Grapefruit juice and drugs. How significant is the interaction?
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Beverages↗
Biomedical subjects
D G Bailey
Publications and source records attributed to D G Bailey.
Effect of grapefruit juice and naringin on nisoldipine pharmacokinetics.
The bioavailability of some dihydropyridine calcium antagonists can be markedly augmented by grapefruit juice and may involve the bioflavonoid naringin. The pharmacokinetics of nisoldipine coat-core tablet were studied in a Latin square-designed trial in which 12 healthy men were administered the drug with water, grapefruit juice, or encapsulated naringin powder at the same amount as that assayed in the juice. Compared with water, grapefruit juice increased the maximum concentration of nisoldipine to 406% +/- 73% (mean +/- SEM; range, 107% to 836%; p < 0.001), increased the area under the plasma concentration-time curve to 198% +/- 46% (range, 81% to 682%; p < 0.001), and reduced time to reach maximum nisoldipine concentration to 58% +/- 9% (range, 13% to 100%; p < 0.01), probably by inhibition of presystemic metabolism and possibly by enhancement of drug dissolution. The interaction could not be predicted from baseline pharmacokinetics with water and resulted in greater interindividual variability. The naringin capsule did not change nisoldipine pharmacokinetics. All treatments produced minor effects on supine blood pressure and heart rate, probably because subjects were normotensive. Current information supports the cautioning of patients about concomitant ingestion of grapefruit juice and nisoldipine.
Adolescent↗
Quinidine interaction with nifedipine and felodipine: pharmacokinetic and pharmacodynamic evaluation.
Conflicting findings suggest that serum quinidine concentrations may be decreased or increased by nifedipine. We performed a double-blind, placebo-controlled trial of Latin-square design. Twelve healthy men received 3 days of pretreatment with nifedipine prolonged action (20 mg twice a day) or felodipine extended release (10 mg every day), another dihydropyridine calcium antagonist, followed by coadministration of quinidine (400 mg). Quinidine pharmacokinetics were not changed by either dihydropyridine. However, 3-hydroxyquinidine area under the concentration-time curve (AUC) and 3-hydroxyquinidine/quinidine AUC ratio were decreased by felodipine, consistent with reduced metabolite formation. Heart rates and adverse events were higher with felodipine, demonstrating lack of bioequivalence with nifedipine. The QTc interval did not deviate from that expected for the observed quinidine concentration, suggesting the pharmacokinetics of active quinidine metabolites were not markedly altered among treatments. Quinidine disposition did not appear to be changed sufficiently to be clinically important by sustained-release nifedipine and felodipine.
Adolescent↗
Grapefruit juice--felodipine interaction: mechanism, predictability, and effect of naringin.
Grapefruit juice produces a marked and variable increase in felodipine bioavailability. The pharmacokinetics of felodipine and its single primary oxidative metabolite, dehydrofelodipine, were studied after drug administration with 200 ml water, grapefruit juice, or naringin in water at the same concentration as the juice in a randomized crossover trial of nine healthy men. With grapefruit juice, mean +/- SEM felodipine area under the plasma concentration-time curve (AUC) and peak plasma concentration (Cmax) were 206% +/- 23% (range, 123% to 330%, p < 0.01) and 170% +/- 24% (range, 127% to 310%, p < 0.02), respectively, compared with water. Dehydrofelodipine/felodipine ratios for AUC (1.5 +/- 0.2 versus 2.2 +/- 0.2, p < 0.001) and felodipine Cmax (1.5 +/- 0.2 versus 2.2 +/- 0.2, p < 0.001) were reduced, consistent with inhibition of presystemic felodipine metabolism. Intersubject changes in felodipine and dehydrofelodipine AUC supported inhibition of both primary and secondary metabolic steps as a mechanism. The interaction could not be predicted from baseline pharmacokinetics with water and did not result in more consistent bioavailability among individuals. Naringin solution produced much less of an interaction, showing that other factors were important.
Adult↗
Interaction of citrus juices with felodipine and nifedipine.
Six men with borderline hypertension took felodipine 5 mg with water, grapefruit juice, or orange juice. The mean felodipine bioavailability with grapefruit juice was 284 (range 164-469)% of that with water. The dehydrofelodipine/felodipine AUC ratio was lower, diastolic blood pressure lower, and heart rate higher with grapefruit juice than with water. Vasodilatation-related side-effects were more frequent. Orange juice had no such effects. Six healthy men took nifedipine 10 mg with water or grapefruit juice; the bioavailability with grapefruit juice was 134 (108-169)% of that with water.
Biological Availability↗
Interaction between oral verapamil and beta-blockers during submaximal exercise: relevance of ancillary properties.
The interaction between verapamil and beta-blockers may involve negative chronotropic, inotropic, and dromotropic effects. Three randomized, double-blind, crossover trials evaluated standardized submaximal exercise hemodynamics after oral verapamil (120 mg) and beta-blocker, alone and in combination, in groups of eight healthy men. The beta-blockers were propranolol (80 mg), metoprolol (100 mg), and pindolol (5 mg). During submaximal exercise, each beta-blocker produced similar reductions in heart rate. Likewise, each verapamil and beta-blocker combination caused greater decreases in heart rate and prolongation of PR interval than did either drug alone. Only the verapamil and propranolol combination produced greater reduction of systolic blood pressure and prolongation of rate-adjusted PR interval. All verapamil and beta-blocker combinations caused frequent adverse events, predominantly exercise fatigue and resting first-degree heart block. Although the verapamil and metoprolol or pindolol combinations produced lesser negative dromotropic or inotropic effects compared with verapamil and propranolol, coadministration of verapamil and any beta-blocker should be performed cautiously.
Administration, Oral↗
Factors influencing difficulty of removing pelts from lamb carcasses.
Forty-eight Suffolk x white-faced ram and wether lambs approximately 5, 7, or 9 mo of age were slaughtered to evaluate the effects of age and gender on difficulty of pelt removal, pelt damage, and leg damage. A commercial belt-type pelt puller and a scale that recorded force required to remove the pelt from the thickest part of the legs was used as lambs hung suspended from their front legs. Rams required more force (P less than .05) to remove the pelt than wethers, and the difference between genders became larger as age increased. Neither pelt damage due to grain crack nor leg damage judged by amount of fell and fat removed by the pelt puller changed with age. Rams possessed thicker pelts (P less than .05) than wethers; this plus a greater amount of collagen crosslinking in ram skins could be responsible for the slightly smaller amount of grain crack observed in ram pelts. Factors involved in difficulty of pelt removal in ram lambs included age, splenius weight, and overall maturity. Difficulty of pelt removal in wether lambs was best predicted by including age and splenius weight in the model. These data tend to support packers' common practice of discounting rams over 5 mo of age because rams develop masculine characteristics and become harder to dress with increasing age.
Age Factors↗
Effects of age, castration, and season on difficulty of pelt removal in lambs.
Sixty-four white-faced rams and wethers were dressed with the aid of a commercial pelt puller. The effects of age, castration, and season on difficulty of pelt removal and pelt damage were evaluated. Lambs were divided into two age groups (5 and 12 mo) within gender (ram and whether) and season (spring and fall). A greater force (P less than .05) was required to remove pelts from rams than from wethers in both 5- and 12-mo-old groups. Older lambs slaughtered in the fall required more force (P less than .05) to remove their pelts than did those slaughtered in the spring, but differences by season did not exist for 5-mo-old lambs. The difference between rams and wethers in percentage of live weight that was closely shorn pelt weight was not significant (P greater than .05). The area of grain crack in the flank expressed as a percentage of total area of the skin was lower (P less than .05) for skins from 5-mo-old lambs and ram lambs than it was for skins from 12-mo-old lambs and wether lambs, respectively. Factors involved in difficulty of pelt removal in ram lambs included crosscut shoulder weight, fat firmness, and carcass weight. Difficulty of pelt removal in wether lambs was best predicted by including crosscut shoulder weight and bodywall thickness in multiple regression equations.
Age Factors↗
Impact of a pharmacist on the educational value of pharmaceutical industry film showings.
A controlled trial was performed to assess the impact of drug information provided by a pharmacist on the educational value to physicians of pharmaceutical manufacturers' film showings. The trial consisted of two teams of physicians who attended pharmaceutical manufacturers' films and who afterward answered multiple choice questions on the drug being promoted. In one group, the liaison pharmacist, who had no knowledge of the content of the questionnaire, presented information on the drug being featured prior to the film showing while the control group did not have a pharmacist presentation. Out of a perfect score of five, there was a higher test score in the group of physicians who attended the pharmacist presentation/film showing (n = 75) than in the group which only attended the film (n = 65) (3.3 +/- 1.1 versus 2.8 +/- 1.2, respectively (p = 0.017)). While there was no difference in the scores obtained by the clerks, interns and residents (3.2 +/- 1.1, 3.3 +/- 0.9, 3.4 +/- 1.2 respectively) when a pharmacist was present, in his or her absence the scores for clerks, interns and residents were 2.5 +/- 1.3, 2.8 +/- 1.0, 3.6 +/- 1.2 respectively with residents scoring higher than clerks (p = 0.047). A pharmacist can enhance the educational value of a pharmaceutical manufacturer's film showing.
Attitude of Health Personnel↗
Synergistic adverse hemodynamic interaction between oral verapamil and propranolol.
The interaction between oral verapamil and propranolol may involve negative chronotropic, inotropic or dromotropic effects. The immediate effects of orally administered verapamil (120 mg) and propranolol (80 mg), alone and combined, on submaximal exercise hemodynamics and on pharmacokinetics were studied in eight healthy male volunteers in a randomized, double-blind, crossover manner. Maximum effects on heart rate, systolic blood pressure, PR interval and rate-adjusted PR prolongation were greatest with the combined administration of verapamil and propranolol. The combination caused a high frequency of adverse drug events, predominantly exercise fatigue. Verapamil increased the AUC and Cmax and shortened the tmax of propranolol. Propranolol decreased the AUC and Cmax of verapamil. The greater reduction of heart rate with the combination of verapamil and propranolol was only partially explained by higher plasma concentrations of propranolol. The combination of propranolol and verapamil produced clinically important synergistic adverse effects during exercise. Negative dromotropic effects occurred primarily by direct AV node inhibition and were more important than previously recognized.
Administration, Oral↗
Ethanol enhances the hemodynamic effects of felodipine.
The acute hemodynamic and pharmacokinetic interactions between the vasodilating/diuretic drugs ethanol and felodipine, a 1,4-dihydropyridine calcium entry blocker, were assessed in 10 patients with untreated borderline hypertension. A non-intoxicating dose of ethanol or placebo was administered in a randomized, crossover, double-blind manner followed by felodipine 5 mg. Maximum hemodynamic effects occurred at four hours. Felodipine plus ethanol decreased mean (+/- SE) supine total peripheral resistance (13 +/- 2 vs 17 +/- 2 mmHg/L/min, p = 0.05) and diastolic blood pressure (68 +/- 3 vs 75 +/- 2 mmHg, p less than 0.05) associated with increased heart rate (72 +/- 3 vs 67 +/- 2 bpm, p less than 0.05) and cardiac index (3.7 +/- 0.4 vs 3.0 +/- 0.3 L/min/m2, p less than 0.05) more than felodipine alone. Greater differences were apparent in standing blood pressure. Co-administration of ethanol decreased standing systolic (113 +/- 8 vs 126 +/- 5 mmHg, p less than 0.01) and diastolic (69 +/- 5 vs 82 +/- 3 mmHg, p less than 0.01) blood pressure to a greater degree, but heart rate was not altered (87 +/- 6 vs 84 +/- 3 bpm). Substantial four hour diuresis occurred with both treatments (807 +/- 126 vs 806 +/- 169 ml). Adverse effects were frequent but most often occurred with felodipine plus ethanol (17 vs 11) as a result of postural lightheadedness (5 vs 1) related to hypotension. Felodipine bioavailability was not influenced by ethanol. However felodipine plasma concentrations greatly exceeded the expected concentrations, possibly due to a pharmacokinetic interaction with the grapefruit juice vehicle. Ethanol can enhance felodipine hemodynamics to produce clinically relevant adverse effects.
Adult↗
Effect of indomethacin on the pharmacokinetics and pharmacodynamics of felodipine.
1. We studied the effects of pre-treatment with oral indomethacin (25 mg four times daily for 3 days) on the pharmacokinetics, haemodynamics and diuretic properties of oral felodipine (10 mg single dose) in 12 healthy male volunteers using a placebo controlled double-blind four-way crossover protocol. 2. Felodipine with or without indomethacin pretreatment reduced standing diastolic blood pressure (P less than 0.001) at 0.5 to 3.0 h after dosing compared with placebo or indomethacin alone. Systolic blood pressures during indomethacin treatment alone were consistently higher than the other three treatment groups (P less than 0.01), presumably due to sodium and fluid retention. 3. Felodipine and felodipine plus indomethacin produced significantly greater excretion of urine and urinary sodium, but not of urinary potassium or creatinine when compared with placebo (P less than 0.01) over an 8 h period. 4. The pharmacokinetic parameters of felodipine (Cmax, tmax, t1/2 and AUC), the concentration-response curves for blood pressure lowering effects, the reflex tachycardia, diuretic properties and side-effects profile of felodipine were not significantly altered by indomethacin pretreatment in normal volunteers.
Adult↗
Tolerance and cardiovascular effects of single dose felodipine/beta-blocker combinations in healthy subjects.
The effects of single oral doses of 10 mg felodipine and four beta-blockers (100 mg metoprolol, 5 mg pindolol, 80 mg propranolol, and 10 mg timolol) were evaluated alone and in combination in a 10-way crossover, double-blind, placebo-controlled trial in 10 healthy male volunteers randomized to the medication sequence according to a latin square design. Adverse effects were recorded from spontaneous complaints and investigator observations. Heart rate (HR), PR interval, systolic blood pressure (SBP), and diastolic blood pressure (DBP) were measured supine, standing, and after treadmill exercise, before and 2 h after drug administration. The adverse effects experienced with felodipine were as expected for a vasodilator. Seven subjects mentioned complaints voluntarily on the combinations while three experienced side effects receiving felodipine or beta-blocker alone. Felodipine increased resting HR significantly. Timolol produced a greater depression of exercise heart rate than the other beta-blockers, indicating that the dose given was not equivalent to that of the other beta-blockers. Pindolol was ineffective in preventing the increase in supine HR produced by felodipine. Felodipine did not alter PR interval at any level of activity, but rate-corrected supine PR interval was prolonged slightly by felodipine. Metoprolol and timolol significantly prolonged standing PR interval. All beta-blockers prolonged exercise PR interval. Felodipine/beta-blocker combinations did not prolong PR interval more than beta-blockers alone. Prolonged PR interval was the result of reduced HR and direct inhibition of atrioventricular (AV) conduction. Only timolol and the timolol/felodipine combination lowered supine systolic blood pressure significantly. Timolol and all beta-blocker/felodipine combinations reduced exercise SBP significantly.
Adrenergic beta-Antagonists↗
In vitro collagen fibril assembly in glycerol solution: evidence for a helical cooperative mechanism involving microfibrils.
Glycerol inhibits the in vitro self-association of monomeric collagen into fibrils and induces the dissociation of fibrils preassembled from NaBH4-reduced collagen. These effects were investigated in an effort to understand the mechanism of fibril assembly of the protein. In PS buffer (0.03 M NaPi and 0.1 M NaCl, pH 7.0) containing 0.1-1.0 M glycerol, the self-association of type I collagen from calf skin took place only if the protein concentration was above a critical value. This critical protein concentration increased with increasing glycerol concentration. Velocity sedimentation studies showed that below the critical protein concentration and under fibril assembly conditions, the collagen was predominantly in a monomeric state. Electron microscopic examinations revealed that the collagen aggregates formed above the critical concentration consisted mostly of microfibrils of 3-5-nm diameter along with some banded fibrils were found. Collagen treated with pepsin to remove its nonhelical telopeptides also self-associated into microfibrils and fibrils in the presence of glycerol, but the reaction did not exhibit any critical concentration. These results are consistent with a mechanism of in vitro collagen fibril assembly which involves the initial formation of microfibrils through a helical cooperative mechanism. They also suggest that contacts of the nonhelical telopeptides of each collagen with its neighboring molecules provide the necessary negative free energy change for the cooperativity and that subsequent lateral association of the microfibrils leads to banded fibrils.
Animals↗
35S-Sulfide incorporation during alkaline treatment of keratin and its relation to lanthionine formation.
Cattle hair exposed to solutions of 35S-sulfide ions at pH 12.5, hydrolyzed with acid, and analyzed for amino acids with simultaneous measurement of the radioactivity of the eluate from the analytical column showed 87 percent of the radioactivity incorporated in the hair in three amino acids: cysteic acid, lanthionine, and cystine. This and other evidence presented lend further support to the intermediacy of dehydroalanyl residues formed by a beta-elimination reaction in the conversion of cystinyl residues to lanthionyl residues in proteins. The presence of radioactively labelled cystine in the hydrolyzate indicates that the dehydroalanyl residues are also capable of reforming cystinyl residues under these same conditions through a series of reversible reactions.
Alanine↗
Epileptiform seizures in domestic fowl. VI. Plasma phenobarbital concentrations and anticonvulsant activity.
The relationship between plasma phenobarbital concentrations and anticonvulsant activity was determined against seizures induced in epileptic chickens by intermittent photic stimulation (IPS). Intraperitoneally administered phenobarbital produced a plasma-concentration-dependent reduction in both the incidence and severity of seizures. Complete protection against IPS-induced seizures was observed for a period of 6 h after acute phenobarbital administration during which the mean plasma phenobarbital concentrations were between 16.2 +/- 0.91 and 13.6 +/- 1.0 microgram/lm. Plasma phenobarbital concentrations below 3.6 +/- 0.06 microgram/ml had no measurable effect.
Animals↗
Improved theophylline serum analysis by an appropriate internal standard for gas chromatography.
A gas chromatographic method is presented for the measurement of theophylline in serum. To serum samples containing the drug the internal standard, 3-isobutyl-l-methylxanthine, was added and the serum was saturated with ammonium carbonate. A mixture of isopropanol-chloroform (5:95) was used for extraction. The organic phase was filtered and evaporated. The residue, dissolved in chloroform, was extracted with sodium hydroxide. The basic solution was acidified, washed with hexane and reextracted with isopropanol-chloroform. The organic phase was dried with anhydrous sodium sulphate before evaporation. The sample was derivatized with n-Butyl-8 reagent. 85% of theophylline was recovered by extraction. 3-Isobutyl-l-methylxanthine was recovered with the same efficiency as theophylline and gas chromatographed well. The standard curve was linear between 1.0 and 50.0 mug/ml theophylline. No interference was encountered from normal serum constituents or methylxanthines such as caffeine, theobromine, or 3-methylxanthine. Serum samples were stared in the refrigerator for two weeks without significant loss of drug. The precision and accuracy of the method were good.
Chromatography, Gas↗
Recurrent benign mixed tumor and the facial nerve.
In surgical treatment of patients with recurrent benign mixed tumor, the surgeon strives to preserve the facial nerve. If there is inadvertent nerve injury, immediate repair is the treatment of choice. We report two patients with recurrent benign mixed tumor in whom the facial nerve was deliberately sacrificed. Repair of the nerve was accomplished by nerve grafts. Gross and microscopic tissue examination are presented in each instance, supporting the concept of en bloc removal of tumor and nerve. Such a surgical procedure is reserved only for a highly selected group of patients.
Adenoma, Pleomorphic↗