Administration of wine and grape juice inhibits in vivo platelet activity and thrombosis in stenosed canine coronary arteries

BACKGROUND: Moderate daily consumption of alcoholic beverages is a negative risk factor for the development of atherosclerosis and coronary artery disease (CAD), especially in France and other Mediterranean areas where red wine is regularly consumed with meals. Platelets contribute to the development of atherosclerosis, CAD, and acute arterial thrombus formation. METHODS AND RESULTS: Anesthetized dogs were prepared with the Folts model of mechanically stenosed coronary arteries and intimal damage. Periodic acute platelet-mediated thrombus formation occurred, causing cyclic flow reductions (CFRs) in coronary blood flow. The CFRs were eliminated by the administration of 1.62 +/- 1.12 mL/kg red wine intravenously (IV) and 4.0 mL/kg intragastrically (IG). The CFRs were abolished by 2.04 +/- 1.42 mL/kg of grape juice IV and 10 mL/kg IG. White wine did not have significant results in eliminating the CFRs, either IV (2.0 mL/kg) or IG (4.0 mL/kg), decreasing the slopes of the CFRs only slightly. CONCLUSIONS: Pure ethanol has been shown to inhibit platelet aggregation in vitro, ex vivo, and in vivo, although a blood alcohol content (BAC) of > or = 0.2 g/dL is usually required. The BAC of dogs administered the red wine-saline solution intravenously was 0.028 g/dL, much less than is usually necessary for platelet inhibition with pure ethanol. Because red wine and grape juice, but not white wine, abolished the CFRs, this suggests there are compounds present in red wine and grape juice that are not present or are present in a lower concentration in white wine. Wine and grape juice contain a wide variety of naturally occurring compounds, including fungicides, tannins, anthocyanins, and phenolic flavonoids (including flavonols and flavones). These compounds have shown platelet inhibition in vitro by a variety of proposed mechanisms. Perhaps the biological activity of these compounds can explain the platelet-inhibitory properties of red wine and grape juice that are observed without high levels of ethanol.     

Inhibition of human breast cancer cell proliferation and delay of mammary tumorigenesis by flavonoids and citrus juices

Two citrus flavonoids, hesperetin and naringenin, found in oranges and grapefruit, respectively, and four noncitrus flavonoids, baicalein, galangin, genistein, and quercetin, were tested singly and in one-to-one combinations for their effects on proliferation and growth of a human breast carcinoma cell line, MDA-MB-435. The concentration at which cell proliferation was inhibited by 50% (IC50), based on incorporation of [3H]thymidine, varied from 5.9 to 140 micrograms/ml for the single flavonoids, with the most potent being baicalein. IC50 values for the one-to-one combinations ranged from 4.7 micrograms/ml (quercetin + hesperetin, quercetin + naringenin) to 22.5 micrograms/ml (naringenin + hesperetin). All the flavonoids showed low cytotoxicity (> 500 micrograms/ml for 50% cell death). Naringenin is present in grapefruit mainly as its glycosylated form, naringin. These compounds, as well as grapefruit and orange juice concentrates, were tested for their ability to inhibit development of mammary tumors induced by 7,12-dimethylbenz[a]anthracene (DMBA) in female Sprague-Dawley rats. Two experiments were conducted in which groups of 21 rats were fed a semipurified diet containing 5% corn oil and were given a 5-mg dose of DMBA intragastrically at approximately 50 days of age while in diestrus. One week later, individual groups were given double-strength grapefruit juice or orange juice or fed naringin or naringenin at levels comparable to that provided by the grapefruit juice; in the second experiment, the rats were fed a semipurified diet containing 20% corn oil at that time. As expected, rats fed the high-fat diet developed more tumors than rats fed the low-fat diet, but in both experiments tumor development was delayed in the groups given orange juice or fed the naringin-supplemented diet compared with the other three groups. Although tumor incidence and tumor burden (grams of tumor/rat) were somewhat variable in the different groups, rats given orange juice had a smaller tumor burden than controls, although they grew better than any of the other groups. These experiments provide evidence of anticancer properties of orange juice and indicate that citrus flavonoids are effective inhibitors of human breast cancer cell proliferation in vitro, especially when paired with quercetin, which is widely distributed in other foods.     

Effect of grapefruit juice on clarithromycin pharmacokinetics

To investigate whether grapefruit juice inhibits the metabolism of clarithromycin, 12 healthy subjects were given water or grapefruit juice before and after a clarithromycin dose of 500 mg in a randomized crossover study. Administration of grapefruit juice increased the time to peak concentration of both clarithromycin (82 +/- 35 versus 148 +/- 83 min; P = 0.02) and 14-hydroxyclarithromycin (84 +/- 38 min versus 173 +/- 85; P = 0.01) but did not affect other pharmacokinetic parameters.     

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.     

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.     

Interstitial pregnancy and management with a single systemic administration of methotrexate

OBJECTIVE: To examine the effect of grapefruit juice on the disposition of oral administered itraconazole in healthy subjects. METHODS: Twenty-two healthy male subjects received a single 100 mg dose of itraconazole with either 350 ml grapefruit juice, orange juice or mineral water. Plasma concentrations of itraconazole were measured by HPLC, and pharmacokinetic parameters; Cmax, Tmax, T1/2, AUC, and AUC corrected by human body surface area: AUC/S, were calculated. RESULTS: Grapefruit juice had no effect on any pharmacokinetic parameter of itraconazole. However, T1/2, AUC, or AUC/S were significantly decreased in orange juice treatment group compared to those in mineral water group (average decrease 56%, p < 0.01, 41%, p < 0.05, and 43%, p < 0.05, respectively). CONCLUSION: Coadministration of grapefruit juice did not affect any pharmacokinetic parameter of itraconazole while that of orange juice decreased the parameters of T1/2, AUC, and AUC/S of the drug.     

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.     

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.     

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.     

Novel variants of voltage-operated calcium channel alpha 1-subunit transcripts in a rat liver-derived cell line: deletion in the IVS4 voltage sensing region

To assess the usefulness of adenosine triphosphate (ATP) as an alternative agent for functional determination of coronary circulation in children and to reveal the dose-response kinetics of intracoronary ATP, systemic hemodynamics and spectral coronary flow velocity dynamics using Doppler guide wire were measured during hyperemic responses to an intracoronary bolus injection of ATP (0.01 microgram/kg, 0.1 microgram/kg and 1.0 microgram/kg) in consecutive 40 Kawasaki disease patients (age: 8.4 +/- 5.1 years, 30 boys and 10 girls) without angiographic coronary lesions. ATP did not produce any significant change in heart rate, systolic blood pressure and mean blood pressure, but mildly decreased diastolic blood pressure. The coronary flow reserve (CFR) calculated as a ratio of hyperemic to basal averaged peak velocity (APV) for ATP was 2.05 +/- 0.31, 2.26 +/- 0.38 and 2.50 +/- 0.51 in LAD, and 2.24 +/- 0.28, 2.44 +/- 0.41 and 2.60 +/- 0.47 in RCA, respectively, for each of the three doses. There was no statistical significance between the mean values of CFR in LAD with ATP (1.0 microgram/kg: 2.39 +/- 0.16) and papaverine (0.15 microgram/kg: 2.43 +/- 0.16) in six patients without angiographic coronary lesions. The maximal coronary hyperemia was reached rapidly after intracoronary bolus injection of ATP in all doses (10, 10-15 and 15-20 seconds in both LAD and RCA, respectively, for each of the three doses). The time required for APV to return to basal levels (< T10%) increased with the dose of ATP (30, 55 and 110 seconds in LAD and 35, 45 and 100 seconds in RCA, respectively, for each of the three doses). Three patients (3/40: 7.5%) developed transient (< 5 seconds) asymptomatic second degree atrioventricular block, but no patient had clinically significant arrhythmias. The change ratio in QTc interval after ATP injection was 1.96 +/- 1.87% (not significant). In addition, an intracoronary injection of ATP did not increase the absolute angiographic coronary luminal diameter. This study indicates that ATP is a safe alternative agent for pharmacological induction of coronary hyperemia for evaluation of coronary stenotic lesions and for the study of coronary circulation and coronary flow reserve in children.     

The in vivo pharmacological profile of the novel glycoprotein IIb/IIIa antagonist, SK&F 106760

The in vivo pharmacological profile of SK&F 106760 [N alpha-acetyl-cyclo(S,S)-cysteinyl-N alpha-methylarginyl-glycyl-aspartyl-penicillamine-amide], a novel, potent glycoprotein IIb/IIIa (GPIIb/IIIa) antagonist has been investigated. In conscious dogs, SK&F 106760 (0.3-3 mg/kg i.v.) produced a dose-related inhibition of ex vivo whole blood platelet aggregation induced by collagen (5 micrograms/ml) with complete inhibition being produced for 5, 90 and 165 min after administration of 0.3, 1 and 3 mg/kg i.v., respectively. Plasma levels of SK&F 106760 were measured by high-performance liquid chromatography after i.v. bolus administration of 1 mg/kg. An initial alpha-disposition phase with a T1/2 of 11 +/- 6 min was followed by a longer terminal beta-elimination phase with a T1/2 of 66 +/- 12 min, which accounted for 79 +/- 9% of the total area under the plasma concentration-time curve. The apparent steady-state volume of distribution was 259 +/- 26 ml/kg and the plasma clearance was 3.4 +/- 0.8 ml/min/kg. The plasma concentration of SK&F 106760 at which collagen-induced ex vivo whole blood aggregation was inhibited by 50% was estimated to be 593 +/- 52 nM. After intraduodenal and intrajejunal administration of 3 mg/kg, SK&F 106760 had a bioavailability of 3 to 6% and produced a peak inhibition of ex vivo platelet aggregation of 40 to 50%. In anesthetized dogs, SK&F 106760 (0.3-3.0 mg/kg i.v.) produced a complete inhibition of platelet-dependent coronary artery thrombosis, with a dose-related duration of action.(ABSTRACT TRUNCATED AT 250 WORDS)     

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.     

Effective Rotation-Vibration Parameters for the nu8 and nu4 + nu12 Bands of Ethane

BACKGROUND: Epidemiologic studies suggest that foods rich in flavonoids might reduce the risk of cardiovascular disease. OBJECTIVE: Our objective was to investigate the effect of intake of flavonoid-containing black currant and apple juice on urinary excretion of quercetin and on markers of oxidative status. DESIGN: This was a crossover study with 3 doses of juice (750, 1000, and 1500 mL) consumed for 1 wk by 4 women and 1 man corresponding to an intake of 4.8, 6.4, and 9.6 mg quercetin/d. RESULTS: Urinary excretion of quercetin increased significantly with dose and with time. The fraction excreted in urine was 0.29-0.47%. Plasma quercetin did not change with juice intervention. Plasma ascorbate increased during intervention because of the ascorbate in the juice. Total plasma malondialdehyde decreased with time during the 1500-mL juice intervention, indicating reduced lipid oxidation in plasma. Plasma 2-amino-adipic semialdehyde residues increased with time and dose, indicating a prooxidant effect of the juice, whereas erythrocyte 2-aminoadipic semialdehyde and gamma-glutamyl semialdehyde concentrations, Trolox-equivalent antioxidant capacity, and ferric reducing ability of plasma did not change. Glutathione peroxidase activity increased significantly with juice dose. CONCLUSIONS: Urinary excretion of quercetin seemed to be a small but constant function of quercetin intake. Short-term, high intake of black currant and apple juices had a prooxidant effect on plasma proteins and increased glutathione peroxidase activity, whereas lipid oxidation in plasma seemed to decrease. These effects might be related to several components of the juice and cannot be attributed solely to its quercetin content.     

Delayed response of myocardial flow reserve to lipid-lowering therapy with fluvastatin

BACKGROUND: Lipid-lowering therapy can improve endothelial function in patients with coronary artery disease (CAD) and hypercholesterolemia. Little is known about induced changes in myocardial microcirculation. This study prospectively investigated the temporal effects of lipid-lowering therapy with fluvastatin on coronary flow and flow reserve (CFR) in patients with CAD assessed by PET. METHODS AND RESULTS: In an open clinical trial, CFR was studied in 15 patients with angiographically documented multivessel CAD and hypercholesterolemia (LDL >160 mg/dL). Dynamic 13N-labeled ammonia PET imaging in conjunction with adenosine was used to assess regional and global CFR at baseline as well as at 2 and 6 months during treatment with fluvastatin (60 to 80 mg/d). Despite a rapid decrease in total cholesterol (29+/-6%) and LDL (37+/-9%), myocardial blood flow at rest and during stress was unchanged after 2 months of treatment (2.7+/-0.9 versus 2.5+/-0.6 mL x g-1 x min-1). At 6 months, stress blood flow as well as CFR increased significantly (3.4+/-1.0 mL x g-1 x min-1). No change in hemodynamic parameters was noted during the entire study. Nine of 15 patients increased CFR by >20%. All responders demonstrated improvement in anginal symptoms, whereas nonresponders stated no change (n=4) or worsening of symptoms (n=2). The improvement in CFR was not related to the amount of lipid lowering and was independent of the severity of stenoses. CONCLUSIONS: Improvement in stress blood flow and CFR is delayed compared with the lipid-lowering effect of fluvastatin, suggesting a slow recovery of the vasodilatory response to adenosine.     

Inhibition of growth and aflatoxin production of Aspergillus parasiticus by citrus oils

Aspergillus parasiticus was inoculated into grapefruit juice and a glucose-yeast extract medium; both contained 500-7000 ppm of citrus oils that were incorporated into the media by sonication. Orange and lemon oil were more inhibitory to mold growth and aflatoxin production than was dlimonene, the main constituent of the two peel oils. After 7 days at 28 degrees C, 2000 ppm of lemon and 3000 ppm of orange oil in grapefruit juice afforded maximum suppression of mold growth and toxin formation. When the glucose-yeast extract medium was used, 3000 ppm of either oil were needed to achieve the same result. After 4 days at 28 degrees C, orange oil at 3500 ppm in either medium markedly inhibited mold growth (as evidenced by dry weight of mold mycelium) and aflatoxin production (only 14 and 1% of the amount normally produced in the juice and artificial medium, respectively). Higher concentrations of orange oil further reduced mold growth and aflatoxin production and also delayed the onset of sporulation, if it occurred. Although aflatoxin was detected in all samples, only 0.2 to 0.5% of the amount found in controls (without the citrus oil) was present when the medium contained 7000 ppm orange oil. The mold consistently grew, albeit very poorly, on the glass at the liquid-atmosphere interface even when the substrate contained a large amount of citrus oil.     

Reduced coronary flow reserve in familial hypercholesterolemia

Familial hypercholesterolemia (FH) presents the highest risk for coronary artery disease (CAD) among patients with hyperlipidemia. Therefore, early detection of coronary arterial atherosclerosis is important for the treatment of FH patients. The aim of this study was to detect early coronary arterial abnormalities that may relate to future atherosclerosis in asymptomatic FH patients by measuring coronary flow reserve (CFR) using PET and 13N-ammonia. METHODS: Twenty-five patients with FH (14 men, 11 women) without a history of myocardial ischemia and 14 control subjects (9 men, 5 women) were studied. Total serum cholesterol (mmole/liter) was 5.33 +/- 0.66 in control subjects and 7.90 +/- 0.77 in FH patients (p < 0.01 versus control subjects). RESULTS: Myocardial blood flow (MBF) at rest and during dipyridamole loading was measured using PET, and CFR was calculated. MBF (ml/min/100 g weight heart) at rest in the FH group (79.0 +/- 20.0) was comparable to that in control subjects (70.0 +/- 17.0). However, MBF during dipyridamole loading was significantly lower in FH patients (163.0 +/- 67.0) than in control subjects (286.0 +/- 120.0, p < 0.01). CFR in FH patients (2.09 +/- 0.62) was also significantly lower than that in control subjects (4.13 +/- 1.38, p < 0.01). CFR showed a gender-specific variance in FH patients (1.85 +/- 0.40 in men versus 2.55 +/- 0.74 in women p < 0.05) but not in control subjects. Significant inverse correlations between CFR and the total plasma cholesterol level as well as plasma LDL cholesterol were observed. CONCLUSION: The CFR was reduced in patients with FH. This abnormality was more prominent in men than in women patients. Noninvasive assessment of CFR by 13N-ammonia PET was useful to detect early abnormalities of the coronary arteries in asymptomatic patients with FH.     

Human platelet Ca2+ mobilization, glycoprotein IIb/IIIa activation, and experimental coronary thrombosis in vivo in dogs are all inhibited by the inotropic agent amrinone

BACKGROUND: Inotropic drugs are often used to treat acute, severe heart failure resulting from acute myocardial infarction and other unstable coronary artery syndromes. However, catecholamine inotropic agents may potentiate coronary thrombosis via a platelet alpha2-adrenergic mechanism, thus exacerbating the original problem. The present studies were designed to determine whether the nonadrenergic inotropic and vasodilator drug amrinone, which elevates platelet cAMP levels, would both inhibit human platelet Ca2+ mobilization and adhesion molecule expression ex vivo and protect against experimental coronary thrombosis in vivo in dogs. METHODS AND RESULTS: Human platelets in suspension were preincubated with amrinone 2.5 to 15 microg/mL; stimulated with the agonists thrombin 0.1 U/mL, ADP 10(-6) mol/L, or arginine vasopressin 10(7) mol/L; and studied for Ca2+ mobilization, glycoprotein IIb/IIIa activation, and P-selectin expression by fluorescent flow cytometry methods. Experimental coronary thrombosis in vivo was studied in an open-chest dog model with critical coronary artery stenosis and deep vessel wall injury. Results showed that at the cellular level, amrinone inhibited agonist-induced Ca2+ mobilization and had modest inhibitory effects on adhesion molecule expression. In vivo in dogs, intravenous amrinone 2 mg/kg plus infusion at 20 microg x kg(1) x min(-1) completely abolished coronary thrombosis. CONCLUSIONS: The fact that amrinone inhibited human platelet activation at the cellular level and protected against experimental coronary thrombosis in vivo in dogs suggests a potentially advantageous antithrombotic action for this inotropic and vasodilator drug.     

Stability of ramipril in water, apple juice, and applesauce

The stability of ramipril in water, in apple juice, and in applesauce was studied. The contents of a single capsule each of ramipril 1.25, 2.5, and 5 mg were mixed in glass beakers with 120 mL of deionized and filtered water, apple juice, or applesauce. Each mixture was apportioned into 10 120-mL amber polyethylene terephthalate (PET) containers. Five of the containers in each set were stored at 23 degrees C, and samples were taken at 0, 1, 2, 6, 12, and 24 hours. The other five containers were stored at 3 degrees C, and samples were taken at 4, 8, 12, 24, and 48 hours. The samples were analyzed for ramipril concentration by stability-indicating high-performance liquid chromatography (HPLC). The quantity of drug remaining in the PET container after "administration" was determined by mixing the contents of single 5-mg ramipril capsules with 60 mL of apple juice, pouring the mixture into a waste receptacle, rinsing the PET container three separate times with 10 mL of water, and analyzing the pooled fluid from these rinses for ramipril concentration by HPLC. Under no condition did the percentage of ramipril remaining drop below 90%. No peaks for degradation products appeared in the chromatograms. The mean +/- S.D. quantity of ramipril remaining in the PET containers after draining was 0.3 +/- 0.3% for the apple juice. Ramipril from 1.25-, 2.5-, and 5-mg capsules mixed in water, in apple juice, and in applesauce was stable for 24 hours at 23 degrees C and for 48 hours at 3 degrees C.     

Antithrombotic effects of MK-0852, a platelet fibrinogen receptor antagonist, in canine models of thrombosis

The antiaggregatory and antithrombotic actions of MK-0852, a cyclic heptapeptide antagonist of the platelet GP IIb/IIIa, were evaluated in a variety of canine models. In vitro, MK-0852 inhibited the aggregation of canine platelet-rich plasma induced by 10 microM ADP in the presence of 1 microM epinephrine with an IC50 value of 0.10 microM. The i.v. infusion of 1.0 and 3.0 micrograms/kg/min MK-0852 to anesthetized dogs significantly inhibited ex vivo platelet aggregation responses to ADP and collagen, with the 3.0 micrograms/kg/min infusion completely inhibiting ex vivo aggregation responses to both agonists. The i.v. administrations of 100 and 300 micrograms/kg MK-0852 suppressed platelet-dependent cyclic flow reductions in stenosed canine left circumflex (LCX) coronary artery for periods of 24 +/- 3 and 64 +/- 4 min, respectively. In a canine model of copper coil-induced femoral arterial thrombosis, i.v. MK-0852 (100 micrograms/kg + 1 microgram/kg/min), initiated 15 min before coil placement, reduced the incidence of occlusive thrombosis during the 45-min post-coil time period of continued therapy (1/5 MK-0852 vs. 7/7 saline; P < .01). MK-0852 was administered as an adjunctive therapy with tPA to evaluate its effects on thrombolysis after copper coil-induced femoral arterial thrombus formation. MK-0852 (i.v.; 100 micrograms/kg + 1 microgram/kg/min), initiated 15 min before tPA, reduced the incidence of post-thrombolysis reocclusion. During the 60-min period of continued drug infusion after the termination of tPA, 0 of 5 animals receiving MK-0852 reoccluded vs. 7/8 saline (P < .01). In a canine model of electrically induced LCX coronary artery thrombosis, i.v. MK-0852 (100 micrograms/kg + 3 micrograms/kg/min), initiated 15 min before the initiation of electrical injury, prevented occlusive thrombosis in 4 of 6 preparations despite the continued electrical stimulation of the vessel for 180 min. Thrombotic occlusion was delayed in the remaining two preparations (99 and 100 min), compared with occlusion in 4 of 4 saline-treated preparations (69.3 +/- 6.3 min). When administered as an adjunct to thrombolytic agents for lysis of electrically induced LCX coronary artery thrombi, i.v. MK-0852 (300 micrograms/kg + 3 micrograms/kg/min), initiated 15 min before tPA or streptokinase, both increased the incidence of reperfusion (tPA: 8/8 MK-0852 vs. 3/8 saline; streptokinase: 5/8 MK-0852 vs. 2/8 saline) and accelerated reperfusion. The incidence of reocclusion during continued adjunctive therapy was reduced.(ABSTRACT TRUNCATED AT 400 WORDS)     

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.