of this study was to determine the structural and functional changes that occur in the artery wall in response to plasma lipid lowering and hormone replacement in surgically postmenopausal monkeys with established coronary artery atherosclerosis. Eighty-eight surgically postmenopausal cynomolgus monkeys were fed an atherogenic diet for 24 months and were then allocated into 4 groups: group 1 (n = 20), a baseline necropsy group; group 2 (n = 25), a lipid-lowering diet only; group 3 (n = 22), lipid lowering plus conjugated equine estrogen treatment equivalent to 0.625 mg/d for a woman; and group 4 (n = 21), lipid lowering plus conjugated equine estrogen and medroxyprogesterone acetate treatment (equivalent to 2.5 mg/d for a woman). Treatment was for 30 months. Histomorphometric analysis of perfusion-fixed coronary arteries revealed that plaque size did not change significantly in any of the groups compared with group 1 (P > .20). Plasma lipid lowering permitted coronary artery remodeling to occur (coronary artery and lumen size doubled compared with group 1) (P < .05); however, hormone therapy did not augment remodeling. Quantitative angiographic analysis of coronary artery reactivity revealed that lipid lowering improved dilator responses to acetylcholine by 22 +/- 4% (P = .01) but not to nitroglycerin (P = .23). Hormone replacement did not further affect vascular reactivity to the agonists tested (P > .4), but addition of medroxyprogesterone acetate diminished the beneficial effects of conjugated estrogens on coronary flow reserve (P = .03). In summary, the major arterial sequelae of lipid lowering in female monkeys were artery and lumen enlargement and improved reactivity of large epicardial coronary arteries. Addition of hormone replacement to the dietary modification did not further augment these improvements, except for the dilator capacity of the coronary microcirculation.

Effects of hormone replacement therapy on reactivity of atherosclerotic coronary arteries in cynomolgus monkeys.

OBJECTIVES: We attempted to determine whether continuous and cyclic medroxyprogesterone acetate modulates the effects of estrogen on dilation of atherosclerotic coronary arteries in surgically postmenopausal female monkeys. BACKGROUND: Estrogen replacement in postmenopausal women preserves normal dilator responses of atherosclerotic coronary arteries. The effects of progestins on coronary artery reactivity have not been determined. METHODS: Repeated quantitative coronary angiography was used to study the effects after 1 month of 1) no hormone replacement (control) or oral administration of 2) continuous conjugated equine estrogens, 3) cyclic high dose medroxyprogesterone acetate (MPA) given on days 16 to 26 of the month, 4) conjugated equine estrogens plus continuous low dose MPA, or 5) conjugated equine estrogens plus cyclic high dose MPA on endothelium-mediated dilation of atherosclerotic coronary arteries in 12 cynomolgus monkeys. Change in diameter of the left circumflex coronary artery was measured in response to intracoronary infusions of acetylcholine (10(-6) mol/liter per min) and nitroglycerin (15 micrograms/min). RESULTS: Coronary arteries constricted during no hormone treatment (-8 +/- 3% [mean +/- SEM]), dilated during conjugated equine estrogen treatment (+3 +/- 1%, p < 0.05 vs. control) and constricted during cyclic MPA treatment (-3 +/- 2%). Addition of cyclic or continuous MPA to the conjugated equine estrogen regimen inhibited acetylcholine responses by 50% (p < 0.05 vs. conjugated equine estrogens). There was no effect of treatment on vascular response to nitroglycerin (p > 0.05). CONCLUSIONS: Treatment with conjugated equine estrogens, but not MPA, augmented endothelium-mediated dilation of atherosclerotic coronary arteries. Addition of cyclic or continuous MPA to the conjugated equine estrogen regimen diminished endothelium-mediated dilation.

Lateral patellar luxation in miniature horses.

Bilateral luxation of the patella in four Miniature Horses was corrected by a lateral release incision and medial imbrication of the parapatellar fascia to the tendon of the sartorius muscle. Before surgery, the four horses had a grade 3 to 4 lateral patellar luxation bilaterally and had difficulty walking. Trochlear ridge hypoplasia was evident on radiographs in each horse. Follow-up information varied from 11 months to 4 years after surgery. Three horses had no patellar luxation or lameness. The other horse had a normal right stifle, but patellar luxation (grade 3) had recurred on the left.