Grapefruit juice-felodipine interaction: effect of naringin and 6',7'-dihydroxybergamottin in humans.

OBJECTIVE: To test whether naringin or 6',7'-dihydroxybergamottin is a major active substance in grapefruit juice-felodipine interaction in humans. METHODS: Grapefruit juice was separated by means of centrifugation and filtration into supernatant and particulate fractions, which were then assayed for naringin and 6',7'-dihydroxybergamottin. The effect of these fractions, grapefruit juice (containing comparable amounts of both fractions), and water on the pharmacokinetics of oral felodipine were assessed in 12 healthy men in a randomized, 4-way crossover study. RESULTS: The amounts of naringin and 6',7'-dihydroxybergamottin in the supernatant fraction (148 mg and 1.85 mg) were greater than in the particulate fraction (7 mg and 0.60 mg). The area under the plasma concentration-time curve (AUC) and the peak concentration (Cmax) of felodipine were higher with supernatant fraction (81 nmol.h/L and 20 nmol/L), particulate fraction (117 nmol.h/L and 24 nmol/L), and grapefruit juice (130 nmol.h/L and 33 nmol/L) compared with water (53 nmol.h/L and 11 nmol/L). However, the supernatant fraction had a lower AUC for felodipine and a similar Cmax of felodipine relative to the particulate fraction. The supernatant fraction neither augmented the AUC of the primary metabolite dehydrofelodipine nor decreased the AUC ratio of dehydrofelodipine to felodipine compared with water. Individually the supernatant fraction consistently produced lower felodipine AUC and Cmax compared with grapefruit juice. In contrast, the particulate fraction had values ranging from more than grapefruit juice to less than supernatant fraction. CONCLUSIONS: Naringin and 6',7'-dihydroxybergamottin are not the major active ingredients, although they may contribute to the grapefruit juice-felodipine interaction. The variable effect with the particulate fraction may result from erratic bioavailability of unidentified primary active substances. The findings show the importance of in vivo testing to determine the ingredients in grapefruit juice responsible for inhibition of cytochrome P450 3A4 in humans.

Grapefruit-felodipine interaction: effect of unprocessed fruit and probable active ingredients.

OBJECTIVES: To determine whether unprocessed grapefruit can cause a drug interaction, whether the active ingredients are naturally occurring, and whether specific furanocoumarins or flavonoids are involved. METHODS: The oral pharmacokinetics of felodipine and its dehydrofelodipine metabolite were determined after administration of felodipine 10 mg extended-release tablet with 250 mL commercial grapefruit juice, homogenized grapefruit segments, or extract of segment-free parts equivalent to one unprocessed fruit or water in a randomized four-way crossover study. Inhibition of recombinant CYP3A4 by furanocoumarins (bergamottin, 6',7'-epoxybergamottin, 6',7'-dihydroxybergamottin) and flavonoids (naringenin optical isomers) was determined. Furanocoumarin and naringenin precursor (naringin) concentrations were measured in each grapefruit treatment. RESULTS: Felodipine AUC with commercial grapefruit juice, grapefruit segments, or grapefruit extract was on average 3-fold higher than that with water. Felodipine peak concentration was higher, but the half-life was unchanged. The dehydrofelodipine/felodipine AUC ratio was reduced. The furanocoumarins produced mechanism-based and competitive inhibition of CYP3A4. Bergamottin was the most potent mechanism-based inhibitor. Naringenin isomers produced only competitive inhibition. Bergamottin, 6',7'-dihydroxybergamottin, and naringin concentrations varied among grapefruit treatments but were sufficient to inhibit markedly in vitro CYP3A4 activity. CONCLUSIONS: Unprocessed grapefruit can cause a drug interaction with felodipine. The active ingredients are naturally occurring in the grapefruit. Bergamottin is likely important in drug interactions with commercial grapefruit juice. 6',7'-Dihydroxybergamottin and naringin may be more important in grapefruit segments because they are present in higher concentrations. Any therapeutic concern for a drug interaction with commercial grapefruit juice should now be extended to include whole fruit and possibly confectioneries made from grapefruit peel.

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.

Calcium and the Fc receptor on human platelets.

We have described the calcium dependence of the IgG Fc receptor (Fc-R) on human platelets by analyzing the direct binding of radiolabelled Fc fragments, monomers and dimers of IgG. Specific binding to platelets was undetectable at 37 degrees C in a calcium-free preparation but readily detected when calcium was restored. Scatchard analysis of the binding data for the calcium-restored platelets permitted calculation of the available Fc-R and the Ka of binding for the different IgG ligands. The mean Ka of binding for 12 normal subjects varied from 10(7) to 10(8) L/M, with an equal receptor number measured by Fc fragments and dimers of IgG, but a lesser amount for monomeric IgG. There was no apparent difference in Fc-R number for platelets from 6 normal male versus 6 normal female subjects. At 4 degrees C binding was detectable for dimers and polymers of IgG in a calcium-free preparation and this was markedly increased with recalcification. Thus, our data are consistent with an Fc receptor population on human platelets whose avidity for binding is significantly enhanced in a calcium-restored medium.

Metronidazole kinetics in dialysis patients.

Five volunteers with normal renal function (NOR) and eight patients with renal insufficiency (REN) were given a single dose of 500 mg metronidazole (MET) intravenously over 26 minutes. Serial venous plasma samples were taken at certain intervals for 30 hours. Four of the eight REN patients were also given the drug at the start of hemodialysis and four simultaneous inflow-outflow samples were taken over 4 hours of dialysis. Plasma MET, the acetic acid metabolite (MTAC), and the hydroxymethyl metabolite (MTOH) were determined by high-pressure liquid chromatography assay. Plasma MET over time curves were analyzed with a nonlinear curve-fitting computer program (ASAAM-27) which employed a two-compartment open model. Plasma MET concentrations were similar in the NOR and REN groups. The volumes of distribution for MET--both V1 and Vdss--were similar in the two groups. Moreover, renal insufficiency did not affect the beta half-life (6.5 hours) or the plasma clearance (10.1 L/hr) of MET. Metabolite concentrations peaked at about 12 hours in both groups, but peak MTAC was five times higher in the REN group and peak MTOH twofold higher. Plasma clearance of MET by dialysis averaged 4.0 L/hr at 30 minutes, but thereafter ranged from 2.9 to 4.2 L/hr. Clearance of MTAC ranged from 5.8 to 7.8 L/hr and that of MTOH 2.7 to 5.6 L/hr. We concluded that renal failure does not alter MET disposition but is associated with significant accumulation of the metabolites of MET, possibly requiring a dose reduction. Moreover, an 8-hour hemodialysis eliminates approximately 50% of an administered dose of MET.

Biologic activity of metronidazole in plasma and urine of volunteers with normal or impaired renal function.

In this study, we have compared a bioassay procedure with high-pressure liquid chromatography (HPLC) for the determination of metronidazole levels in serum and urine. Plasma and urine of volunteers with normal or impaired renal function were obtained at various intervals after a single intravenous dose of 500 mg metronidazole. In plasma of normal volunteers 30 hours after dosing, the bioassay gave results comparable to the total values of the parent compound plus metabolites. In patients with renal failure, the course of the plasma regression curve of metronidazole as measured by the bioassay procedure was intermediate between the values of metronidazole alone and the total values of parent compound plus metabolites. Recovery of metronidazole activity in urine, as determined by this bioassay method, was somewhat less than one half (in normal volunteers) to one quarter (in patients with renal failure) of metronidazole plus metabolites as measured by HPLC. These discrepancies might be explained by the lower antibacterial activity of the hydroxy (congruent to 40%) and acetic acid (congruent to 2%) metabolites as compared with that of the parent compound in the test system used.

EEG and clinical associations with mortality in comatose patients in a general intensive care unit.

The authors examined EEG findings and clinical factors for their association with outcome in comatose patients in their general intensive care unit. The following individual and combinations of factors were strongly related to mortality, with positive predictive values of >0.80 and odds ratios >2.0: age over 65 years, anoxic/ischemic encephalopathy, EEG suppression, lack of EEG reactivity; anoxia-ischemia with partial or complete cranial nerve areflexia, anoxia-ischemia with EEG suppression; anoxia-ischemia and generalized epileptiform activity; anoxia-ischemia with partial cranial nerve areflexia and EEG suppression. Conversely, the following factors favored survival rather than death: systemic infection/sepsis, metabolic derangement (excluding anoxic-ischemic insult), trauma; dysrhythmia, focal epileptiform activity, and regional delta and reactivity on EEGs. The findings of this study support the integration of these data into intensive care unit prognostic scoring systems, such as later versions of the Acute Physiology and Chronic Health Evaluation (APACHE).

Comparison of headache parameters using headache type and emotional status.

OBJECTIVE: The literature on the impact of headache has traditionally focused on the relationship of subject variables to specific headache types. Recently, increasing attention is being paid to the impact on disease of emotional distress. The current study was designed to determine whether differences in subject variables arose when comparing them by headache type vs. empirically derived emotional distress clusters. METHOD: A review of responses to measures of headache impact (e.g., duration, medication use) and emotional distress (Brief Symptom Inventory, BSI) completed by 292 patients attending a headache clinic was conducted. Patient responses were analyzed by headache type and emotional distress cluster. RESULTS: Comparison by headache type revealed that combined headaches were of longer duration, used more medications, and were more likely to have seen a chiropractor. Comparison by distress cluster revealed high-distress patients to have missed more days of work, have legal involvement, have sought psychological services, and to be male. CONCLUSION: The results suggest that clinically useful information can be obtained by using both headache diagnosis and emotional status. In addition, this information may be useful by providing additional knowledge that may lead to different clinical protocols in headache management.

Efficient pharmacokinetic modeling of complex clinical dosing regimens: the universal elementary dosing regimen and computer algorithm EDFAST.

Dosing regimens used in clinical practice are often complex, involving several different routes of administration, dose sizes, dosing rates, and dosing intervals and durations. A novel universal elementary dosing regimen (uedr), that allows general pharmacokinetic modeling of these clinical regimens, is presented and developed mathematically. The uedr concept is computationally efficient, mathematically exact, and logically simple, and can replace the disparate standard concepts and equations of elementary infusion, "bolus" injection, multiple injection, oral dosing, zero-order-release dosing, etc. An optimized computer algorithm (EDFAST) based on the uedr approach, that readily permits the creation of a single fast and versatile microcomputer program for the analysis of all complex dosing regimens in any set of linear compartmental models, is presented. This is of particular relevance to three areas of application in clinical pharmacokinetics: compartmental drug concentration or amount versus time course prediction (simulation) with known model parameter values; parameter estimation (curve-fitting) from measured concentration versus time data; and individualized complex dosing regimen calculation (optimization) for target sets of concentration-time points. Application examples that show the versatility of the uedr approach are presented in detail.

The effects of a thromboxane synthase inhibitor, a prostacyclin analog and PGE1 on the nephritis of the NZB/W F1 mouse.

One hundred NZB/W F1 female mice were studied to compare the effects of a thromboxane synthase inhibitor (TSI), a stable prostacyclin analog (iloprost) and prostaglandin E1 (PGE1) in the evolution of the nephritis. At 10 weeks of age mice were randomly assigned to cohorts of 20 to receive either no treatment, vehicle control, PGE1, iloprost or TSI. Proteinuria, mortality, systemic blood pressure, renal immune complex deposition, urinary TX B2 and 6 keto PGF1 alpha levels were measured. Mice receiving PGE1 and iloprost had a significant delay in the onset of proteinuria and reduction in mortality at 40 weeks. The TSI treatment had no apparent effect on proteinuria or mortality. The amelioration of the nephritis was not associated with an alteration in immune complex deposition in survivors at 40 weeks. Although PGE1 and iloprost lessened the age related increase in urinary TX B2, increased the urinary 6 keto PGF1 alpha levels and the ratio of 6 keto PGF1 alpha to TX B2; so did the TSI. The PGE1 treated mice did experience a marked and persistent reduction in blood pressure but this was not observed in the iloprost- or the TSI-treated mice. All drugs tested reduced the age-related increase in thromboxane B2 but only the PGE1 and iloprost had a significant effect on the evolution of the nephritis.

Comparative efficacy of dietary treatments on renal function in rats with sub-total nephrectomy: renal polyunsaturated fatty acid incorporation and prostaglandin excretion.

The efficacy of dietary intervention with either 6% protein restriction, fish oil or safflower oil was assessed in the remnant nephron model. Female Munich Wistar rats were prefed for one week prior to 5/6 nephrectomy and followed for the ensuing 28 days. Fish oil, safflower oil and protein restriction prevented the gammaglobulinuria but only fish oil lessened the albuminuria in this model. The remnant nephrons of the fish oil treated rats contained less arachidonic acid and greater quantities of eicosapentaenoic and docosahexaenoic acid than the safflower oil or lab chow fed control rats. The fish oil, and to a lesser extent the safflower oil, treated animals had a higher ratio of 6 keto PGF1 alpha to TX B2 metabolites in their urine. We suggest these changes may be responsible for the lessening in urine protein excretion. Fish oil feeding was more effective than severe protein restriction or safflower oil dietary supplementation in lessening both the gammaglobulinuria and albuminuria of the remnant nephron model.

An electroencephalographic classification for coma.

BACKGROUND: The assessment of thalamocortical function in comatose patients in the intensive care unit (ICU) can be difficult to determine. Since the electroencephalogram (EEG) affords such assessment, we have developed an EEG classification for comatose patients in our general ICU. METHODS: One hundred EEGs were classified in a blinded fashion by two EEGers, using our method and that of Synek. Interobserver agreement was assessed using kappa score determination. RESULTS: Kappa scores were 0.90 for our system and 0.75 for the Synek system. (The Kappa score represents the inter-rater agreement that is beyond chance; 0.90 is almost perfect agreement, while 0.75 is substantial agreement). CONCLUSION: Our system for classifying EEGs in comatose patients has a higher interobserver reliability than one that was previously published. This EEG classification scheme should be useful in clinical electrophysiological research involving ICU patients, allowing for internal consistency and comparisons among centres.

Comparison of the efficacy and safety of flunarizine to propranolol in the prophylaxis of migraine.

This study was designed to compare flunarizine, a cerebro-specific calcium channel antagonist, and propranolol in the prophylaxis of migraine with or without aura. Following a 1 month single-blind placebo baseline period, 94 patients were equitably randomised under double-blind conditions to take flunarizine 10 mg daily or propranolol 80 mg twice daily for 4 months. Both treatments led to a significant reduction in the frequency of migraines and use of rescue analgesics with a significantly greater decrease in number of attacks for flunarizine after 1 and 4 months. Neither treatment affected the severity nor duration of migraines. Overall, 67% of flunarizine patients and 51% of propranolol patients responded positively. Propranolol significantly reduced blood pressure and heart rate; flunarizine had no effect on cardiovascular function. Weight gain was noted with both treatments. Flunarizine is at least as effective as propranolol in the prophylactic treatment of migraine and may have a better safety profile.

Ataxia in institutionalized patients with epilepsy.

Fifty-four per cent of 41 chronically institutionalized adult patients with epilepsy had ataxia of gait (wide mean stride width). None of the following correlated with stride width: serum phenytoin, previous phenytoin toxicity, seizure frequency, or status epilepticus. Seventeen of the 41 patients had computed tomographic head scans. Patients with radiological evidence of cerebellar atrophy had a wider mean stride width, later age of onset of seizures, greater peak serum concentrations of phenytoin than did those without cerebellar atrophy. Ataxia of gait was inconsistently associated with cerebellar atrophy. Elevated serum/plasma concentrations of phenytoin may be a risk factor for cerebellar atrophy, but seizure frequency or status epilepticus are not independently related to this complication.

A comparative analysis of two dosing strategies of flurbiprofen in rheumatoid arthritis: an application of sequential trial design.

Forty patients with classic or definite rheumatoid arthritis were entered into a double-blind, randomized, multiple crossover, sequential trial comparing two doses (300 mg vs 150 mg per day) and two dosing schedules (b.i.d. vs t.i.d.) of flurbiprofen. Clinical assessments (Ritchie Index, grip strength, walking time, physician and patient global assessments) were made at baseline and at biweekly intervals during the next six weeks of active treatment. Overall there were no statistically significant differences either between the two dosage levels or the dosing schedules. This study demonstrates the utility of the sequential trial design in assessing drug efficacy. The data confirm a lack of difference between the two doses of flurbiprofen selected and suggest that twice-daily dosing with flurbiprofen is similar in efficacy to thrice-daily dosing.

Ethanol 'dose-dependent' elimination: Michaelis-Menten v classical kinetic analysis.

1 To compare classical linear regression techniques and a Michaelis-Menten elimination model eight normal human volunteers each received three intravenous doses (0.375, 0.5, and 0.75 g/kg) of ethanol and four of the subjects each received four oral doses (0.5, 0.65, 0.95, 1.25 g/kg) of ethanol. 2 Computerized analysis of the time-plasma concentration profiles using a two-compartment Michaelis-Menton elimination model yielded a median absorption constant of 1.29 h-1; volume of distribution of 0.47 l/kg; Vmax of 0.12 g h-1 kg-1; and Km of 0.03 g/l. Classical techniques resulted in a slope of 0.20 g l-1 h-1, volume of distribution of 0.55 l/kg, and a B60 of 0.11 g h-1 kg-1. 3 Transient post-prandial decreases in elimination slope occurred at higher oral doses. A trend of increasing slope with increasing oral dose was seen at concentrations well above the Km. Time to sobriety (0.8 g/l) increased nonlinearly with increasing peak concentration. 4 Maximal ethanol elimination rates are determined equally well by the two techniques. Classical analyses overestimate the volume of distribution of ethanol by 17%. Neither technique helps explain the post-prandial changes in slope or increasing slope with dose at high concentrations.

Comparison of chlorthalidone and spironolactone in low--renin essential hypertension.

Nineteen patients with uncomplicated essential hypertension and low activity of plasma renin in response to a change from recumbency to an upright posture along with furosemide administration were given spironolactone, 400 mg/d, or chlorthalidone, 100mg/d, in a double-blind, random-sequence, crossover trial. The sequence of treatments was placebo for 2 months, one active drug for 2 months, placebo again for 1 month and the other active drug for 2 months. With both active treatments the average systolic, diastolic and mean arterial pressures decreased significantly. The two agents were equally efficacious in lowering the blood pressure regardless of the severity of hypertension during placebo treatment. Body weight, 24--hour urinary excretion of sodium, the plasma renin activity and the plasma aldosterone level at the end of the initial placebo period did not allow us to predict the response to either drug. Both drugs reduced the body weight and increased the stimulated plasma renin level activity. Chlorthalidone significantly increased the serum uric acid level and significantly reduced the serum potassium level. Three patients experienced orthostatic dizziness during spironolactone therapy, but no adverse symptoms were observed with chlorthalidone therapy. Thus, spironolactone is an effective alternative to thiazide-type drugs in patients with low-renin essential hypertension.