Single-dose pharmacokinetics of bupropion in adolescents: effects of smoking status and gender.

Sustained-release (SR) bupropion (Zyban) is approved as a smoking cessation aid for adults. Since smoking often begins in adolescence, we determined the single-dose pharmacokinetics of bupropion SR in 75 adolescent subjects ranging from 13 to 18 years old. Subjects self-reported their smoking status. Urinary cotinine concentration was used to verify smoking status. Thirty-seven subjects (18 males, 19 females) were classified as cigarette smokers and 38 were nonsmokers (19 males, 19 females). Fasted subjects received one tablet (150 mg) of bupropion SR, and plasma samples were collected before (0) and 1/2, 1, 2, 3, 4, 6, 8, 24, 48, and 72 hours after dosing. Plasma samples were analyzed for bupropion and its three major metabolites (hydroxybupropion and the aminoalcohol isomers, erythrohydrobupropion plus threohydrobupropion, expressed as a composite) by solid-phase extraction, followed by LC/MS/MS. Factorial analysis of variance (ANOVA) was used to evaluate the effects of smoking and gender on pharmacokinetic parameters. Smokers and nonsmokers differed significantly (p < 0.05) in age and urinary cotinine (p < 0.01) concentration but did not differ significantly in mean weight, height, body surface area, or body mass index. The pharmacokinetic (PK) parameters for bupropion and hydroxybupropion did not differ between smokers and nonsmokers, but differences were found between male and female subjects. Mean values for area under the plasma concentration versus time curve (AUC0-->infinity), volume of distribution (Vd beta) normalized to body weight, maximum plasma concentration (Cmax), and elimination half-life (t1/2 beta) for bupropion were significantly (p < 0.05) greater in females than males, while clearance of bupropion normalized to body weight (CL/f) did not differ between males and females. Females also exhibited significantly (p < 0.05) larger values for hydroxybupropion mean AUC0-->infinity and Cmax than males. The mean ratio of hydroxybupropion to bupropion AUC for adolescents was approximately 4 to 5, which is lower than that previously reported for adults. In conclusion, smoking status does not affect the single-dose pharmacokinetics of bupropion SR in adolescents. However, females differ from males in several potentially important PK parameters for bupropion and its major metabolite, hydroxybupropion.

Prokinetic effects of erythromycin after antimotion sickness drugs.

Motion sickness and the antimotion sickness drugs scopolamine (SCP) and promethazine (PMZ) inhibit gastric emptying (GE). This study was conducted to determine if erythromycin would exert its well-known prokinetic effects in normal and motion-sick subjects given antimotion sickness drugs. Fifteen fasted volunteers (11 males, 4 females) participated in the study. In control tests, 8 subjects were given intramuscular (i.m.) saline (SAL, 0.5 ml), SCP (0.1 mg), or PMZ (25 mg). GE of liquid (300 ml) containing 1 mCi of Tc 99m diethylenetriaminepentaacetic acid (DTPA) was measured by sequential gastric scintigraphy 30 minutes after i.m. treatments. In other tests, GE was measured in 8 subjects after each i.m. treatment, followed 10 minutes later by 200 mg of erythromycin ethylsuccinate (ESS) suspension given orally. In a third group of tests, 7 subjects received an i.m. treatment, oral EES 10 minutes later, and were then brought to an advanced level of motion sickness short of vomiting. To induce motion sickness, blindfolded subjects made timed head movements while seated in a rotating chair. GE was measured immediately after rotation. GE half-life, rate constant, area under the curve (AUC), and lag time were calculated using conventional mathematical methods for analyzing exponential rate processes. GE parameters calculated for normal and motion-sick subjects given antimotion sickness drugs and EES were compared with those from subjects given i.m. treatments (control) only. In normal subjects, EES significantly (p < 0.05) increased the GE rate constant for all i.m. treatments and reduced the AUC for SAL, SCP, and PMZ by 49% (p < 0.05), 44% (p < 0.05), and 69% (p < 0.01), respectively. In motion-sick subjects, lag time was significantly (p < 0.05) increased, and the rate constant and AUC values were unchanged from control for all i.m. treatments. The authors conclude that oral EES reverses the gastrostatic actions of the antimotion sickness drugs but does not affect the inhibition of gastric emptying associated with motion sickness. The results suggest that motion sickness and antimotion sickness drugs reduce GE through different mechanisms.

Pharmacotherapy of depression in children.

Depression can interfere with the overall functioning of children and adolescents. It can impair normal cognitive and social development. The use of antidepressant medications in children and adolescents has grown in the past decade. Newer antidepressant agents, the selective serotonin reuptake inhibitors, appear very promising, but their safety and efficacy have not been established for children. This review focuses on depression and the design of studies for its treatment with newer antidepressant drugs in children.

Nedocromil sodium.

OBJECTIVE: To summarize the available pharmacokinetic and pharmacologic data on nedocromil sodium and to present representative clinical trials of this new agent in both mild-to-moderate and severe chronic asthma and allergic rhinitis. Adverse effects are reviewed. DATA SOURCES: A MEDLINE search was used to identify pertinent literature, excluding reviews and foreign-language articles. All available English-language studies were reviewed. DATA EXTRACTION: Pivotal and representative studies are discussed relating to the following issues: pharmacology and pharmacokinetics, management of patients with non-steroid-dependent and steroid-dependent asthma, comparison with sodium cromoglycate (cromolyn), comparison with inhaled beclomethasone dipropionate, management of exercise-induced asthma, use in children with asthma, and use in allergic rhinitis. DATA SYNTHESIS: Nedocromil sodium is chemically grossly unrelated to cromolyn but has similar pharmacology, pharmacokinetics, and therapeutic benefits. Although ineffective in relieving acute asthma attacks, nedocromil appears to be superior to placebo in lessening the severity of chronic asthma and protecting against allergen-induced asthma when taken as chronic prophylaxis. Single doses attenuate exercise-induced asthma. It is also effective in the management of allergic rhinitis. Results have varied when nedocromil has been compared with cromolyn or inhaled beclomethasone. Studies to date indicate that, overall, nedocromil is not significantly better than cromolyn and is no better than or is inferior to inhaled beclomethasone, although individual response appears to be variable, with no identifiable predictive factors. CONCLUSIONS: Individual patients may receive marked improvement from nedocromil therapy, but there are no factors that identify which patients will respond. Nedocromil may be particularly useful in adults who frequently fail to respond to cromolyn.

Optimized formulation of magnetic chitosan microspheres containing the anticancer agent, oxantrazole.

A combined emulsion/polymer cross-linking/solvent evaporation technique was used to prepare magnetic chitosan microspheres (MCM) containing the anticancer drug, oxantrazole. A central composite experimental design was used to simultaneously evaluate a variety of formulation factors on a number of response variables, such as the percentage of oxantrazole entrapped in the MCM. In association with the study design, statistical optimization procedures indicated the factors that significantly influence MCM preparation and what levels of the factors are needed to produce optimum MCM. Entrapment of anticancer agents into biodegradable microspheres is difficult because of low aqueous drug solubility and porosity of the particles. The latter effect was circumvented by a chitosan cross-linking step that resulted in approximately 3% (w/w) oxantrazole entrapment in the MCM via the optimization procedures. The combined formulation and statistical optimization strategy provide a basis to develop other microparticulate systems and led to a dosage form that can be used for future in vivo investigations.

Adverse effects of angiotensin converting enzyme (ACE) inhibitors. An update.

The angiotensin converting enzyme (ACE) inhibitors are a group of effective drugs with a unique mechanism of action. These drugs have proven to be useful for hypertension and congestive heart failure. Early clinical trials of captopril used doses that are now known to be inappropriately high, and dose-related adverse effects were observed frequently. The recognition that lower doses are effective has reduced the incidence of adverse reactions and resulted in improved patient tolerance. When patients are properly selected and correctable risk factors are removed, serious side effects are uncommon. Unfortunately, the early reputation of nephrotoxicity persists, as does the belief that significant blood dyscrasias, endocrine effects and rash are serious risks for the average patient. After wide use of captopril, enalapril and lisinopril, and investigational trials of nearly a dozen newer agents, a sufficiency of clinical observation, experimental evidence and accurate postmarketing recording of events is accumulating to allow insight into the major toxicities with regard to more intelligent patient selection, more rational dosing and proper identification of risk factors. The most common adverse reactions are cough and skin rash. It appears that the agents are generally not cross-reactive with regard to skin rash, although it is not clear whether this effect is drug-specific or class-specific with regard to cough. Statistically but not clinically significant lowering of haemoglobin and hematocrit is common; these effects are inconsequential in most patients. Neutropenia, once thought to be prevalent, now appears to be so only in patients with autoimmune or collagen-vascular disease; the majority of patients outside these groups are at low risk. Hyperkalaemia is a frequent occurrence. This should not be surprising in view of the effect of the ACE inhibitors on plasma aldosterone. When dietary potassium intake is regulated and sources of altered potassium excretion are identified, hyperkalaemia is seldom a serious problem. Identification of sodium and water deficits allows correction before the drugs are started, and the frequency of hypotension and hyperkalaemia caused by the drugs is quite low if these factors are properly managed. An unexpected finding emerging in recent years is the dry cough associated with ACE inhibitor therapy. Its mechanism is not definitely known. Nonsteroidal anti-inflammatory drugs may control this symptom in some patients. The frequent observation of proteinuria in patients taking ACE inhibitors has gained notice and sometimes caused undue alarm. It is difficult to separate disease effects in diabetes and hypertension from true drug effects.(ABSTRACT TRUNCATED AT 400 WORDS)

Lack of effect of a high-fat meal on the volume of distribution of theophylline in humans.

The pharmacokinetics of intravenously administered theophylline were studied in five healthy nonsmokers. Each subject received 5 mg/kg of theophylline as aminophylline after an overnight fast and again after a standard high-fat meal. Although there was wide between-day variation in the elimination rate constant in three of the five subjects, no statistically significant differences were observed in area under the time-versus-concentration curve, maximum serum theophylline concentration, elimination rate constant, or apparent volume of distribution between the two treatments. A statistical power analysis indicated that if differences in volume of distribution and maximum serum theophylline concentration occur in the general population, the mean differences are less less than 15% and 20%, respectively. This suggests that alterations in intravascular drug distribution resulting from eating a high-fat meal do not contribute importantly to previously reported effects of food on serum theophylline concentrations after oral dosing.

Influence of menstrual cycle phase on serum concentrations of alpha 1-acid glycoprotein.

Serum concentrations of alpha 1-acid glycoprotein (AAG) were studied in nine healthy women at four times in their menstrual cycles. AAG concentrations were significantly higher on day 4 than on days 12, 20, and 28 (with the first day of menstrual flow considered to be day 1). The mean AAG concentration (mg dl-1) on day 4 was 78.55 +/- 5.03 (mean +/- s.e. mean), 70.19 +/- 4.80 on day 12, 70.63 +/- 6.67 on day 20, and 70.40 +/- 5.97 on day 28. Although these results should be considered preliminary because of the small sample size, we conclude that physiologic changes over the course of the menstrual cycle may affect serum AAG concentrations. Since AAG is a major binding protein for several important drugs, the potential exists for altered drug binding and drug effects, and further study of individual drugs is justified.

Pharmacokinetics of methotrexate administered by intramuscular and subcutaneous injections in patients with rheumatoid arthritis.

The serum concentrations and the pharmacokinetics of low-dose methotrexate (MTX) were compared after both intramuscular (IM) and subcutaneous (SQ) injections in 5 patients with rheumatoid arthritis. Values for the observed peak concentration, the time to the observed peak concentration, and the area under the time versus concentration curve for IM injections were not significantly different from these values for SQ injections. These results suggest that IM and SQ are interchangeable routes of administration. SQ administration may be a more convenient and less painful way of administering low-dose MTX.

Stability of phenytoin in blood collected in vacuum blood collection tubes.

The stability of phenytoin in blood collected in plain and serum separator tubes (SSTs) was investigated under simulated storage and transport conditions. The drug was generally more stable in plain collection tubes than in SSTs. No degradation occurred in plain red-top tubes or in refrigerated SSTs, but clinically significant degradation was present in SSTs stored at room temperature (25 degrees C) and at elevated temperature (32 degrees C) 24 h after collection. The mean loss was 17.9% at 25 degrees C and 25.9% at 32 degrees C. It is recommended that if blood is to be transported or stored in SSTs, the samples be refrigerated unless assay can be performed within 8 h.

Comparison of linear regression methods when both variables contain error: relation to clinical studies.

Five common linear regression methods were evaluated for their ability to determine the correct values of slope and intercept of a known function after random errors were added to x and y. The error variances were controlled to simulate research problems commonly studied by linear regression. The total error of each method was assessed by the absolute value of the bias in the estimate of slope. Whenever differences among methods were observed, the mean of the slope determined by two reciprocal techniques performed as well as or better than orthogonal regression, regression of y upon x, or x upon y. All the methods studied appeared to perform equally well when x and y errors were heteroscedastic or when the data set was small (n = 7). Regression of y upon x was equal or superior to other methods when n = 7 or n = 20 and y and x errors were homoscedastic. When the data set was large (n = 50) and the error in x greater than that in y, the standard method (regression of y upon x) was inferior to all other methods. It is suggested that linear regression by the traditional method of y upon x (a method present in many hand-held calculators) is appropriate in the majority of clinical situations, but when n is large and errors in x are much larger than those in y, orthogonal regression or the averaging method may be preferable.

Georgia pharmacists' attitudes toward cigarettes and smokeless tobacco.

To determine the degree to which pharmacists might cooperate with other health-care providers in reducing tobacco use, the authors surveyed 500 Georgia pharmacists on their knowledge, attitudes, and sales practices regarding cigarettes and smokeless tobacco (ST). Analysis of the 152 questionnaires (30.3%) returned showed that respondents' knowledge of the effects of tobacco use, especially cigarettes, was high. Overall, pharmacists believe that pharmacies should not sell cigarettes and ST; sales to minors and radio and television advertising of tobacco should be prohibited; and ST is not a safe alternative to cigarettes. More employee pharmacists than managers sold cigarettes when they did not believe they should, citing the reason that higher management makes the decision. Managers who didn't believe they should sell tobacco products said they did so because they felt the public should be free to choose. These findings may reflect a tendency of pharmacists to accept employment without control over conditions, and suggest that encouraging pharmacists to use their influence to discourage tobacco use might be acceptable to practitioners.

Clinical pharmacokinetics of theophylline and levels of alpha 1-acid glycoprotein in smokeless tobacco users.

Elimination half-life and apparent volume of distribution of theophylline were determined in ten healthy volunteers who used smokeless tobacco (snuff or chewing tobacco) regularly but did not smoke cigarettes. Serum concentrations of the acute phase reactant alpha 1-acid glycoprotein (AAG) were also measured. The elimination half-life of theophylline was 9.32 +/- 3.40 hours (mean +/- standard deviation), the apparent volume of distribution was 0.45 +/- 0.03 L/kg, and AAG concentrations were 63.8 +/- 15.76 mg/dL. All these values are comparable to values reported for nonsmokers. These results suggest that nonsmoking users of ST should be considered to be tobacco nonusers for purposes of planning theophylline dosing and monitoring strategies.

Lack of theophylline assay interference from pentoxifylline and its metabolites.

Pentoxifylline, a hemorheologic agent, and its metabolites are structurally similar to theophylline and other xanthines; therefore, they have the potential to interfere with serum assays for theophylline. Any false elevation of theophylline serum concentrations could have a significant impact on drug therapy decisions. Serum was obtained from six elderly subjects who had been taking 400 mg of pentoxifylline three times daily for at least six months. A serum assay using the TDx fluorescence polarization immunoassay failed to detect any measurable amount of theophylline. Normal doses of pentoxifylline and the resulting metabolites do not appear to interfere with the TDx method of serum assay for theophylline.

Cimetidine does not increase alpha 1-acid glycoprotein serum concentrations.

Serum concentrations of alpha 1-acid glycoprotein (AAG) were studied in six healthy, male volunteers before and after administration of cimetidine, 300 mg by mouth every 6 h for 2 days. Serum AAG concentrations were measured at three different times during the first day, i.e. before cimetidine administration, and on the fourth and sixth days, after commencing cimetidine administration. Neither cimetidine treatment nor time of day contributed significantly to differences in serum AAG concentration, and no interaction of these factors was observed. It is concluded that altered drug-AAG binding as a result of cimetidine therapy is not likely to be an important mechanism contributing to cimetidine drug interactions.

Serum lidocaine concentrations following application to the oropharynx: effects of cimetidine.

Solutions of lidocaine hydrochloride are widely used for anesthesia of the oropharynx and respiratory tract prior to endoscopic procedures. It is commonly believed that this route of administration is not associated with clinically significant systemic absorption of the drug, and large doses of topical lidocaine are routinely used in this setting. Serious adverse effects, including seizures, occasionally occur. The extent of absorption of lidocaine from the oropharynx was studied in eight healthy volunteers. Wide variation in serum lidocaine concentrations was observed. A 14-fold range of peak lidocaine concentrations occurred following identical, accurately metered doses of a lidocaine aerosol spray preparation. The effects of cimetidine on lidocaine pharmacokinetics were also studied. Therapeutic doses of oral cimetidine significantly increased the area under the lidocaine time-concentration curve (p = 0.019), but no effect on the terminal-phase elimination rate constant was observed. Serum concentrations of alpha 1-acid glycoprotein, a major binding protein of lidocaine, were significantly elevated following cimetidine (p = 0.030). Maximum lidocaine concentration, time to reach maximum concentration, and mean residence time of lidocaine were unchanged following cimetidine. These observations suggest an effect of cimetidine on the volume of distribution of lidocaine. Because of the wide variability in lidocaine pharmacokinetics and the potentially serious nature of adverse reactions, caution is advised in the use of topical lidocaine solutions in "standard" doses.

Treatment of Amanita mushroom poisoning: a review.

Poisoning with mushrooms of the genus Amanita, members of which occur frequently in both North America and Europe, accounts for a significant number of deaths annually. Liver damage is the main clinical feature and death rates are variously reported to be from 11.3% to 51.3% of patients. The amount of mushroom ingested appears to be the main prognostic indicator and a fatal outcome appears inevitable if a large amount is eaten. In sublethal exposures, supportive therapy seems effective; when definitive treatment is considered, hyperbaric oxygen, penicillin and silymarin are indicated in conjunction with careful management of blood glucose concentration. Charcoal hemoperfusion, forced diuresis, hyperbaric oxygen, and thioctic acid may also be considered, although these treatment modalities are not clearly associated with increased survival.