Grape juice but not orange or grapefruit juice inhibits platelet activity in dogs and monkeys

Platelet aggregation (PA) contributes to both the development of atherosclerosis and acute platelet thrombus formation (APTF) followed by embolization producing cyclic flow reductions (CFR) in stenosed and damaged dog and human coronary arteries. In seven anesthetized dogs with coronary stenosis and medial damage, CFR occurred at 7 +/- 3/30 min and were abolished 127 +/- 18 min after gastric administration of 10 mL of purple grape juice/kg. Collagen-induced ex vivo whole blood PA decreased by 49 +/- 9% after the abolishment of CFR with grape juice. Ten mL of orange juice/kg (n = 5) and 10 mL of grapefruit juice/kg (n = 5) had no significant effect on the frequency of the CFR or on ex vivo PA. In vitro studies have suggested that flavonoids bind to platelet cell membranes and thus may have an accumulative or tissue-loading effect over time. To test this we fed 5 mL of grape juice/kg to 5 cynomologous monkeys for 7 d. Collagen-induced ex vivo PA decreased by 41 +/- 17% compared to control (pre-reatment) after 7 d of feeding. In the same 5 monkeys, neither 5 mL of orange juice/kg nor 5 mL of grapefruit juice/kg given orally for 7 d produced any significant change in PA. Grape juice contains the flavonoids quercetin, kaempferol and myricetin, which are known inhibitors of PA in vitro. Orange juice and grapefruit juice, while containing less quercetin than grape juice, primarily contain the flavonoids naringin, luteolin and apigenin glucoside. The flavonoids in grapes were shown in vitro to be good inhibitors of PA, whereas the flavonoids in oranges and grapefruit to be poor inhibitors of PA. The consumption of grape juice, containing these inhibitors of PA, may have some of the protection offered by red wine against the development of coronary artery disease (CAD) and acute occlusive thrombosis, whereas orange juice or grapefruit juice may be ineffective. Thus, grape juice may be a useful alternative dietary supplement to red wine without the concomitant alcohol intake.     

Grapefruit juice increases felodipine oral availability in humans by decreasing intestinal CYP3A protein expression

The increase in oral availability of felodipine and other commonly used medications when taken with grapefruit juice has been assumed to be due to inhibition of CYP3A4, a cytochrome P450 that is present in liver and intestine. To evaluate the effect of repeated grapefruit juice ingestion on CYP3A4 expression, 10 healthy men were given 8 oz of grapefruit juice three times a day for 6 d. Before and after receiving grapefruit juice, small bowel and colon mucosal biopsies were obtained endoscopically, oral felodipine kinetics were determined, and liver CYP3A4 activity was measured with the [14C N-methyl] erythromycin breath test in each subject. Grapefruit juice did not alter liver CYP3A4 activity, colon levels of CYP3A5, or small bowel concentrations of P-glycoprotein, villin, CYP1A1, and CYP2D6. In contrast, the concentration of CYP3A4 in small bowel epithelia (enterocytes) fell 62% (P = 0.0006) with no corresponding change in CYP3A4 mRNA levels. In addition, enterocyte concentrations of CYP3A4 measured before grapefruit juice consumption correlated with the increase in Cmax when felodipine was taken with either the 1st or the 16th glass of grapefruit juice relative to water (r = 0. 67, P = 0.043, and r = 0.71, P = 0.022, respectively). We conclude that a mechanism for the effect of grapefruit juice on oral felodipine kinetics is its selective downregulation of CYP3A4 in the small intestine.     

Resting hemodynamics after total versus standard orthotopic heart transplantation in patients with high preoperative pulmonary vascular resistance

OBJECTIVE: Pretransplant pulmonary vascular resistance > or = 4 Wood-units predisposes to right ventricular failure after heart transplantation. Total orthotopic heart transplantation with bicaval and pulmonary venous anastomoses offers synchronous contractions of the atria and a normal ventricular filling pattern, but requires longer ischemic time than standard orthotopic heart transplantation. To test if total orthotopic heart transplantation improves resting hemodynamics in pts with high preoperative pulmonary vascular resistance, we analyzed 65 pts with standard and 65 with total orthotopic heart transplantation transplanted between 12/88 and 7/94. Of these, 18 with total and 15 with standard orthotopic heart transplantation had a preoperative pulmonary vascular resistance > or = 4 Wood-units. METHODS: Right heart catheterization data were obtained at each endomyocardial biopsy. All data from biopsies at both 2 weeks and 1 year posttransplant that were free from humoral or greater than 1A cellular rejection (9 versus 13 pts) were included in a two way ANOVA. Pts with postop pacemakers, atrial fib or beta-blocker therapy at the time of biopsy were excluded. RESULTS: Ischemic time was different (172 +/- 44 versus 142 +/- 28 min, P = 0.03). Demographics, NYHA class, pre-TX hemodynamics, donor age and inotropes were similar. Cardiac output and index were higher in the total orthotopic group at 2 weeks (6.5 +/- 1.7 versus 5.1 +/- 1.0 l/min; 3.4 +/- 0.9 versus 2.8 +/- 0.6 l/min per m2) and 1 year (7.1 +/- 2.0 versus 4.9 +/- 1.1 l/min, P = 0.002; 3.6 +/- 1.1 versus 2.6 +/- 0.5 l/min per m2, P = 0.009). Right atrial and pulmonary arterial mean pressure (mmHg) were lower with total orthotopic heart transplantation at 2 weeks (6 +/- 4 versus 9 +/- 5, P = 0.04; 22 +/- 3 versus 25 +/- 7, P = 0.1) and 1 year (5 +/- 2 versus 7 +/- 3, P = 0.02; 19 +/- 4 versus 25 +/- 7, P = 0.03). Pulmonary capillary wedge pressure (mmHg) was borderline nonsignificant (11 +/- 4 versus 13 +/- 7 at 2 weeks, 8 +/- 3 versus 14 +/- 5 at 1 year, P = 0.055), as well as pulmonary vascular resistance (1.9 +/- 1 versus 2.5 +/- 1 at 2 weeks, 1.5 +/- 0.6 versus 2.7 +/- 1.7 WU at 1 year, P = 0.051). CONCLUSIONS: Total orthotopic heart transplantation improves cardiac output and index in pts with high preoperative pulmonary vacular resistance. There is a lower mean RA and PA pressure perhaps due to less tricuspid and mitral regurgitation. In view of the frequently observed restrictive filling pattern after cardiac transplantation, total orthotopic heart transplantation can be beneficial until this pattern has subsided by preserving atrioventricular synchrony and offering better atrial transport.     

Primary pulmonary artery sarcoma

1. The aim of the present study was to evaluate the effect of grapefruit juice on urinary 6 beta-hydroxycortisol and cortisol excretion in healthy subjects. 2. The ratio of 6 beta-hydroxycortisol/cortisol was significantly decreased (P = 0.036) in the 0-4 h fraction of urine after ingestion of grapefruit juice, but not in the 4-24 h fraction (P = 0.218) or for the compiled data, fraction 0-24 h (P = 0.114). 3. These results indicate that endogenous cortisol metabolism may not only be of hepatic origin, but may also be dependent on the metabolic capacity of cytochrome P450 IIIA (CYP3A) in the gut mucosa. 4. This finding may cast further doubts of the usefulness of the 6 beta-hydroxycortisol/cortisol ratio as an indicator of hepatic CYP3A activity.     

Enhanced coronary vasoconstriction in the Syrian myopathic hamster supports the microvascular spasm hypothesis

This study examines the relation between blood pressure and insulin resistance in obese, sedentary middle-aged and older men. Eleven hypertensive and 17 normotensive subjects of comparable age (58.6 +/- 1.0 years, mean +/- SEM), percent body fat (27.7 +/- 0.7%), and maximal aerobic capacity (30.2 +/- 0.9 mL.kg-1.min-1) participated in this study. Glucose disposal (M, milligrams per kilogram of fat-free mass per minute) determined during a three-dose hyperinsulinemic euglycemic clamp was lower in the hypertensive than normotensive subjects at the low (M at 120 pmol/m2.min: 2.3 +/- 0.2 versus 3.2 +/- 0.3, P = .06), intermediate (M at 600 pmol/m2.min: 8.0 +/- 0.6 versus 10.4 +/- 0.6, P = .02), and high (M at 3000 pmol/m2.min: 13.5 +/- 0.5 versus 15.5 +/- 0.7, P = .04) insulin infusion rates. The calculated insulin concentration necessary for a half-maximal effect (EC50) was greater in the hypertensive than normotensive subjects (1164 +/- 168 versus 864 +/- 66 pmol/L, P = .03). In this population of normotensive and hypertensive men, systolic, diastolic, and mean arterial blood pressures were related to glucose disposal at these insulin infusion rates (r = -.35 to -.46, P < .05) as well as the EC50 (r = .42 to .44, P < .05). Thus, hypertensive obese, sedentary older men have a reduction in both sensitivity and maximal responsiveness to insulin that is directly related to the severity of hypertension independent of obesity and physical fitness.     

The role of endothelin-1 as a mediator of the pressure response after air embolism in blood perfused lungs

BACKGROUND: Irritable bowel syndrome is a common cause of abdominal pain and discomfort and may be related to disordered gastrointestinal motility. Our aim was to assess the effects of long-term treatment with a prokinetic agent, cisapride, on postprandial jejunal motility and symptoms in the irritable bowel syndrome (IBS). METHODS: Thirty-eight patients with IBS (constipation-predominant, n = 17; diarrhoea-predominant, n = 21) underwent 24-h ambulatory jejunal manometry before and after 12 week's treatment [cisapride, 5 mg three times daily (n = 19) or placebo (n = 19)]. RESULTS: In diarrhoea-predominant patients significant differences in contraction characteristics were observed between the cisapride and placebo groups. In cisapride-treated diarrhoea-predominant patients the mean contraction amplitude was higher (29.3 +/- 3.2 versus 24.9 +/- 2.6 mm Hg, cisapride versus placebo (P < 0.001); pretreatment, 25.7 +/- 6.0 mm Hg), the mean contraction duration longer (3.4 +/- 0.2 versus 3.0 +/- 0.2 sec, cisapride versus placebo (P < 0.001); pretreatment, 3.1 +/- 0.5 sec), and the mean contraction frequency lower (2.0 +/- 0.2 versus 2.5 +/- 0.4 cont./min, cisapride versus placebo (P < 0.001); pretreatment, 2.5 +/- 1.1 cont./min] than patients treated with placebo. No significant differences in jejunal motility were found in the constipation-predominant IBS group. Symptoms were assessed by using a visual analogue scale before and after treatment. Symptom scores relating to the severity of constipation were lower in cisapride-treated constipation-predominant IBS patients [score, 54 +/- 5 versus 67 +/- 14 mm, cisapride versus placebo (P < 0.05); pretreatment, 62 +/- 19 mm]. Diarrhoea-predominant IBS patients had a higher pain score after cisapride therapy [score, 55 +/- 15 versus 34 +/- 12 mm, cisapride versus placebo (P < 0.05); pretreatment, 67 +/- 19 mm]. CONCLUSION: Cisapride affects jejunal contraction characteristics and some symptoms in IBS.     

Interaction of citrus juices with pranidipine, a new 1,4-dihydropyridine calcium antagonist, in healthy subjects

OBJECTIVES: The study was conducted to investigate whether oral co-administration with citrus juices significantly affects the pharmacokinetics and/or pharmacodynamics of pranidipine, a new 1,4-dihydropyridine calcium antagonist, in healthy male subjects. Grapefruit juice and orange juice, which were both commercially available, were used in this study. METHODS: Sixteen healthy male Japanese subjects participated in this study and were divided into two groups for grapefruit juice and orange juice treatment. The study followed an open-labelled crossover design, comparing the effects of a single oral dose of 2 mg pranidipine taken together with 250 ml citrus juice or 250 ml water. Serum pharmacokinetics of pranidipine, adverse reactions, blood pressure, heart rate, 12-lead ECG, haematology, clinical chemistry and urinalysis were measured throughout the study. RESULTS: For grapefruit juice, mean Cmax and AUC0-24 h were significantly higher than those of water (P=0.0003 and 0.0005, respectively, ANOVA) with the ratios of log transformed values being 1.50 and 1.74, respectively. There were no differences in tmax and t1/2 between the juice and water treatments. A significant increase in heart rate (P=0.0240, ANOVA with repeated measurements) was observed in the juice treatment whereas there were no significant differences in systolic and diastolic blood pressure between the two treatments. For orange juice, a small decrease in mean Cmax was observed compared with water (P=0.0218, ANOVA) with the ratio being 0.86, but there was no significant difference in AUC0-24h between the two treatments. No marked differences were observed in tmax and t1/2. Oral pranidipine administration with orange juice did not affect heart rate, systolic and diastolic blood pressures or other parameters for safety evaluation. CONCLUSIONS: Oral co-administration with grapefruit juice and pranidipine was associated with increased bioavailability and changed the pharmacodynamics of pranidipine, particularly with regard to heart rate. Orange juice intake with pranidipine did not markedly affect the pharmacokinetics and no clinically significant changes were observed in the pharmacodynamics and safety evaluation.     

In vivo metabolism of a new anticancer agent, 6-N-formylamino-12, 13-dihydro-1,11-dihydroxy-13-(beta-D-glucopyranosil)5H-indolo [2,3-a]pyrrolo [3,4-c]carbazole-5,7(6H)-dione (NB-506) in rats and dogs: pharmacokinetics, isolation, identification, and quantification of metabolites

BACKGROUND: Epidemiologic studies have shown alcohol consumption to be inversely as well as positively related to body weight and body fat. Metabolic studies have shown an increase in energy intake as well as compensation after alcohol consumption. OBJECTIVE: Our objective was to assess the effects on energy intake of an apéritif compared with those of a water appetizer and 3 fruit juice appetizers. DESIGN: Fifty-two men and women aged 20-45 y with a body mass index (in kg/m2) between 20 and 32 were randomly given 1 MJ (340 mL) alcohol (wine or beer), fat (cream fruit juice), protein (protein fruit juice), carbohydrate (grape juice), or water, or no preload 30 min before an ad libitum lunch consumed from the universal eating monitor. RESULTS: Energy intake (3.5+/-0.3 MJ compared with 2.7+/-0.2 MJ, P < 0.001) and eating rate were higher (44+/-3 g/min compared with 38+/-3 g/min, P < 0.01), meal duration was longer (14 min compared with 12.0 min, P < 0.01), satiation started to increase later (3.5 min compared with 1.5 min, P < 0.01), and eating was prolonged after maximum satiation (2.5 min compared with 0.6 min, P < 0.01) after an apéritif than after a fat, protein, or carbohydrate appetizer,. Twenty-four-hour energy intake was higher on a day that an apéritif was consumed than after water or no preload. CONCLUSION: Twenty-four-hour energy intake was elevated with a 1-MJ apéritif but not with a 1-MJ liquid carbohydrate, fat, or protein appetizer.     

Myocardial perfusion and function in dogs with moderate coronary stenosis

MRI studies of first-pass contrast enhancement with polylysine-Gd-DTPA and myocardial tagging using spatial modulation of magnetization (SPAMM) were performed to assess the feasibility of a combined regional myocardial blood flow and 2D deformation exam. Instrumented closed-chest dogs were imaged at a baseline control state (Cntl) followed by two interventions: moderate coronary stenosis (St) achieved by partial occlusion of the left anterior descending (LAD) and moderate coronary stenosis with dobutamine loading (StD). Hypoperfusion of the anterior region (ANT) of the myocardium (LAD distribution) relative to the posterior wall (POS) based on the upslope of the signal intensity time curve from the contrast-enhanced MR images was demonstrated only with dobutamine loading (ANT:POS Cntl = 1.077 +/- 0.15 versus ANT:POS StD = 0.477 +/- 0.11, P < 0.03) and was confirmed with radiolabeled microspheres measurements (ANT:POS Cntl = 1.18 +/- 0.2 ml/min/g versus ANT:POS StD = 0.44 +/- 0.1 ml/min/g; P < 0.002). Significant changes in regional myocardial shortening were only seen in the StD state (P < 0.02); the anterior region showed impaired myocardial shortening with dobutamine loading (P = NS), whereas the nonaffected POS region showed a marked increase in shortening when compared with Cntl (Cntl = 0.964 +/- 0.02 versus StD = 0.884 +/- 0.03; P < 0.001). These results demonstrate that an integrated quantitative assessment of regional myocardial function and semiquantitative assessment of myocardial blood flow can be performed noninvasively with ultrafast MRI.     

Racial differences in nitric oxide-mediated vasodilator response to mental stress in the forearm circulation

An abnormal hemodynamic response to stressful stimuli has been proposed as a mechanism involved in the higher prevalence of hypertension in blacks. Given the important role of nitric oxide (NO) in the regulation of cardiovascular homeostasis, we investigated the possibility of racial differences in vascular NO activity during mental stress. To test this hypothesis, we compared the forearm blood flow (FBF) response to mental stress in 14 white and 12 black healthy subjects during intra-arterial infusion of either saline or NO synthesis inhibitor N(G)-monomethyl-L-arginine (L-NMMA; 4 micromol/min). We also examined vascular responses of the two groups to intra-arterial infusion of sodium nitroprusside (0.8 to 3.2 microg/min), an exogenous NO donor. During saline infusion, the increase in FBF from baseline induced by mental stress was significantly higher in whites than in blacks (109+/-20% versus 58+/-8%; P=0.03). L-NMMA significantly reduced stress-induced increase in FBF in whites (from 109+/-20% to 54+/-11%; P=0.004) but not in blacks (from 58+/-8% to 42+/-10%; P=0.24); thus, the vasodilator effect of stress testing during L-NMMA was similar in whites and blacks (54+/-11% versus 42+/-10%; P=0.44). The vasodilator response to sodium nitroprusside was also lower in blacks than in whites (maximum flow, 6.9+/-2 versus 11.6+/-3.5 mL x min(-1) x dL(-1); P=0.001) and was not significantly modified by L-NMMA in either group. Our findings indicate that blacks have a reduced NO-dependent vasodilator activity during mental stress. This difference seems related to reduced sensitivity of smooth muscle to the vasodilator effect of NO and may play some role in the increased prevalence of hypertension and its complications in blacks.     

Gene therapy for myocardial angiogenesis: initial clinical results with direct myocardial injection of phVEGF165 as sole therapy for myocardial ischemia

BACKGROUND: We initiated a phase 1 clinical study to determine the safety and bioactivity of direct myocardial gene transfer of vascular endothelial growth factor (VEGF) as sole therapy for patients with symptomatic myocardial ischemia. METHODS AND RESULTS: VEGF gene transfer (GTx) was performed in 5 patients (all male, ages 53 to 71) who had failed conventional therapy; these men had angina (determined by angiographically documented coronary artery disease). Naked plasmid DNA encoding VEGF (phVEGF165) was injected directly into the ischemic myocardium via a mini left anterior thoracotomy. Injections caused no changes in heart rate (pre-GTx=75+/-15/min versus post-GTx=80+/-16/min, P=NS), systolic BP (114+/-7 versus 118+/-7 mm Hg, P=NS), or diastolic BP (57+/-2 versus 59+/-2 mm Hg, P=NS). Ventricular arrhythmias were limited to single unifocal premature beats at the moment of injection. Serial ECGs showed no evidence of new myocardial infarction in any patient. Intraoperative blood loss was 0 to 50 cm3, and total chest tube drainage was 110 to 395 cm3. Postoperative cardiac output fell transiently but increased within 24 hours (preanesthesia=4.8+/-0.4 versus postanesthesia=4.1+/-0.3 versus 24 hours postoperative=6. 3+/-0.8, P=0.02). Time to extubation after closure was 18.4+/-1.4 minutes; average postoperative hospital stay was 3.8 days. All patients had significant reduction in angina (nitroglycerin [NTG] use=53.9+/-10.0/wk pre-GTx versus 9.8+/-6.9/wk post-GTx, P<0.03). Postoperative left ventricular ejection fraction (LVEF) was either unchanged (n=3) or improved (n=2, mean increase in LVEF=5%). Objective evidence of reduced ischemia was documented using dobutamine single photon emission computed tomography (SPECT)-sestamibi imaging in all patients. Coronary angiography showed improved Rentrop score in 5 of 5 patients. CONCLUSIONS: This initial experience with naked gene transfer as sole therapy for myocardial ischemia suggests that direct myocardial injection of naked plasmid DNA, via a minimally invasive chest wall incision, is safe and may lead to reduced symptoms and improved myocardial perfusion in selected patients with chronic myocardial ischemia.     

Antimicrobial activity produced by six dentifrices

OBJECTIVE: To examine the effect of grapefruit juice on the bioavailability of carbamazepine in patients with epilepsy. METHODS: This was a randomized crossover study consisting of 2 phases. Ten patients with epilepsy who had received therapy with 200 mg carbamazepine 3 times a day for the previous 3 to 4 weeks participated. They were given either grapefruit juice or 300 mL water at 8 am along with 200 mg carbamazepine. Each treatment was separated by 2 days; subjects continued to receive carbamazepine therapy during the 2-day period. On both occasions, blood samples were collected at different time intervals between 0 to 8 hours. Carbamazepine levels were estimated by reversed-phase HPLC technique. RESULTS: Compared with water, grapefruit significantly increased the steady peak concentration (6.55 versus 9.20 microgram/mL), trough concentration (4.51 versus 6.28 microgram/mL), and area under the plasma concentration-time curve (43.99 versus 61.95 micrograms.h/mL) of carbamazepine. No significant effect was found in the time to reach peak plasma concentration. CONCLUSION: Grapefruit juice increases the bioavailability of carbamazepine by inhibiting CYP3A4 enzymes in gut wall and in the liver.     

Self-awareness, task failure, and disinhibition: how attentional focus affects eating

Prolonged continuous blood pressure (BP) and heart rate (HR) recordings from neonates of 35 to 42 weeks gestation were studied during and after ECMO. Data segments with significant deviation of BP were extracted for further analysis. The simultaneous changes in BP and HR were compared and the slope of the regression determined baroreflex sensitivity (BRS). Of 464 BP deviations, 98% produced curves with a negative slope consistent with the presence of a baroreflex. The average BRS was -1.0 +/- 0.8 bpm/mmHg (mean +/- S.D.) and curves were steeper during rising BP than falling BP (-1.1 +/- 0.9 beats/min per mmHg versus -0.9 +/- 0.6, P = 0.001). The baroreflex was more sensitive during ECMO than after ECMO to both rising BP (-1.0 +/- 0.5 beats/min per mmHg versus -0.7 +/- 0.5, P = 0.004) and falling BP (-1.0 +/- 0.6 beats/min/mmHg versus -0.7 +/- 0.5, P = 0.04). HR response curves obtained during different BP fluctuations on the same recording had varying threshold, consistent with acute resetting. One infant demonstrated chronic baroreceptor resetting over 3 days to a rise in resting BP. The near-term, critically ill neonate has an active baroreflex which is capable of resetting. ECMO was associated with accentuation of the baroreflex response.     

Grapefruit juice and the response to warfarin

The effect if any of prepared frozen grapefruit juice on prothrombin times (PTs) in patients undergoing stabilized warfarin therapy was studied. Patients receiving low-intensity warfarin therapy (targeted International Normalized Ratio [INR], 2-3) who had two consecutive baseline PTs within 10% of each other were recruited. Patients who regularly consumed grapefruit juice or alcohol or who were taking drugs known to interact with grapefruit juice were excluded. A one-week supply of freshly prepared frozen grapefruit juice in individual 8-oz containers was given to all the subjects, who were told to drink the entire contents of on container three times a day for one week. PTs were measured and INRs calculated on the day before grapefruit juice ingestion began (day 0) and a days 2, 6, and 8. Ten men (mean age, 66 years) were enrolled; one withdrew because of diarrhea. Compliance in consuming the juice was reported to range from 85.7% to 100% among patients. There was no significant difference among PT or INR values over the course of the study in any of the nine subjects. Ingestion of grapefruit juice prepared from frozen concentrate did not change PTs in patients treated with warfarin.     

Influence of grapefruit juice on caffeine pharmacokinetics and pharmacodynamics

The influence of grapefruit juice (GFJ) on caffeine's metabolism and the hemodynamic effects of this potential food interaction were studied in 10 normotensive volunteers. In this crossover study, caffeine (3.3 mg/kg) and water or caffeine and GFJ were given to participants. Nine serum caffeine concentrations were determined within 24 hours of each phase. In another phase of this study, caffeine was given with multiple GFJ doses to 6 of the 10 participants. Ambulatory blood pressure (BP) monitors were used for 12 hours to assess treatment hemodynamic effects. The mean area under the serum caffeine concentration-time curve (AUC0-infinity) values +/- SD for the caffeine with water group, caffeine with GFJ group, and caffeine with multiple GFJ group were 47.0 +/- 10.8, 48.7 +/- 15.2, and 49.6 +/- 7.0 micrograms/ml.hr, respectively (NS). There was no significant difference on the ambulatory systolic BP, diastolic BP, percentage of the time with a diastolic BP greater than 90 mm Hg, or heart rate area under the effect curves. We conclude that grapefruit juice had no effect on caffeine pharmacokinetics or hemodynamic effects.     

Intrapericardial delivery of L-arginine reduces the increased severity of ventricular arrhythmias during sympathetic stimulation in dogs with acute coronary occlusion: nitric oxide modulates sympathetic effects on ventricular electrophysiological properties

BACKGROUND: Nitric oxide (NO) modulates autonomic effects on myocardial contractility and sinus and atrioventricular nodal function of the heart. Whether NO influences autonomic actions on ventricular electrophysiological properties and arrhythmogenesis is not known. METHODS AND RESULTS: Four groups consisting of 43 autonomically denervated dogs were studied. To "superfuse" sympathetic nerves innervating the ventricles, test drugs were introduced into the pericardial sac for 30 minutes, and their effects on ventricular effective refractory period (ERP) and arrhythmia development were assessed before and during sympathetic stimulation (SS). In group 1 (n=12), ventricular ERPs showed no significant difference between control and superfusion with L-arginine, a NO precursor (222+/-20 versus 222+/-19 ms, P=.485). However, L-arginine significantly reduced SS-induced ERP shortening compared with control (9+/-7 versus 13+/-7 ms, P<.001). Simultaneous administration of N(G)-monomethyl-L-arginine (2 mg/mL) abolished the inhibitory effects of L-arginine (13+/-7 versus 13+/-7 ms, P=.885). In group 2 (n=15), the severity of ventricular arrhythmias significantly increased during SS. L-Arginine reduced this increase caused by SS. In group 3 (n=8), plasma norepinephrine spillover measured from the coronary sinus significantly increased during SS and was reduced by pericardial superfusion with L-arginine compared with control (6005.2+/-1525.6 versus 8503.4+/-2044.5 pg/min, P=.012). In group 4 (n=8), L-arginine pericardial superfusion significantly increased NO overflow measured from the coronary sinus during SS (93.25+/-59.20 versus 114.82+/-74.92 nmol/min, P=.043). CONCLUSIONS: Pericardial L-arginine reduces ERP shortening and increased severity of ischemic ventricular arrhythmias during SS in dogs. NO-induced reduction of norepinephrine release in the heart may be one of the underlying mechanisms.     

A comparison of a fluoroscopy-free mechanical targeting system and a free-hand technic for the placement of distal interlocking screws of tibial nails

Recently, radiation-independent aiming devices for the tibia which compensate for insertion-related implant deformation have been developed, but the benefits of such systems have not been determined. This study prospectively evaluated the duration of the nailing procedure, the length of radiation time, and the accuracy of interlocking screw placement with a radiation-independent distal aiming system and the free-hand technique. In an oblique cadaveric tibial fracture, a surgeon inexperienced with either technique performed a statically locked intramedullary nailing. For the aiming system and free-hand technique respectively, the total operation time was 25.4 +/- 11.3 vs 30.9 +/- 14.3 min (P = 0.029), the distal locking time was 16.7 +/- 8.6 vs 21.9 +/- 10.5 min (P = 0.004), the total fluoroscopy time was 9 +/- 5 vs 93 +/- 34 s (P < 0.0001), the distal locking fluoroscopy time was 0 versus 88 +/- 33 s (P < 0.0001), and the screw destruction was -0.7 +/- 5.2 vs 26.8 +/- 31.6 microns (P = 0.001). The failure rate was 1.6% (1 of 60 screws) in both groups. These results suggest that aiming devices can eliminate the need for radiation during distal interlocking screw placement.     

The character of inhibition of the metabolism of 1,2-benzopyrone (coumarin) by grapefruit juice in human

OBJECTIVE: Constituents of grapefruit juice are known to interfere with mammalian cytochrome P450 isozymes such as intestinal CYP3A4 and hepatic CYP2A6, lowering the biotransformation of drugs and increasing their bioavailability. The aim of this study was to investigate whether the presence of naringin is demanded for the inhibition of the coumarin 7-hydroxylase in man or other compounds are responsible for it. METHODS: In cross-over studies, doses of 10 mg coumarin, together with combinations of grapefruit juice, water and naringin, were given orally to one healthy male volunteer, We investigated increasing amounts of grapefruit juice, keeping the volume of liquid constant at 1 L; increasing doses of naringin given in water; increasing amounts of juice, keeping the dose of naringin constant; or increasing doses of naringin, keeping the amount of juice constant. Urine samples were collected up to 24 h after dosing and 7-hydroxycoumarin was quantified fluorimetrically in urine hydrolysates after HPLC separation to determine the excretion rates. RESULTS: While increasing amounts of grapefruit juice delay the excretion of 7-hydroxycoumarin by 2 h, increasing doses of naringin in water up to twofold (i.e. naringin content of 2 L grapefruit juice) do not cause any alteration in the time course of excretion. Experiments with increasing amounts of juice, keeping the dose of naringin constant, indicate that the inhibitory potency of small amounts of grapefruit juice can be amplified by naringin. The same is true when the ratio between juice constituents and naringin is enhanced up to threefold by adding naringin. CONCLUSION: As naringin alone is ineffective, the inhibitory effect of grapefruit juice on the metabolism of coumarin is caused by at least one compound other than naringin. The persistency of the primary inhibitor not identified yet can obviously be modulated by the naring(en)in-system.     

Drug interactions with grapefruit juice. Extent, probable mechanism and clinical relevance

Concomitant intake with grapefruit juice increases the concentrations of many drugs in humans. The effect seems to be mediated mainly by suppression of the cytochrome P450 enzyme CYP3A4 in the small intestine wall. This results in a diminished first pass metabolism with higher bioavailability and increased maximal plasma concentrations of substrates of this enzyme. The effect was most pronounced in drugs with a high first pass degradation and in many cases has the clear potential to reach clinical relevance, as shown by an occasional change in drug effects or tolerability. For felodipine, nitrendipine, nisoldipine and saquinavir, the interaction was most marked with median increases of area under the curve (AUC) and/or the maximum (peak) plasma drug concentration after single-dose administration (Cmax) values exceeding 70% of respective control periods. Less pronounced, but possibly relevant, concentration increases were found for nifedipine, nimodipine, verapamil, cyclosporin, midazolam, triazolam and terfenadine. This list is not complete because many drugs have not been studied yet. The components of grapefruit juice which are the most probable causes of the interactions are psoralen derivatives, but the flavonoid naringenin may also contribute. Concomitant grapefruit juice intake does not generally decrease the variability of drug pharmacokinetic parameters. Therefore, it is recommended that patients refrain from drinking grapefruit juice when they are taking a drug that is extensively metabolised, unless a lack of interaction has already been demonstrated for the drug. It is also recommended that drugs possibly interacting with grapefruit juice should be appropriately labelled. A place for grapefruit juice as a drug-sparing agent in treatment involving expensive medicine cannot be derived from the information currently available on grapefruit juice interactions.     

Inhibition of hypoxic pulmonary hypertension by heparins of differing in vitro antiproliferative potency

Heparin inhibits smooth-muscle cell (SMC) growth in vitro and inhibits the development of hypoxic pulmonary hypertension and vascular remodeling in vivo. We wondered whether preparations of heparin with different antiproliferative potency in vitro would differ in their ability to inhibit the development of hypoxic pulmonary hypertension in vivo. Two such heparins, a weakly antiproliferative lot of Elkins-Sinn (E-S) (% inhibition of SMC growth at 10 micrograms/ml = 13 +/- 9% [mean +/- SEM, n = 24]) and a more active lot from Upjohn (UJ) (% inhibition = 71 +/- 12% [n = 12, p < 0.05 versus E-S]), were infused subcutaneously (300 U.S.P. units/day; E-S 300 versus UJ 300) via an osmotic pump into guinea pigs exposed to hypoxia (10% O2) for 10 d, after which pulmonary artery pressure (PAP; mm Hg) and cardiac index (CI; ml/min/kg) were measured in room air. Hypoxic controls (HC) received saline. PAP increased from 11 +/- 1 mm Hg in normoxic controls (NC) (n = 5) to 24 +/- 1 mm Hg in HC (n = 8, p < 0.05). The PAP was lower in the E-S 300 (21 +/- 1; n = 7, p < 0.05 versus HC and NC) and even lower in the UJ 300-treated group (18 +/- 0.5; n = 7, p < 0.05 versus HC and NC). Total pulmonary vascular resistance (TPR; mm Hg/ml/min/kg) increased significantly from 0.038 +/- 0.002 in NC to 0.076 +/- 0.003 (p < 0.05) in HC. There was no difference in TPR between the HC and the E-S 300-treated group.(ABSTRACT TRUNCATED AT 250 WORDS)