Showing papers in "The Journal of Clinical Pharmacology in 1989"

Pharmacokinetics of midazolam following intravenous and oral administration in patients with chronic liver disease and in healthy subjects

Abstract: To study the effects of cirrhosis of the liver on the pharmacokinetics of midazolam single IV (7.5 mg as base) and p.o. (15.0 mg as base) doses of midazolam were administered to seven patients with cirrhosis of the liver and to seven healthy control subjects. One cirrhotic patient did not receive the oral dose. The distribution of midazolam in both study groups was alike as indicated by similar values of t1/2 alpha, V1 and Vss. Also the plasma protein binding of midazolam was unchanged in the patients with cirrhosis. The elimination of midazolam was significantly retarded in the patients as indicated by its lower total clearance (3.34 vs. 5.63 ml/min/kg), lower total elimination rate constant (0.400 vs. 0.721 h-1), and longer elimination half-life (7.36 vs. 3.80 h). The bioavailability of oral midazolam was significantly (P less than 0.05) higher in patients than controls (76% vs. 38%). The antipyrine-half-life was 32.4 h in the patients and 11.8 h in the controls. There were statistically significant (P less than 0.01) correlations between the clearances of the two drugs (r = 0.680) and between their half-lives (r = 0.755). The hypnotic effects of midazolam were similar in both groups. However, on a pharmacokinetic basis a reduced dosage of midazolam to patients with advanced cirrhosis of the liver is recommended.

Drug delivery systems. 1. site-specific drug delivery using liposomes as carriers.

Abstract: Drug delivery systems, offering controlled delivery of biologically active agents, are rapidly gaining importance in pharmaceutical research and development. To achieve controlled drug delivery, i.e., the administration of drugs so that optimal amount reaches the target site to cure or control the disease state, increasingly sophisticated systems containing different carriers have been developed. Macromolecules represent one of the carriers involved, and they have taken on a significantly prominent role in various modes of administration of therapeutic agents. Among macromolecules, for example, synthetic copolymers, polysaccharides, liposomes, polyanions and antibodies, as drug carriers, liposomes have proved most effective for diseases affecting the reticuloendothelial system and blood cells in particular. Liposomes, which are vesicles consisting of one or more concentrically ordered assemblies of phospholipids bilayers, range in size from a nanometer to several micrometers. Phospholipids such as egg phosphatidylcholine, phosphatidylserine, synthetic dipalmitoyl-DL-alpha-phosphatidylcholine or phosphatidylinositol, have been used in conjunction with cholesterol and positively or negatively charged amphiphiles such as stearylamine or phosphatidic acid. Alteration of surface charge has been shown to enhance drug incorporation and also influence drug release. Because of the multifold characteristics as drug carriers, liposomes have been investigated extensively as carriers of anticancer agents for the past several years. Liposomal entrapments include a variety of pharmacologically active compounds such as antimalarial, antiviral, anti-inflammatory and anti-fungal agents as well as antibiotics, prostaglandins, steroids and bronchodilators to name a few. The liposomal entrapment has been shown to have considerable effect on the pharmacokinetics and tissue distribution of administered drugs. Despite the potential value of liposomes as unique carriers, the major obstacles are the first order targeting of a systemically given liposomes, physical stability and manufacture of the liposomal products and these problems still remain to be overcome. Drug delivery systems evolving in the 1980s have become increasingly dependent on fundamental cell-biology and receptor-mediated endocytotic mechanisms. Drug delivery systems during the 1990s may take advantage of the specificity of receptor-mediated uptake mechanisms as well as polymer chemistry and cell-biology in order to introduce more precise and efficient target-specific delivery systems that are based especially on the liposome technology.

Spironolactone Metabolism: Steady‐State Serum Levels of the Sulfur‐Containing Metabolites

Abstract: Metabolism of spironolactone in man is extensive and complex. For many years the dethioacetylated metabolite, canrenone, was assumed to be the major metabolite. However, recent studies using specific high performance liquid chromatography (HPLC) have demonstrated the presence of spironolactone and the sulfur-containing metabolites 7α-thiomethylspirolactone (IV) and 6β-hydroxy-7α-thiomethylspirolactone (V), in addition to canrenone, in the serum after a single oral dose of spironolactone. The importance of spironolactone and metabolites IV and V relative to canrenone at steady state remains unknown and was the subject of the present investigation. Twelve healthy males received 100 mg spironolactone, once daily, for 15 days. Repeated blood samples were taken on days 1, 8 and 15 for estimation of spironolactone and its metabolites. Peak serum levels [mean (SD)] of spironolactone, canrenone, and sulfur-containing metabolites IV and V were 72 (45), 155 (43), 359 (106) and 101 (26) ng/ml, respectively on day 1 and 80 (20), 181 (39), 391 (118) and 125 (24) ng/ml, respectively on day 15. The AUC (0–24) values of these compounds on day 15 were 231 (50), 2173 (312), 2804 (777) and 1727 (367) ng·hr/ml, respectively and the post-steady state elimination half-life (t1/2) values were 1.4 (0.5), 16.5 (6.3), 13.8 (6.4), and 15.0 (4.0) hours, respectively. It was concluded that unmetabolized spironolactone is present in the serum and that the sulfur-containing metabolite IV rather than canrenone is the major metabolite in serum following single or repeated doses of spironolactone.

Implications of Altered Drug Disposition in the Elderly: Studies of Benzodiazepines

Abstract: Article de synthese sur l'alteration de la pharmacocinetique en fonction de l'âge, chez l'homme. Exemple des benzodiazepines chez le vieillard

Ibuprofen and Acetaminophen in the Relief of Acute Pain: A Randomized, Double-Blind, Placebo-Controlled Study

Abstract: To determine the relative analgesic efficacy of ibuprofen 400 mg and acetaminophen 1000 mg, we conducted a single-dose, double-blind, placebo-controlled, randomized clinical trial using a standard assay for analgesic agents, the dental pain model. At regular intervals over 6 hours, 184 patients who had undergone dental impaction surgery rated pain intensity and relief on categorical scales and pain half-gone on a dichotomous nominal scale; a categorical overall evaluation was completed at the end of 6 hours. Both active agents were effective compared to placebo. Ibuprofen 400 mg was more effective than acetaminophen 1000 mg for Sum Pain Intensity Difference (SPID), Total Pain Relief (TOTPAR), sum pain half-gone, and overall evaluation (P less than .05 to P less than .001). The time-effect curves demonstrated a greater peak effect and longer duration of action for ibuprofen 400 mg compared to acetaminophen 1000 mg. Side effects were reported in five ibuprofen patients, 11 acetaminophen-treated patients, and seven placebo patients. Based on the results of this clinical study, we conclude that ibuprofen 400 mg is a safe and more effective analgesic than acetaminophen 1000 mg for patients with acute pain.

Acute hemodynamic responses to weightlessness in humans.

Abstract: As NASA designs space flights requiring prolonged periods of weightlessness for a broader segment of the population, it will be important to know the acute and sustained effects of weightlessness on the cardiovascular system since this information will contribute to understanding of the clinical pharmacology of drugs administered in space. Due to operational constraints on space flights, earliest effects of weightlessness have not been documented. We examined hemodynamic responses of humans to transitions from acceleration to weightlessness during parabolic flight on NASA's KC-135 aircraft. Impedance cardiography data were collected over four sets of 8-10 parabolas, with a brief rest period between sets. Each parabola included a period of 1.8 Gz, then approximately 20 seconds of weightlessness, and finally a period of 1.6 Gz; the cycle repeated almost immediately for the remainder of the set. Subjects were semi-supine (Shuttle launch posture) for the first set, then randomly supine, sitting and standing for each subsequent set. Transition to weightlessness while standing produced decreased heart rate, increased thoracic fluid content, and increased stroke index. Surprisingly, the onset of weightlessness in the semi-supine posture produced little evidence of a headward fluid shift. Heart rate, stroke index, and cardiac index are virtually unchanged after 20 seconds of weightlessness, and thoracic fluid content is slightly decreased. Semi-supine responses run counter to Shuttle crewmember reports of noticeable fluid shift after minutes to hours in orbit. Apparently, the headward fluid shift commences in the semi-supine posture before launch. is augmented by launch acceleration, but briefly interrupted immediately in orbit, then resumes and is completed over the next hours.

Ibuprofen and acetaminophen in the relief of postpartum episiotomy pain.

Abstract: A single-dose, double-blind, randomized clinical trial was conducted to examine the relative analgesic efficacy of ibuprofen 400 mg (n = 36), acetaminophen 1000 mg (n = 37), and placebo (n = 38) in postpartum patients who had moderate to severe pain after episiotomy. At regular intervals over 4 hours, patients evaluated pain severity and relief on categorical scales and completed a categorical overall evaluation at the end of the trial. Both active agents were effective compared with placebo (P less than .05). Ibuprofen 400 mg was more effective than acetaminophen 1000 mg for the sum of pain intensity difference, total pain relief, and reduction of pain by more than 50% (P less than .05), suggesting a more rapid onset of action and a more prolonged effect by ibuprofen 400 mg. No adverse effects were reported. Based on the results of this conventional postpartum episiotomy pain model, both agents are considered efficacious and ibuprofen 400 mg is a more effective analgesic for the relief of acute pain than acetaminophen 1000 mg.

The monoamine oxidase inhibitor-tyramine interaction.

Abstract: Reports of hypertensive reactions from monoamine oxidase inhibitors (MAOI) began to proliferate in the early 1960s. Asatoor did extensive research and found that the combination of an MAOI and a food containing tyramine resulted in the hypertensive interaction ("the cheese reaction"). Because of the risk of intracerebral hemorrhage and death, clinicians were hesitant to use the MAOIs. Although progress on the metabolic effects of MAOIs has been slow, use of clinical information in addition to analysis of bioactive amine content of foods has allowed the formulation of dietary recommendations, which are thought to be useful clinically in the administration of MAOIs. This has resulted in the gradual return to use of these psychotropic compounds.

Ciprofloxacin Pharmacokinetics After a Standard or High‐Fat/High‐Calcium Breakfast

Abstract: C iprofloxacin is a new, widely used antibacterial agent of the quinolone group, which has a broad spectrum of activity against both gram-positive and gram-negative bacteria. It is active against Enterobacteriaceae and Pseudomonas aeruginosa”2 and both methicillin-sensitive and methicillin-resistant strains of Staphylococcus aureus.’ It is well documented that food can alter the rate and extent of drug absorption.46 In addition, other antibiotics, such as tetracycline, which form chelation complexes with divalent cations, have been shown to interact with dairy products that are high in calcium.7 Therefore, the two objectives of this study were to evaluate the effect of a “standard” breakfast and to assess the influence of a high-fat/high-calcium meal on the bioavailability of ciprofloxacin.

Acetazolamide Blood Concentrations are Excessive in the Elderly: Propensity for Acidosis and Relationship to Renal Function

Abstract: Elderly glaucoma patients are often treated with acetazolamide, a carbonic anhydrase inhibitor with clearance dependent on renal function. A high incidence of metabolic acidosis and other adverse effects have been noted among these patients but the reasons for this have not been explained. We hypothesized that commonly used doses of acetazolamide among the elderly result in excessive blood concentrations and that these concentrations are related to acid-base disturbances. We measured steady-state acetazolamide levels in plasma, plasma ultrafiltrate (unbound), and erythrocytes among 12 elderly subjects (79.2 +/- 7.6 years old). Mean plasma (18.9 +/- 10.9 micrograms/mL) and ultrafiltrate concentrations (1.0 +/- 0.7 microgram/mL) exceeded the therapeutic range (plasma 5-10 micrograms/mL; ultrafiltrate 0.25-0.50 microgram/mL) for glaucoma control by two fold and were elevated in 75% of subjects. Plasma and ultrafiltrate acetazolamide levels significantly correlated with the dose adjusted for creatinine clearance (r = 0.91, P less than 0.001; r = 0.89, P less than 0.001, respectively). Acidotic subjects (serum total carbon dioxide less than or equal to 22 mEq/L) tended to have higher plasma, ultrafiltrate, and erythrocyte acetazolamide levels compared with nonacidotic subjects. Serum total carbon dioxide levels were significantly correlated with erythrocyte acetazolamide concentrations (r = -0.75, P = 0.03). The ratio of erythrocyte acetazolamide concentration to creatinine clearance separated acidotic from nonacidotic subjects (P less than 0.01). These findings suggest that some of the adverse effects of acetazolamide can be avoided by reducing the dose to compensate for age-related reductions in renal drug clearance.

Single and Multiple Dose Pharmacokinetic Evaluation of Flutamide in Normal Geriatric Volunteers

Abstract: Single dose and steady-state pharmacokinetics of flutamide (F) and its active plasma metabolite, hydroxyflutamide (HF) were studied in twelve healthy geriatric volunteers administered 250 mg flutamide capsules on day 1 and 250 mg flutamide capsules three times a day on days 2 through 9 After oral administration, F was rapidly absorbed and metabolized It was present in the plasma in small and variable concentrations, which precluded quantitative assessment of pharmacokinetic parameters for individual subjects Steady-state plasma concentrations were reached on or before Day 6 The mean steady state Cmax (Day 9), 1127 ng/ml, occurred at 13 hr Pharmacokinetic analysis of mean data at steady-state gave a distribution and elimination half-life of 08 hr and 78 hours, respectively The plasma levels for HF were much higher and less variable than F The mean Cmax for HF averaged 894 ng/ml at 27 hours after a single dose and 1719 ng/ml (Day 9) at 19 hr after multiple doses The distribution and elimination half-lives of HF at steady-state were 19 and 96 hours, respectively The steady-state HF plasma concentrations were also achieved on or before Day 6 and were approximately twice those obtained after a single dose From this study, it has been demonstrated that the pharmacokinetics of F and HF do not change appreciably upon multiple dosing of 250 mg F capsule given three times a day

Effects of food and antacid on oral absorption of misoprostol, a synthetic prostaglandin E1 analog

Abstract: Misoprostol, a synthetic PGE1 analog with mucosal protective and antisecretory properties, is rapidly and essentially completely metabolized to its active metabolite, misoprostol acid Relative to fasting conditions administration of misoprostol with antacid resulted in reduced bioavailability, as manifested by lower AUC(0-4) values from (mean +/- SD; n = 12) 417 +/- 135 to 349 +/- 108 pghr/ml (P less than 005), without significant changes in the rate of absorption (tmax = 14 +/- 8 [fasting] vs 20 +/- 14 min [with antacid]) The observed Cmax values were also reduced (from 811 +/- 317 to 689 +/- 315 pg/ml), however, the difference was not statistically significant Drug administration with a high-fat content meal resulted in a marked slowing in the absorption rate without a substantial decrease in the extent Relative to fasting conditions food decreased misoprostol acid Cmax from 811 +/- 317 to 303 +/- 176 pg/ml (P less than 005) and increased tmax from 14 +/- 8 to 64 +/- 79 min (P less than 005): the AUC changes remained statistically insignificant from 417 +/- 135 to 373 +/- 111 pghr/ml Administration of misoprostol with food could potentially decrease the incidence of systemic side effects by reducing the early high peak plasma concentrations of misoprostol acid

Enterohepatic Circulation of Drugs

Abstract: Review on the processes of biliary excretion and enterohepatic circulation of drugs and the pharmacokinetic and pharmacodynamic consequences thereof

Pharmacokinetics of nifedipine slow release tablet in Mexican subjects: further evidence for an oxidation polymorphism.

Abstract: Nifedipine kinetics after ingestion of 20 mg slow release tablets were studied in 12 young, healthy, Mexican subjects. Plasma levels were determined by a nifedipine-specific HPLC assay. Levels rose after drug administration reaching a maximum concentration of 48.7 +/- 7.3 ng/ml in 2.1 +/- 0.7 h (mean +/- SEM). Concentrations then decayed with a terminal half-life of 16.9 +/- 3.1 hours. AUC was 526 +/- 62 ng h/ml. Five individuals were fast and seven were slow nifedipine metabolizers, according to the AUC criterion proposed by Kleinbloesem and coworkers. Individual AUC/Dose values from this and from other two studies on oral nifedipine kinetics in Mexicans were cumulated and the frequency histogram and probit analyses were performed (N = 30). A bimodal distribution was clearly observed. Fast and slow metabolizers were distinguished as those subjects with AUC/Dose values either lower or higher than 22.5 ng h/ml mg. Unlike European populations, it appears that slow metabolization is more frequent in Mexicans. Data strongly support the hypothesis of the existence of a polymorphism concerning nifedipine disposition kinetics due to genetic basis.

A Double-Blind Study with Placebo Control of Intramuscular Ketorolac Tromethamine in the Treatment of Cancer Pain

Abstract: The analgesic efficacy of ketorolac tromethamine was compared to placebo in 126 patients suffering moderate or severe chronic pain due to cancer in a double-blind parallel randomized study. Ketorolac was administered intramuscularly in doses of 10, 30 or 90 mg. Pain intensity and pain relief were assessed for 6 hours by scoring standard verbal scales and an overall assessment of the medication was given by the patients and the observer on completion of the study. Each dose of ketorolac was statistically superior to placebo for the sum of pain intensity difference (SPID) but no difference was seen between the three ketorolac regimens. When the ketorolac groups are combined, there was a significantly better pain relief as compared to placebo. The global evaluation scores were also statistically superior in the ketorolac groups combined than in the placebo group. A total of 15 patients reported minor adverse events, 10 being after ketorolac doses. This study shows that single intramuscular doses of ketorolac of 10 mg and above are effective in the relief of cancer pain, and are associated with a low incidence of side-effects.

Pharmacokinetics of capacity-limited systems.

Abstract: Nonlinearities are commonplace in pharmacokinetics and most frequently occur because of a limited concentration of biological material available for interaction with relatively high concentrations of drugs. The Michaelis-Menten-type function can be applied to metabolism, transport, and binding phenomena that display capacity-limitation. Nonlinear systems can be handled with differential equations (directly or converted to linear form), integrated equations (in non-closed form) or with relatively new area/moment or MRT relationships. Drug disposition studies should include several dose levels and recommendations are provided for detecting the presence of one or more nonlinear absorption or disposition processes in typical experimental data.

Glipizide Pharmacokinetics: Effects of Age, Diabetes, and Multiple Dosing

Abstract: Aging and disease may contribute to alterations in drug pharmacokinetics. The purpose of this study was to determine the effects of aging, the presence of NIDDM, and multiple dosing on the pharmacokinetics of glipizide, an oral hypoglycemic drug. Ten healthy young men (under age 25), ten healthy older men (over age 65) and 15 older diabetic men ingested a single 5 mg tablet of glipizide after an overnight fast. Blood samples for measurement of serum glipizide were obtained over the next 24 hours. The study was repeated in the diabetics after 2 weeks of daily therapy. The mean values for Tmax (range 2.0-2.5 hours), Cmax (385-465 micrograms/l), and t1/2 (4.0-4.2 hours) were not significantly different in the three populations after single doses of glipizide. Several subjects in each population had slow absorption, with peak concentrations delayed for up to 12 hours. Only one elderly diabetic subject had evidence of drug accumulation at steady state. AUC, Cl, Vss and V area were not significantly different in the three populations or at steady state, but there was a trend for AUC to be smaller and each of the other parameters to be increased in the older diabetics. The young subjects had a significantly higher fp (0.83%) than either of the two elderly groups (0.55-0.64%), but Cl int did not differ between groups. Age, diabetes, and multiple dosing appear to have little effect on the pharmacokinetics of glipizide and should have little influence on the clinical response to this drug.

Dose Dependent Effect of Diltiazem on the Pharmacokinetics of Nifedipine

Abstract: The effect of diltiazem pretreatment on the pharmacokinetics of nifedipine were determined in six healthy male volunteers. Placebo or diltiazem (30 mg and 90 mg) was given orally three times daily for 3 days in a double-blind, Latin square method. On the fourth day, a 20-mg nifedipine was given orally 1 hour after the last dose of placebo or diltiazem. The mean elimination half-life of nifedipine prolonged significantly following diltiazem (2.54 hours on placebo vs 3.40 hours on 30 mg diltiazem and 3.47 on 90 mg diltiazem, both P less than .01). The mean AUC of nifedipine increased during diltiazem (1726.6 nmol X hr/ml on placebo vs 3838.0 on 30 mg diltiazem, and 5370.0 on 90 mg diltiazem, both P less than .05, 30 mg vs 90 mg, 0.1 less than P less than .05). The ratio of the AUC of primary metabolite (nitropyridine form) to the AUC of nifedipine was reduced by diltiazem pretreatment in a dose-dependent manner. ICG clearance was not influenced following diltiazem. These results indicate that diltiazem dose-dependently alters the pharmacokinetic profiles of nifedipine. The ICG clearance test showed that the liver blood flow did not decrease during diltiazem therapy, therefore, the reduction in the metabolic clearance of nifedipine might be caused by inhibiting effect of diltiazem on the activity of drug oxidizing enzymes.

Bronchial and cardiovascular effects of ocular topical B-antagonists in asthmatic subjects: comparison of timolol, carteolol, and metipranolol.

Abstract: B antagonists eye drops are most effective for the treatment of chronic open angle glaucoma By this way of administration they have a very good systemic bioavailability Bronchial, and cardiovascular effects of three of these topicals: timolol, carteolol and metipranolol have been evaluated in three parallel groups of asthmatic patients The three topics induce bronchoconstriction without significant difference between them, and lower heart rate (sometimes very intensely) whatever the B antagonist studied From these data, it is recommended to practitioners to follow carefully the rules of administration of B blockers, even in eye drops

Long-term Efficacy and Toxicity of High- and Low-Dose Amiodarone Regimens

Abstract: Amiodarone is an effective antiarrhythmic drug for the control of potentially lethal and lethal ventricular arrhythmias (VA) In the United States, a high-dose regimen has been used at the expense of a high toxicity profile for the control of lethal VAs Significant antiarrhythmic efficacy has also been established with low-dose regimens, which carry a low rate of intolerable side effects (54%) when compared with the high-dose regimen (167%) The high incidence of tolerable and intolerable adverse side effects is probably related to high amiodarone loading (3192 g) and maintenance doses (520 mg/d) In contrast, the low-dose regimen uses much lower loading (72 g) and maintenance (280 mg/d) doses

Basic and Clinical Pharmacology of Amiodarone: Relationship of Antiarrhythmic Effects, Dose and Drug Concentrations to Intracellular Inclusion Bodies

Abstract: Amiodarone is a unique class III antiarrhythmic drug with several unusual pharmacokinetic, pharmacodynamic, and toxicological actions which are quite distinct from those of the standard antiarrhythmic drugs. Extensive animal and clinical studies have demonstrated that amiodarone and its major metabolite, desethylamiodarone, both produce a marked increase in the duration of transmembrane action potential, which may be related to their antiarrhythmic as well as clinical electrophysiological activity. Unlike most other cardiovascular drugs, it has been recognized for more than 20 years that optimal antiarrhythmic effects may take several days to weeks after onset of oral therapy. Amiodarone is highly lipid soluble and exhibits at least three separate compartments of drug distribution, with a long elimination half-life of 14-120 days after chronic therapy. The pharmacokinetic profile of desethylamiodarone is qualitatively similar to that of amiodarone, but its elimination half-life is even longer and its tissue distribution may be slightly different. Although there may not be any correlation between serum drug levels and clinical toxicity of amiodarone during long-term therapy, recent animal as well as clinical data suggest that multilamellar intracellular inclusions can be dissociated from cell death or clinical toxicity. Thus, it is possible that amiodarone toxicity can be minimized with low doses or low serum drug concentrations. The metabolite(s) of amiodarone may play a major role in its pharmacological and toxicological actions.

Pharmacokinetics of chloroquine and some of its metabolites in healthy volunteers: a single dose study.

Abstract: Eight healthy volunteers who had not taken chloroquine 2 to 12 months previously participated in a single dose study designed to evaluate the pharmacokinetics of chloroquine and some of its metabolites. Each subject received two tablets of chloroquine sulfate (300 mg base) only. Blood and urine samples were collected just before and periodically after chloroquine administration. These samples were assayed for chloroquine and its N-dealkylated metabolites (monodesethylchloroquine, didesethylchloroquine, 7-chloro-4-aminoquinoline), chloroquine side chain N-oxide and chloroquine di-N-oxide using a high performance liquid chromatographic method. Residual levels of chloroquine and its N-oxidation metabolites were found in all subjects. 7-chloro-4-aminoquinoline was eliminated more slowly (t1/2z = 126.48 +/- 20.13 h) than the other metabolites and the unchanged drug (t1/2z = 106.43 +/- 10.13 h). Also, 7-chloro-4-aminoquinoline had a significantly faster (Student's t-test, P less than 0.05) formation clearance when compared with the other metabolites. The plasma concentration of 7-chloro-4-aminoquinoline was about twice that of the unchanged drug while the plasma concentration of monodesethylchloroquine was about 46% that of the unchanged drug. In order to investigate whether the metabolites were produced from the same binding sites or closely related sites on the cytochrome P-450 system, their formation clearances were correlated. The best correlation (r2 = 0.83) was observed for didesethylchloroquine and monodesethylchloroquine, and a fair correlation (r2 = 0.59) was observed for monodesethylchloroquine and 7-chloro-4-aminoquinoline. Formation clearances of the other metabolites were poorly correlated.(ABSTRACT TRUNCATED AT 250 WORDS)

Pharmacokinetics and pharmacodynamics of alprazolam following single and multiple oral doses of a sustained-release formulation

Abstract: The pharmacokinetics and pharmacodynamics of alprazolam after IV and oral sustained-release (SR) tablet administration were evaluated in 42 healthy, normal, male volunteers. All 42 subjects received a single 1-mg intravenous (IV) alprazolam dose. After a 1-week washout period, the subjects received one of three SR treatments as a single dose: one 1-mg SR tablet, three 1-mg SR tablets, or six 1-mg SR tablets. Beginning 2 days after single-dose SR treatment, each subject received the above SR doses for 3 days. The daily dose for the multiple-dose study was the same as the subject received in the single-dose study. Serial blood samples were collected after each treatment (single-dose IV, single-dose SR, and after the last SR multiple dose), and plasma samples were analyzed by high performance liquid chromatography. Sedation was assessed by a blinded observer at each blood sampling time. Mean pharmacokinetic parameters for IV administration were consistent with previous results. Pharmacokinetic parameters for the SR doses were consistent with linear kinetics over the dosage range studied. The mean absolute bioavailabilities of the SR tablets were greater than 0.84 after single SR doses. Maximal sedation was related to dose after single-dose SR administration. During multiple dosing, chronic tolerance was observed. Maximal sedation scores after 3 days of alprazolam SR administration were independent of the dose administered and were lower after multiple-dose administration than scores observed after single oral SR doses, although plasma alprazolam concentrations were at least 1.5 times higher with multiple dosing. Sedation data indicate that oral SR doses were well tolerated in multiple dosing.(ABSTRACT TRUNCATED AT 250 WORDS)

Interaction between propranolol and propafenone in healthy volunteers.

Abstract: The effects of propafenone on the pharmacokinetics and pharmacodynamics of propranolol were evaluated in 12 healthy male subjects. Both propafenone and propranolol were each administered alone for one week followed by concomitant administration for an additional week. Blood samples, obtained at steady-state, were analyzed for propafenone and its two metabolites as well as for propranolol and 4-hydroxypropranolol. Left ventricular function, exercise performance and electrocardiographic intervals were assessed. Coadministration of propranolol did not produce any significant change in propafenone kinetics including peak plasma concentration (Cmax), time to peak plasma concentration (Tmax), elimination rate constant (t1/2), mean steady-state plasma concentration (Css), or area under the concentration vs time curves. However, concomitant propafenone administration significantly increased Cmax (83%), Tmax (55%), t1/2 (30%), and Css (213%) which were accompanied by significant decreases in plasma levels of 4-hydroxy-propranolol. Propafenone and propranolol significantly reduced supine systolic and diastolic blood pressure by 2.5 to 15.4%. The combination did not reduce diastolic blood pressure further (64.0 +/- 2.8 to 59.7 +/- 1.7 mmHg) nor did it produce a supplemental reduction in heart rate (12% reduction with propranolol, 10% reduction with concomitant administration). Propranolol, but not propafenone, significantly decreased end-diastolic volume index (13%), stroke volume index (15%), and velocity of circumferential fiber shortening (19%). The combination did not cause any further changes in echocardiographic measurements. Electrocardiographic intervals were not altered by either drug use alone or in combination.(ABSTRACT TRUNCATED AT 250 WORDS)

Instruction in clinical pharmacology: changes in the wind.

Abstract: We have presented some views on past, present and potential trends for teaching clinical pharmacology in the medical curriculum. Clinical pharmacology as subject matter in the medical curriculum has been operationally defined for our purposes as: (1) the application of fundamental principles of basic pharmacology to rational drug therapy in humans; and (2) the application of appropriate nuances of the human pharmacology of individual drugs to their use in particular disease states. In terms of improving the results of drug therapy, arguments were advanced for the importance of teaching clinical pharmacology at all levels in the medical curriculum and in postgraduate medical education. The introduction of so many new and potent pharmaceuticals over the past 25 years requires well educated and skilled medical practitioners adept and well versed in the fundamental principles of basic and applied pharmacology, so as to achieve the most prudent, effective and economically sound use of these drugs as possible. This creates a challenge to medical educators, particularly those involved in teaching clinical pharmacology, to devise innovative teaching techniques and curricular changes that foster these goals. In an attempt to address these challenges, we have reviewed some innovative teaching approaches and curricular reforms, both published and unpublished, that have already met with success, and we have also discussed some future trends in teaching both undergraduate and graduate physicians the fundamental principles of rational drug therapy. The challenges and issues involved in these future trends have been identified and will be addressed in subsequent articles in this journal. These will be concerned with teaching clinical pharmacology: (1) in basic medical pharmacology courses; (2) to upperclass medical students; and (3) in continuing medical education programs. Subsequent articles will also deal with new and innovative teaching modalities for clinical pharmacology and with the role of the drug industry in these modalities.

Chronopharmacokinetic Study of Valproic Acid in Man: Comparison of Oral and Rectal Administration

Abstract: Circadian stage-dependent changes of valproic acid (VPA) kinetics was examined after rectal administration comparing after oral dosing. Eight healthy volunteers took a single oral or rectal dose of VPA 400 mg, in a form of sodium valproate, on two occasions, at 8:30 A.M. or 8:30 P.M. Subjects were synchronized with diurnal activity and nocturnal rest as their usual life under standardized meal conditions. After oral administration, mean total VPA concentrations in plasma were significantly higher in the morning than in the evening during the absorption phase. Cmax tended to be higher, tmax was shorter (P less than 0.05) and absorption rate constant (ka) tended to be larger (0.05 less than P less than 0.1) for VPA in the morning than in the evening, although no difference was demonstrated in other pharmacokinetic values between morning and evening trials. After rectal administration, no significant difference was demonstrated in VPA kinetics between morning and evening trials. The rectal administration might have an advantage to eliminate the time-dependent changes of VPA kinetics. Thus the current practice of giving a rectal dose seems to be justified because the time-dependent changes in VPA kinetics observed after oral administration may be reduced without compromising therapeutic efficacy.

The Pharmacokinetics and Pharmacodynamics of Hydroxyzine in Patients with Primary Biliary Cirrhosis

Abstract: Hydroxyzine, a potent H1-receptor antagonist often used for relief of pruritus in patients with hepatic dysfunction, was studied in eight patients, mean age 53.4 +/- SD 11.2 years, with primary biliary cirrhosis. The patients ingested a single dose of hydroxyzine, 0.7 mg/kg (mean dose 43.9 +/- 6.6 mg). Before the dose, then hourly for 6 hours, every 2 hours from 6-12 hours, at 24 hours, and every 24 hours for 6 days, serum hydroxyzine and cetirizine were measured and an intradermal injection of 0.01 mL of a 0.1 mg/mL solution of histamine phosphate was performed. Wheals and flares were traced at 10 minutes and the areas were calculated. Mean peak hydroxyzine levels of 116.5 +/- 60.6 ng/mL occurred at 2.3 +/- 0.7 hours and mean peak cetirizine levels of 500.4 +/- 302.0 ng/mL occurred at 4.8 +/- 2.8 hours. The mean serum elimination half-life of hydroxyzine was 36.6 +/- 13.1 hours, and the mean serum elimination half-life of cetirizine was 25.0 +/- 8.2 hours. The mean hydroxyzine clearance rate was 8.65 +/- 7.46 mL/min/kg, and the mean volume of distribution was 22.7 +/- 13.3 L/kg. The mean wheal area was suppressed (P less than 0.01) from 1 to 120 hours, with maximal suppression from 2 to 48 hours. The mean flare area was suppressed from 1 to 144 hours, with maximal suppression from 3 to 24 hours (P less than 0.01). All patients became sleepy from 0.5 to 6 hours. Blurred vision, dizziness and dry mouth each occurred in two patients. Hydroxyzine elimination is impaired in patients with primary biliary cirrhosis.(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of coadministration of propafenone on the pharmacokinetics of digoxin in healthy volunteer subjects.

Abstract: Previous reports have suggested an interaction between propafenone and digoxin. We investigated the pharmacokinetics of IV digoxin when given alone (Phase I), after pretreatment with propafenone 150 mg every 8 hours for seven days (Phase II), and after propafenone 300 mg every 8 hours for 7 days (Phase III). The total body clearance of digoxin during Phase I was 2.45 ml/min/kg and was 2.17 ml/min/kg during Phase II (NS) and decreased to 1.92 ml/min/kg during Phase III (P less than 0.05). The renal clearance and half-life of digoxin were not significantly altered by propafenone. There was a trend towards a decrease in the volume of distribution of digoxin from 9.43 L/kg in Phase I, to 9.33 L/kg in Phase II, and 8.02 L/kg in Phase III. Similarly there was a trend towards a decreased nonrenal clearance of digoxin from 1.21 ml/min/kg during Phase I to 1.01 ml/min/kg during Phase II and to 0.75 ml/min/kg during Phase III. The changes in volume of distribution and nonrenal clearance parallel each other resulting in no change in the elimination half-life of digoxin. It is postulated that the mechanism of this interaction is due to decreases in the volume of distribution and nonrenal elimination of digoxin by propafenone. The degree of this interaction was related to the dose of propafenone. The magnitude of this interaction may be greater in patients and, thus, may require a reduction in the digoxin dose.

Single dose safety, tolerance, and pharmacokinetics of HP 029 in healthy young men: a potential Alzheimer agent.

Abstract: 1,2,3,4-tetrahydro-9-aminoacridin-1-ol maleate (HP 029) is a new cholinergic compound that has been shown to enhance memory in animals and therefore may be potentially effective in humans for the treatment of Alzheimer's disease (AD). The initial safety, tolerance, and pharmacokinetics of HP 029 after single oral doses were assessed in a randomized, double-blind, placebo controlled study in 70 healthy young men (eight dose groups). The test doses ranged from 5 to 200 mg. There were 9 subjects per dose group, 6 on HP 029 and 3 on placebo. The 5 and 100 mg dose groups had only 8 subjects. Plasma and urine samples were analyzed for nonconjugated HP 029 using an HPLC assay with a detection limit of 1 ng/ml. HP 029 was rapidly absorbed after oral dosing with mean peak plasma levels occurring between 0.75 and 1.2 hours. The mean peak levels ranged from 12.7 and 234.7 ng/ml after the 10 and 200 mg doses, respectively. There were dose related increases in peak plasma levels, AUCs, and the amounts of drug excreted in the urine. The mean plasma half-life was about 2.0 hours and was not affected by dose. About 6 to 11% of the dose was eliminated in the urine. HP 029 was renally cleared at a high rate and independent of dose. There were no clinically important or drug-related changes in any of the physical examinations, audiograms, or ophthalmologic examinations. There were only minor within-subject fluctuations in vital signs, ECGs, and laboratory values, none of which were clinically meaningful or drug related after any of the doses of HP 029.(ABSTRACT TRUNCATED AT 250 WORDS)

Lovastatin and other HMG-CoA reductase inhibitors

Abstract: Revue concentrant toutes les donnees recentes concernant la pharmacologie, la pharmacocinetique et l'efficacite clinique ainsi que les effets indesirables de la levastatine, la provastatine et la simvastatine chez l'animal et l'homme