Duloxetine pharmacokinetics in cirrhotics compared with healthy subjects.

OBJECTIVE: To compare the pharmacokinetics of single-dose duloxetine in cirrhotic and healthy subjects. METHODS: An open-label inpatient study compared duloxetine pharmacokinetics in six subjects with moderate liver cirrhosis (Child-Pugh class B) to those in six healthy subjects. Subjects received a single 20 mg capsule of duloxetine following overnight fasting. Blood samples were collected up to 120 h post dose for determination of plasma concentrations of duloxetine and its major metabolites using a validated LC/MS/MS method. Plasma concentration-time data for duloxetine and its major metabolites were analyzed by noncompartmental methods. Specific pharmacokinetic parameters were assessed statistically using a mixed-effects model. RESULTS: Duloxetine apparent clearance was significantly lower (24 vs 160 l/h, p < 0.05) and AUC values were substantially higher (775 vs 268 ng x (h/ml) in cirrhotic compared to healthy subjects. The half-life of duloxetine was about three times longer (47.8 vs 13.5 h) in cirrhotic than in healthy subjects (p < 0.05). In contrast, there was no significant difference in Cmax or apparent volume of distribution between the two groups. The metabolites exhibited lower levels and longer half-lives in cirrhotic subjects compared to healthy subjects. The lower clearance and slower elimination of duloxetine in cirrhotic individuals is likely attributable to impaired duloxetine metabolism. CONCLUSIONS: The rate of duloxetine elimination is reduced for cirrhotic subjects, making dosage adjustments appropriate. Based on simulations, the duloxetine dose for at least an initial treatment period may need to be reduced and/or less frequently administered for patients with moderate cirrhosis.

Evaluation of the IITC tail cuff blood pressure recorder in the rat against intraarterial pressure according to criteria for human devices.

National standards govern the manufacture and marketing of medical devices in the United States, including those for indirect blood pressure measurement in man. There are no comparable standards for devices for recording in laboratory animals. Noninvasive tail cuff blood pressure (BP) recording in the rat is widely accepted, but beset by methodologic difficulties. Intraarterial recording is regarded as the "gold standard" but is invasive and also susceptible to methodologic error. We compared the IITC Mark 12 photoelectric/oscillometric tail cuff system (IITC Life Sciences, Woodland Hills, CA) versus simultaneous femoral intraarterial recordings in spontaneously hypertensive rats, during anesthesia and 1 to 2 days after recover (150 recordings under each condition), according to the guidelines for human data collection and analysis suggested the American National Standard for automated sphygmomanometers. Within- and between-observer disagreements in estimates made by two observers from 40 anesthetized recordings were less for intraarterial measurements than for the tail cuff method. Within-observer differences (mean +/- SD of differences [SDD]) for systolic, diastolic, and mean pressure were 0 +/- 1, 0 +/- 1, and 0 +/- 1 mm Hg for intraarterial versus -1 +/- 3, 0 +/- 8, and 0 +/- 5 mm Hg for tail cuff. Between-observer differences were 0 +/- 2, 0 +/- 1, and 6 +/- 2 mm Hg versus 5 +/- 4, 13 +/- 7, and 0 +/- 5 mm Hg, respectively. Differences between tail cuff and intraarterial methods were 16 +/- 13, -5 +/- 11, and 2 +/- 8 mm Hg in anesthetized animals and 8 +/- 14, -5 +/- 9, and 0 +/- 9 mm Hg in conscious animals (39% to 82% of differences exceeded 5 mm Hg). The upper limits of clinically acceptable disagreement in the American National Standard are: mean of 5 mm Hg, SDD of 8 mm Hg. The disagreement between tail cuff and intraarterial recordings cannot be ascribed to either method with certainty. These findings do not support the manufacturer's guarantee of tail-cuff readings within "5 mm Hg of intraarterial." Inaccuracy and unreliability of devices intended for laboratory animal use have considerable scientific, fiscal, and ethical implications. Marketing of these devices should also be governed by rigorous standards.

A simple computer based system to analyze Morris water maze trials on-line.

The development of a system for the acquisition, analysis and storage of data from open-field water-maze procedures in which rats learn to escape from water onto a hidden platform is described. The use of an object-oriented programming language simplifies the programming of the application and provides scientists without formal training in computer programming the ability to create their own software application. The core hardware is an IBM-compatible AT 486 computer and a video capture board. The Microsoft Windows compatible software is written in G (LabVIEW) and presents the user a graphically based 'virtual instrument' thus simulating functions of real instruments which can be interactively accessed. The graphical approach allows the programmer to make fast and simple adaptations of the software to suit the specific experimental problem. Image analysis software tools (Concept V.i) were integrated into this system which has been used successfully for over 2 years in our lab.

Effects of captopril and propranolol on cognitive function and cerebral blood flow in aged hypertensive rats.

Chronic hypertension has been reported to produce adverse cognitive effects in elderly individuals, perhaps by altering central nervous system hemodynamics. The beneficial or adverse effects of antihypertensive drugs on these processes are not well understood. We examined the effects of captopril (90 mg/kg/day) and propranolol (80 mg/kg/day) on cognitive function and brain blood flow in hypertensive and normotensive rats. Cognitive function was assessed by the Morris water maze, and regional brain blood flow was measured by the [14C]iodoantipyrine method. Nineteen-month-old propranolol-treated hypertensive rats exhibited poorer performance (p < .05) than control rats and had lower brain blood flows, particularly in white matter regions (p < .01). Captopril-treated hypertensive rats did not differ significantly from control rats with regard to either cognitive performance or brain blood flow. In the normotensive rats, there were no effects of either drug on cognitive performance or brain blood flow. Thus, blood pressure reduction by propranolol but not captopril has an adverse effect on cognitive function and brain blood flow in hypertensive rats.

The clinical pharmacokinetics of rifabutin.

Rifabutin is structurally similar to rifampin, but there are important pharmacokinetic differences between the two drugs. Rifabutin is more lipid soluble than is rifampin, resulting in more-extensive tissue uptake, a larger volume of distribution, lower maximum plasma concentrations, lower trough concentrations, a longer terminal half-life, and higher tissue-to-plasma drug concentration ratios. The oral bioavailability of rifabutin is low. Like rifampin, rifabutin induces its own metabolism during multiple dosing. Rifabutin is extensively metabolized. The two major metabolites of rifabutin contribute to its antimicrobial activity. Rifabutin induces hepatic metabolism but is not as potent an inducer as is rifampin. Rifabutin does not affect the pharmacokinetics of antiretroviral drugs that are excreted in the urine. Although rifabutin decreases plasma concentrations of zidovudine, this finding does not appear to be clinically relevant. When administered during rifabutin prophylaxis, fluconazole decreases the incidence of Mycobacterium avium complex bacteremia. The coadministration of clarithromycin and rifabutin results in increased plasma concentrations of rifabutin and decreased plasma concentrations of clarithromycin; however, the plasma concentration of clarithromycin's active metabolite is increased.

Clinical pharmacokinetics of rifabutin.

The clinical effectiveness of rifabutin for prophylaxis of disseminated Mycobacterium avium complex infection has recently been demonstrated in HIV-positive patients with low CD4 counts. Rifabutin is a newly marketed, semisynthetic antimycobacterial agent similar to rifampicin (rifampin) in structure and activity. However, rifabutin has important pharmacokinetic differences compared with rifampicin. Rifabutin has relatively low oral bioavailability; about 20% after single dose administration. With long term administration rifabutin induces its own metabolism and the metabolism of some other drugs. The elimination half-life of rifabutin is long (45 hours) but, as a result of a very large volume of distribution (> 9 L/kg), average plasma concentrations remain relatively low after repeated administration of standard doses. In vitro rifabutin is more active against M. avium-intracellulare complex and at least as active against M. tuberculosis as rifampicin. In vivo the advantage of rifabutin is less apparent due to its lower plasma concentrations at equivalent doses. Adverse effects are unusual at the recommended oral dosage of 300 mg/day, but become common as the total daily dose approaches 1 g. Dose-limiting toxicity consists of a polyarthralgia/arthritis syndrome, possibly complicated by uveitis. More clinical studies are needed to establish the role of rifabutin in combination therapy for M. avium-intracellulare complex and other mycobacterial infections.

Effects of antihypertensive drugs atenolol and nifedipine on sexual function in older men: a placebo-controlled, crossover study.

Investigated the adverse sexual effects of two antihypertensive drugs, atenolol and slow-release nifedipine, in a placebo-controlled, randomized, crossover study. Subjects were 16 older men (mean age = 66.6 years, SEM = 1.4) with mild to moderate hypertension. Subjects completed daily self-reports on 13 measures of sexuality: frequency of desire, coitus, noncoital partner sex, masturbation, morning erections, spontaneous erections, orgasms in coitus and masturbation, firmness of morning, masturbatory and coital erections, and subjective pleasure in coitus and masturbation. Except for a significant decrease in masturbatory erectile firmness with nifedipine therapy, variables did not differ between the two drug treatments or between either drug and placebo. Although the sample was relatively small, small differences between treatment means suggest that these antihypertensive agents are fairly benign relative to sexual function in men.

Pharmacologic considerations in the treatment of substance abuse.

Drug and alcohol abuse continue to be commonly encountered problems in most patient populations. To deal effectively with these problems, the primary care physician must have a thorough knowledge of the pharmacology of commonly abused drugs and the adjunctive agents used in treatment. Management of alcoholism may involve a range of medical interventions, including the treatment of alcohol intoxication, the use of benzodiazepines for alcohol withdrawal, and possibly the short-term administration of disulfiram to maintain sobriety. Successful management of cocaine or amphetamine abuse requires an understanding of the powerful reinforcing properties of these drugs and the unique problems that arise in the recovery period. Barbiturate intoxication and withdrawal are potentially life-threatening events requiring skilled in-patient treatment. Prolonged use of benzodiazepines can lead to drug dependence; successful withdrawal involves gradual dosage reduction. Acute intoxication from marijuana or hallucinogenic drugs may occasionally result in adverse reactions requiring medical intervention, but significant withdrawal reactions are rare. Management of opioid overdose, whether illicit or iatrogenic, requires the prompt and skillful use of opioid overdose, whether illicit or iatrogenic, requires the prompt and skillful use of opioid antagonists. Promising new pharmacologic approaches are now being successfully applied to the management of opioid dependence. An acceptance of nicotine as the addictive component of tobacco smoke has led to the development of nicotine gum as substitution therapy for cigarette smoking. Successful pharmacologic management of overdose or withdrawal is often the prerequisite for effective long-term treatment and recovery.

Atenolol compared with nifedipine: effect on cognitive function and mood in elderly hypertensive patients.

OBJECTIVE: To compare the effects of atenolol and nifedipine on mood and cognitive function in elderly hypertensive patients. DESIGN: Randomized, double-blind, crossover trial. PATIENTS: Thirty-one elderly volunteers (7 women and 4 men) 60 to 81 years of age with mild to moderate hypertension were recruited from the general community and a Veterans Affairs hospital hypertension clinic. Six volunteers withdrew at early phases of the study for reasons unrelated to adverse drug effects. INTERVENTIONS: Participants had 2 weeks of placebo, to 6 weeks of titration with atenolol or nifedipine, and weeks of treatment followed by similar periods with the other drug. MEASUREMENTS: Psychometric tests designed to assess mood and cognitive function. RESULTS: In the group first treated with nifedipine, the summed recall score on the Buschke selective reminding test (a test of verbal learning and memory) decreased by 9.3 words (95% CI, 2.8 to 15.6 words), or 0%, during nifedipine treatment compared with placebo (P = 0.031). The group first treated with atenolol showed no improvement in summed recall scores when results seen during atenolol therapy and placebo administration were compared (P = 0.10); however, this group had an improvement of 16.1 words (CI, 5.6 to 26.5 words), or of 16%, when the atenolol score was compared with the nifedipine score (P = 0.026). In the group first treated with nifedipine, 6 of 11 patients 55%) showed a decrease of 5 words or more during nifedipine therapy compared with placebo, whereas only 1 of the 14 patients (7%) in the group first treated with atenolol showed a similar decrease (P less than 0.01). On the digit symbol test (a psychomotor test), patients treated first with atenolol tended to improve, whereas patients treated first with nifedipine tended to decline. The difference between nifedipine and atenolol, in terms of the change from the score seen during placebo, was 4.3 codings (CI, 0.7 to 7.9 codings) or 10% (P = 0.043). No statistically significant differences were seen between nifedipine and atenolol therapy regarding the other measures of psychomotor ability, sustained attention, motor performance, verbal fluency, or abstract reasoning, and no effects of either drug on mood or psychopathologic symptoms were noted. CONCLUSIONS: Although atenolol and nifedipine are generally free of gross effects on cognition or mood, nifedipine may subtly impair learning and memory in some elderly hypertensive patients.

Rapid method for the determination of ketanserin in rat serum by high-performance liquid chromatography with fluorimetric detection.

A simplified high-performance liquid chromatographic (HPLC) assay for the determination of ketanserin in rat serum is described. The chromatographic method allowed complete resolution of ketanserin from two of its metabolites. A protein precipitation extraction procedure was employed which allowed rapid sample preparation for injection into the HPLC system. Both intra- and inter-assay coefficients of variation at serum ketanserin concentration of 200 and 800 ng/ml were less than 6% and the accuracy was excellent. The assay has been applied for determining the elimination kinetics of ketanserin in the rat.

Ranitidine alters antipyrine metabolism in control and phenobarbital-treated mice.

The effect of ranitidine on both induced (phenobarbital) and uninduced cytochrome P450 enzymes was investigated in mice using the [14C]-labeled antipyrine breath test. Ranitidine administration resulted in a decrease in the fraction of the administered dose of antipyrine exhaled as radiolabeled CO2 (CERAUC0-infinity) indicating inhibition in the demethylase pathway (Kdm), and resulted in induction of enzymes in the non-demethylase pathways (Kndm) as well. No change in antipyrine total elimination rate constant (Kel) was seen after ranitidine administration alone. Concurrent administration of ranitidine and phenobarbital resulted in an increase in the (Kel) but the change was less than that seen after phenobarbital alone. A reduction in CERAUC0-infinity was seen after the combination treatment while phenobarbital alone resulted in an increase in this parameter. Ranitidine, therefore, alters the pattern of antipyrine metabolism by inhibition of demethylase enzymes and induction of non-demethylase enzymes, the former activity being more pronounced in induced forms. Because of the simultaneous occurrence of both effects, no change in antipyrine half-life was noted with uninduced P450 isozymes.

Acetaminophen metabolism in recovering alcoholics.

The mercapturic acid conjugate of acetaminophen has been proposed as an index of the toxic intermediate of acetaminophen metabolism which is responsible for the increased incidence of liver injury in alcoholics taking the drug. Previous studies which compared alcoholics with normal patients failed to show any significant difference in mercapturic acid production. We undertook a longitudinal study in recovering alcoholics to test the hypothesis that abstinence should lead to a decrease in acetaminophen-mercapturic acid excretion. The patients were given a 1500 mg dose of acetaminophen soon after they stopped drinking then again approximately 2 weeks later. Urine was collected for 24 h and assayed for mercapturic acid conjugate. There was no significant difference in mercapturic acid excretion when the two measurements were compared. If the toxic intermediate hypothesis is correct, either the effect of alcohol is prolonged, or additional factor other than alcohol exposure may influence mercapturic acid excretion.

Adverse reactions and interactions with theophylline.

Despite the trend towards newer therapeutic agents, theophylline continues to play a major role in the treatment of reversible airway obstruction. Clinical use of the drug is complicated by a relatively narrow therapeutic range and a large pharmacokinetic variability between patients. Generally, however, theophylline toxicity is foreseeable and preventable. Most cases can be attributed to either inadvertent or intentional overdosing of the drug. Age, disease state and drug interactions are other factors which may contribute to its toxicity. Nausea, vomiting and tachycardia are common signs of mild theophylline toxicity; seizures, ventricular arrhythmias and hypotension are life-threatening manifestations of severe toxicity which may respond poorly to standard therapy. Although serum theophylline concentration correlates with toxicity in a general fashion, life-threatening adverse reactions are not readily predictable from the drug concentration alone. Treatment of theophylline toxicity primarily involves supportive care along with gastric lavage and administration of activated charcoal to facilitate drug removal. The early use of haemoperfusion may be life-saving in cases of severe toxicity.

Pharmacokinetics of rifabutin.

We investigated the pharmacokinetics of rifabutin in 15 male patients as part of a phase I trial of the treatment of early symptomatic human immunodeficiency virus infection. Six or more patients were studied at each of four different oral dosage levels: 300, 600, 900, and 1,200 mg/day. Twelve studies were also conducted with tracer doses of intravenous radiolabeled [14C]rifabutin. Blood and urine samples were collected for at least 72 h after the first (day 1) and last (day 28) doses of rifabutin and analyzed by high-pressure liquid chromatography. The plasma concentration data were best described by a two-compartment open model with a terminal half-life of 36 h. Rifabutin was rapidly absorbed, reaching a peak concentration about 2 to 3 h after an oral dose. Peak and trough concentrations for the 1,200-mg dose were 907 and 194 ng/ml, respectively. Total body clearance was 10 to 18 liters/h. Oral bioavailability was 12 to 20%. The drug was moderately bound to plasma proteins with a free fraction of 29 +/- 2% (mean +/- standard deviation). About 10% of an administered intravenous dose of rifabutin is excreted into the urine unchanged. Renal clearance was 1.5 +/- 0.2 liters/h. The volume of distribution was large (8 to 9 liters/kg), suggesting extensive distribution into the tissues. The area under the curve for the last dose was smaller than that of the first dose, suggesting possible induction of drug-metabolizing enzymes.

Sulindac inhibits bumetanide-induced sodium and water excretion.

In an open-label pilot study, we investigated the effect of sulindac on bumetanide-induced diuresis. Nine healthy volunteers were placed on diets with a standard sodium and potassium content. Each volunteer received 1 mg bumetanide orally, and blood and urine samples were collected during an 8-hour period. Urinary losses were replaced isovolumetrically with intravenous normal saline solution. Creatinine clearance and sodium and potassium excretion were compared with and without sulindac pretreatment (200 mg administered orally b.i.d. for 5 days). Sulindac pretreatment resulted in a 22% decrease in the mean cumulative sodium excretion after 3 hours (p less than 0.05) and a 21% decrease in the mean urine flow rate after 2 hours (p less than 0.05). The results suggest that sulindac has an effect on the kidney similar to that of other nonsteroidal agents.