Aryeh Hurwitz
University of Kansas
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Cancer Epidemiology, Biomarkers & Prevention | 2006
Gregory A. Reed; Dora W. Arneson; William C. Putnam; Holly J. Smith; John C. Gray; Debra K. Sullivan; Matthew S. Mayo; James A. Crowell; Aryeh Hurwitz
We have completed a phase I trial in women of the proposed chemopreventive natural product indole-3-carbinol (I3C). Women received oral doses of 400, 600, 800, 1,000, and 1,200 mg I3C. Serial plasma samples were analyzed by high-performance liquid chromatography-mass spectrometry for I3C and several of its condensation products. I3C itself was not detectable in plasma. The only detectable I3C-derived product was 3,3′-diindolylmethane (DIM). Mean Cmax for DIM increased from 61 ng/mL at the 400-mg I3C dose to 607 ng/mL following a 1,000-mg dose. No further increase was observed following a 1,200-mg dose. A similar result was obtained for the area under the curve, which increased from 329 h ng/mL at the 400-mg dose to 3,376 h ng/mL after a 1,000-mg dose of I3C. Significant interindividual quantitative variation was seen in plasma DIM values within each dosing group, but the overall profiles were qualitatively similar, with no quantifiable DIM before dosing, tmax at ∼2 h, and DIM levels near or below 15 ng/mL (the limit of quantitation), by 24 h. Different results were obtained for 14 subjects who received a 400-mg dose of I3C after 8 weeks of twice-daily I3C dosing. Although the predose sampling occurred at least 12 h after the last known ingestion of I3C, 6 of 14 subjects exhibited Cmax for DIM in their predose plasma. Despite this high initial value, plasma DIM for all subjects decreased to near or below the limit of quantitation within the 12-h sampling period. Possible reasons for this disparity between apparent t1/2 of DIM and the high predose values are discussed. (Cancer Epidemiol Biomarkers Prev 2006;15(12):2477–81)
Cancer Epidemiology, Biomarkers & Prevention | 2005
Gregory A. Reed; Kirstin S. Peterson; Holly J. Smith; John C. Gray; Debra K. Sullivan; Matthew S. Mayo; James A. Crowell; Aryeh Hurwitz
We completed a phase I trial of indole-3-carbinol (I3C) in 17 women (1 postmenopausal and 16 premenopausal) from a high-risk breast cancer cohort. After a 4-week placebo run-in period, subjects ingested 400 mg I3C daily for 4 weeks followed by a 4-week period of 800 mg I3C daily. These chronic doses were tolerated well by all subjects. Hormonal variables were measured near the end of the placebo and dosing periods, including determination of the urinary 2-hydroxyestrone/16α-hydroxyestrone ratio. Measurements were made during the follicular phase for premenopausal women. Serum estradiol, progesterone, luteinizing hormone, follicle-stimulating hormone, and sex hormone binding globulin showed no significant changes in response to I3C. Caffeine was used to probe for cytochrome P450 1A2 (CYP1A2), N-acetyltransferase-2 (NAT-2), and xanthine oxidase. Comparing the results from the placebo and the 800 mg daily dose period, CYP1A2 was elevated by I3C in 94% of the subjects, with a mean increase of 4.1-fold. In subjects with high NAT-2 activities, these were decreased to 11% by I3C administration but not altered if NAT-2 activity was initially low. Xanthine oxidase was not affected. Lymphocyte glutathione S-transferase activity was increased by 69% in response to I3C. The apparent induction of CYP1A2 was mirrored by a 66% increase in the urinary 2-hydroxyestrone/16α-hydroxyestrone ratio in response to I3C. The maximal increase was observed with the 400 mg daily dose of I3C, with no further increase found at 800 mg daily. If the ratio of hydroxylated estrone metabolites is a biomarker for chemoprevention, as suggested, then 400 mg I3C daily will elicit a maximal protective effect.
Clinical Pharmacokinectics | 1977
Aryeh Hurwitz
SummaryAntacids are commonly used drugs which are considered inert and free of pharmacological effect by many patients and physicians. When administered with other drugs, antacids can alter absorption or excretion of these agents, at times reducing their plasma level and effect and in other cases causing toxicity.Although many antacid-drug interaction studies have been performed in animals or in vitro and others show only minor effects in man, several clinically important interactions and their mechanisms have been verified in man. Antacids which reduce drug dissolution or bind drugs in the gastrointestinal tract have been shown to inhibit absorption and reduce efficacy of tetracyclines, digoxin, phenytoin and certain psychotherapeutic agents. Aluminium hydroxide gel delays gastric emptying, delaying isoniazid absorption and lowering blood levels. By elevating urine pH, antacids cause accelerated excretion of acidic drugs like salicylate and per contra may cause retention of basic drugs like quinidine or amphetamine.While the efficacy of many drugs may not be affected by antacids, the absorption or excretion of other drugs which have not yet been studied are undoubtedly altered by antacid administration. It is therefore advisable, where possible, to administer other drugs at least a half to 1 hour before antacid ingestion to ensure consistent absorption and effect. Long-term antacid ingestion should be avoided when other drugs are taken, unless antacid use is clinically indicated and is of proven benefit.
Cancer Epidemiology, Biomarkers & Prevention | 2008
Gregory A. Reed; Jean M. Sunega; Debra K. Sullivan; John C. Gray; Matthew S. Mayo; James A. Crowell; Aryeh Hurwitz
We have completed a single ascending dose clinical study of the proposed chemopreventive agent 3,3′-diindolylmethane (DIM). The study agent was nutritional-grade, absorption-enhanced BioResponse 3,3′-diindolylmethane (BR-DIM). We determined the safety, tolerability, and pharmacokinetics of single doses of BR-DIM in drug-free, non-smoking, healthy men and women. Groups of four subjects were enrolled for each dose level. After randomization, one subject in each group received placebo whereas three received active BR-DIM. The doses administered were 50, 100, 150, 200, and 300 mg, with the 300-mg dose repeated in an additional group. No BR-DIM–related adverse effects were reported at doses up to 200 mg. At the 300-mg dose, one of six subjects reported mild nausea and headache and one also reported vomiting. Only the latter effect was judged as probably related to the study agent. Analysis of serial plasma samples showed that only one subject at the 50-mg dose had detectable concentrations of DIM. The single 100-mg dose of BR-DIM resulted in a mean maximum plasma concentration (Cmax) of 32 ng/mL and a mean area under the curve (AUC) of 128 h ng/mL, and a single 200-mg dose produced a mean Cmax of 104 ng/mL and a mean AUC of 553 h ng/mL. The single 300-mg dose of BR-DIM resulted in a mean Cmax of 108 ng/mL and a mean AUC of 532 h ng/mL. We conclude that BR-DIM is well tolerated at single doses of up to 200 mg, and that increasing the dose to 300 mg did not result in an increase in Cmax. (Cancer Epidemiol Biomarkers Prev 2008;17(10):2619–24)
American Heart Journal | 1992
Thomas Rosamond; James L. Vacek; Aryeh Hurwitz; A.Jody Rowland; Gary D. Beauchamp; Linda J. Crouse
Hypotension during exercise treadmill testing is correlated with the presence of coronary artery disease, its severity, and prognosis. The importance of hypotension during dobutamine stress testing has not been previously reported to our knowledge. We reviewed 43 cases of hypotension occurring in 42 patients out of a total of 116 consecutive stress dobutamine echocardiographic procedures performed in a total of 112 patients. Of the 42 patients with hypotension, 20 underwent cardiac catheterization. Regional wall motion abnormalities induced by dobutamine infusion were found in 13 of these patients, all of whom had significant (greater than or equal to 70% diameter reduction) coronary artery disease. The remaining seven patients without regional wall motion abnormalities did not have significant coronary artery disease at catheterization. Of the remaining 22 patients with dobutamine-induced hypotension, 20 had no induced regional wall motion abnormalities, were not catheterized, and were followed clinically. None of these patients had a cardiac event during a mean follow-up period of 11.5 months. We conclude that hypotension during dobutamine stress echocardiography in the absence of regional wall motion abnormalities does not indicate significant coronary artery disease or portend an adverse prognosis.
Clinical Pharmacology & Therapeutics | 1985
Aziz Karim; Thomas S. Burns; Denis Janky; Aryeh Hurwitz
Theo‐24 (G. D. Searle & Co.) is an ultra‐slow‐absorbing formulation of theophylline suitable for once‐a‐day dosing in slow and normal metabolizers of theophylline. Relative to fasting conditions, increased rate and extent of theophylline absorption occur when this product is administered immediately after a breakfast with a high fat content. Our study demonstrated that factors such as meal composition (fat content) or dosing time relative to meal intake can modify the high fat–induced changes in absorption. For consistent, slow absorption, patients taking high doses (≥ 900 mg) of Theo‐24 once a day should take this product in the morning under fasting conditions or with a breakfast containing ≤ 10 gm fat. If a high‐fat breakfast (> 55 gm fat) is taken, then Theo‐24 should be administered at least 1 hour before the meal.
Gastroenterology | 1991
Andrew Parkinson; Aryeh Hurwitz
Abstract Concerns have been expressed that omeprazole may increase the cancer-causing effects of certain chemical carcinogens due to the ability of this antiulcer drug to induce certain forms of cytochrome P-450 (IA1 and IA2) in human liver. These concerns are largely unfounded. Induction of these same P-450 enzymes in rodents invariable decreases, not increases, the tumorigenic effects of a wide variety of chemical carcinogens. Concerns have also been expressed that the induction of P-450 IA enzymes by omeprazole may potentiate that hepatotoxic effects of phenacetin and/or acetaminophen. Although cigarette smoking and consumption of charcoal-broiled beef are known to induce liver IA2 in humans, they are not known to potentiate the hepatotoxic effects of phenacetin or acetaminophen. Omeprazole treatment does not alter the metabolism of theophylline, which is stimulated in cigarette smokers. When interactions with omeprazole have been observed, they invariably involve an inhibition, not induction, of drug metabolism. In conclusion, concerns about the potential adverse effects of omeprazole are not supported by experimental evidence, and the results from recent in vitro and ex vivo experiments do not appear to be pharmacologically or toxicologically relevant to the in vivo situation.
Clinical Pharmacology & Therapeutics | 1980
Moshe Garty; Aryeh Hurwitz
In a randomized crossover study, five normal subjects were given 250‐mg capsules of tetracycline at weekly intervals with cimetidine 300 mg, sodium bicarbonate 2 gm in water, magnesium–aluminium hydroxide gel 30 ml, or water alone. Gastric pH was monitored by radiotelemetry. Antibiotic bioavailability as measured by area under the serum level–time curve, peak serum level, and urinary elimination was not affected by cimetidine or sodium bicarbonate. Magnesium–aluminum hydroxide gel reduced bioavailability by 90%. The data show that gastric pH does not affect absorption of oral tetracycline and that cimetidine can be used in place of antacids to control gastric acid in patients using tetracycline.
European Journal of Pharmacology | 1973
Milos Hava; Aryeh Hurwitz
Abstract M. HAVA and A. HURWITZ, The relaxing effect of aluminum and lanthanum on rat and human gastric smooth muscle in vitro, European J. Pharmacol. 22 (1973) 156–161. Aluminum and lanthanum relaxed and partly blocked the acetylcholine-evoked contractions of rat and human stomach smooth muscle strips. In the perfused isolated rat stomach, intraluminal administration of 3 ml of 5 mM AlCl3 or LaCl3 caused a reversible reduction of contractions evoked by serosal administration of acctylcholine in the organ bath after a 90-min delay. The concentration of aluminum in solution in rat stomachs after administration of aluminum hydroxide in vivo was 0.015 M. This concentration was 30 times that which blocked contraction of isolated muscie strips and 3 times the concentration effective in perfused rat stomachs in vitro.
Clinical Pharmacology & Therapeutics | 1977
Aryeh Hurwitz; Ralph G. Robinson; William F. Herrin
The present study shows that a single oral recommended dose of propantheline bromide normally doubles the mean gastric half‐emptying time in man. In a prospective, double‐blind, randomized crossover design 13 normal subjects were given 30 mg propantheline or placebo 90 min before taking a l l Sm‐indium‐labeled liquid test meal, the volume of which was adjusted to body weight . The disappearance of radioisotope from the area of the stomach was determined by external gamma counting . After placebo the mean half‐emptying time was 68 min and after propantheline it was 135 min (p < 0.005). Although salivary fiow decreased and pulse rate increased there were no visual disturbances . In studies already reported maximally tolerated oral doses of quaternary ammonium anticholinergic drugs have not consistently retarded gastric emptying in man.