Miguel A. Zinny

Time course of recovery of cytochrome p450 3A function after single doses of grapefruit juice

Components of grapefruit juice may impair the activity of intestinal cytochrome P450 (CYP) 3A enzymes, sometimes resulting in clinically important drug interactions. The time course of recovery from CYP3A inhibition after a single exposure to grapefruit juice is not clearly established.

Pomegranate juice does not impair clearance of oral or intravenous midazolam, a probe for cytochrome P450-3A activity : Comparison with grapefruit juice

The effect of pomegranate juice (PJ) or grapefruit juice (GFJ) on CYP3A activity was studied in vitro and in healthy human volunteers. In human liver microsomes, the mean 50% inhibitory concentrations (IC50) for PJ and GFJ versus CYP3A (triazolam α‐hydroxylation) were 0.61% and 0.55%, (v/v) respectively, without preincubation of inhibitor with microsomes. After preincubation, the IC50 for PJ increased to 0.97% (P < .05), whereas the IC50 for GFJ decreased to 0.41% (P < .05), suggesting mechanism‐based inhibition by GFJ but not PJ. Pretreatment of volunteer subjects (n = 13) with PJ (8 oz) did not alter the elimination half‐life, volume of distribution, or clearance of intravenous midazolam (2 mg). Administration of PJ also did not affect Cmax, total area under the curve (AUC), or clearance of oral midazolam (6 mg). However, GFJ (8 oz) increased midazolam Cmax and AUC by a factor of 1.3 and 1.5, respectively, and reduced oral clearance to 72% of control values. Thus, PJ does not alter clearance of intravenous or oral midazolam, whereas GFJ impairs clearance and elevates plasma levels of oral midazolam.

Interaction of flurbiprofen with cranberry juice, grape juice, tea, and fluconazole : In vitro and clinical studies

Recent anecdotal, unvalidated case reports have suggested potentiation of warfarin‐induced anticoagulation by cranberry juice, possibly through inhibition of human cytochrome P450 (CYP) 2C9, the enzyme responsible for the clearance of the active S‐enantiomer of warfarin. To address this question, the effect of cranberry juice and other beverages on CYP2C9 activity was evaluated in vitro and in vivo.

Effect of Gradual Withdrawal on the Rebound Sleep Disorder after Discontinuation of Triazolam

Abstract Sixty volunteers with insomnia participated in a randomized, double-blind, controlled clinical trial. After an initial six nights of placebo, 30 subjects (the abrupt-withdrawal group) received 0.5 mg of triazolam nightly for 7 to 10 nights, after which they received placebo. The other 30 subjects (the tapered-dosage group) received the same initial placebo treatment, then triazolam at 0.5 mg for seven nights, at 0.25 mg for two nights, and at 0.125 mg for two nights, and then placebo. As compared with the initial placebo period, the triazolam period significantly reduced the interval before the onset of sleep (sleep latency), and it prolonged sleep duration, reduced the number of awakenings, and improved the self-rated soundness of sleep in all cohorts. In the abrupt-withdrawal group, plasma levels of triazolam were undetectable the morning after the first night of placebo substitution, and subjects reported prolongation of sleep latency (57 minutes longer than base line), reduction in sleep dura...

Sitagliptin, an dipeptidyl peptidase‐4 inhibitor, does not alter the pharmacokinetics of the sulphonylurea, glyburide, in healthy subjects

AIMS Sitagliptin, a dipeptidyl peptidase-4 inhibitor, is an incretin enhancer that is approved for the treatment of Type 2 diabetes. Sitagliptin is mainly renally eliminated and not an inhibitor of CYP450 enzymes in vitro. Glyburide, a sulphonylurea, is an insulin sensitizer and mainly metabolized by CYP2C9. Since both agents may potentially be co-administered, the purpose of this study was to examine the effects of sitagliptin on glyburide pharmacokinetics. METHODS In this open-label, randomized, two-period crossover study, eight healthy normoglycaemic subjects, 22-44 years old, received single 1.25-mg doses of glyburide alone in one period and co-administered with sitagliptin on day 5 following a multiple-dose regimen for sitagliptin (200-mg q.d. x 6 days) in the other period. RESULTS The geometric mean ratios and 90% confidence intervals [(glyburide + sitagliptin)/glyburide] for AUC(0-infinity) and C(max) were 1.09 (0.96, 1.24) and 1.01 (0.84, 1.23), respectively. CONCLUSION Sitagliptin does not alter the pharmacokinetics of glyburide in healthy subjects.

A dose-response study of the efficacy and safety of ipratropium bromide nasal spray in the treatment of the common cold

Rhinorrhea is an annoying symptom of the common cold for which effective therapy is not currently available. Ipratropium bromide (IB) is an anticholinergic drug that has been shown to decrease glandular secretion when applied topically to the nasal mucosa. The purpose of this study was to compare the efficacy and safety of three doses of IB nasal spray versus either vehicle or no treatment in relieving rhinorrhea in patients with naturally acquired colds. Rhinorrhea severity was measured objectively by determining nasal discharge weights and subjectively by means of visual analog scale scores. Compared with either vehicle or no treatment, IB nasal spray produced a significant decrease in the severity of rhinorrhea. A dose of 84 micrograms (two sprays of a 0.06% solution in buffered saline solution) in each nostril was more efficacious than a 42 microgram per nostril dose and only marginally less efficacious than a 168 micrograms per nostril dose. The 84 micrograms per nostril dose also was associated with fewer adverse events than was the higher dose. None of the adverse events related to intranasal IB therapy was of a serious nature. The use of IB nasal spray appears to be a rational and safe approach to relieving rhinorrhea associated with the common cold.

Effect of food on nifedipine pharmacokinetics

The effect of food on the bioavailability of nifedipine (Procardia), 10 mg capsules, was studied. Each of 15 male volunteers received a single oral 10 mg dose with 120 ml water under three conditions: fasting, after a low‐fat (high‐carbohydrate) meal, and after a high‐fat meal. An open, three‐way Latin‐square design was employed with a 4‐day washout period between administrations. Serial blood samples were collected just before the dose (0 hour) and from 0 to 8 hours after administration. Nifedipine assays were performed by GLC/electron capture detection. Diet did not appreciably alter the AUC from 0 to 8 hours, the AUC from 0 to infinity, or the elimination half‐life. The time to peak (tmax) and peak concentrations (Cmax) were significantly altered by food. The mean Cmax values for fasting, low‐fat, and high‐fat meals were 78.9, 42.2, and 58.7 ng/ml, respectively. The mean tmax values for these three conditions were 0.97, 1.89, and 1.07 hours, respectively. The results indicate that food, in particular a low‐fat (high‐carbohydrate) meal, slows the rate but does not alter the extent of nifedipine absorption. Insofar as certain side effects (e.g., flushing and headache) may be related to the high peak plasma levels associated with rapid absorption, administration with meals might serve to reduce the incidence of such effects. Clinical trials would be necessary to confirm this possibility. For the majority of patients on routine maintenance therapeutic regimens, nifedipine capsules may be administered without regard to food intake.

Gastrointestinal Absorption of Pravastatin in Healthy Subjects

The bioavailability of pravastatin, a hypocholesterolmic agent, may be enhanced by decreasing its exposure to stomach contents, where it may be converted nonenzymatically to a relatively inactive metabolite. The pharmacokinetics of pravastatin and its metabolite were determined after infusion of pravastatin directly into the stomach (locus for greatest bioavailability for the metabolite), duodenum (greastest bioavailability for pravastatin), jejunum, or ileum. An enterically coated formulation of pravastatin may increase its bioavailability.

Effects of Carvedilol on Blood Pressure in Patients with Mild to Moderate Hypertension: A Dose Response Study

SummaryCarvedilol 12.5, 25 and 50mg was administered once daily for 4 weeks to patients with mild to moderate hypertension. The purpose of the study was to investigate the antihypertensive action of carvedilol when administered once daily and to investigate the pharmacokinetics of carvedilol in patients with mild to moderate hypertension.Measurable decreases in blood pressure (BP) occurred within 1 hour after the first dose. Peak decreases in supine diastolic blood pressure (DBP) were 9.0 ± 6.8, 15.5 ± 6.7, 14.7 ± 10.6 and 22.5 ± 7.6mm Hg (± SD) for the placebo, 12.5, 25 and 50mg carvedilol groups, respectively, and occurred between 3 and 7 hours after the dose. Administration of carvedilol once daily for 4 weeks kept supine DBP below baseline levels for 24 hours. Trough supine DBP after 4 weeks of treatment were 0.6 ± 6.5, 7.3 ± 7.9, 8.8 ± 7.4 and 12.1 ± 3.8mm Hg (± SD) below baseline. Serum levels of carvedilol were proportional to the dose. Peak serum levels were 39 ± 27, 75 ± 38 and 161 ± 131 μ/L for carvedilol 12.5, 25 and 50mg. The kinetics of carvedilol did not change with repeated administration. Carvedilol was well tolerated; 2 patients experienced dizziness associated with postural hypotension after administration of the 50mg dose. Carvedilol 12.5, 25 and 50mg effectively reduced BP for 24 hours when administered once daily.

A double-blind, placebo-controlled study of the safety and efficacy of ipratropium bromide nasal spray versus placebo in patients with the common cold

Ipratropium bromide (IB) has been found to reduce secretions in the upper respiratory tract; this is accomplished through competitive inhibition of acetylcholine at muscarinic receptors that control rhinorrhea production. This study compared the safety and efficacy of IB with placebo in the symptomatic relief of rhinorrhea in patients with the common cold. Human subjects with symptoms of a common cold, primarily rhinorrhea, were enrolled and treated with either IB (84 micrograms/nostril) or placebo; each was administered as two sprays per nostril, four times a day, for 4 days. Primary efficacy analyses were in-clinic measurements of nasal discharge weights over a 3-hour period after administration on days 1 and 2 and assessment of rhinorrhea symptoms by use of a subjective patient-completed visual analog rating scale. IB significantly reduced rhinorrhea an average of 18% over placebo for days 1 and 2 (p = 0.01). Visual analog scale scores showed an average improvement in rhinorrhea of 22% over placebo (p = 0.001). When patients with relatively minor rhinorrhea (baseline weight of nasal discharge < or = 1.0 gm) were excluded, IB produced an average reduction in nasal discharge of 23% over placebo for days 1 and 2 (p = 0.003).