A risk-benefit assessment of intranasal triamcinolone acetonide in allergic rhinitis.

The efficacy of intranasal triamcinolone acetonide in seasonal and allergic rhinitis has been evaluated in clinical trials and has been compared with antihistamines and other intranasal corticosteroids. Intranasal corticosteroids are either as equally effective as or more effective than comparative drugs. Intranasal corticosteroids are particularly useful as they decrease membrane permeability and inhibit both early and late phase reactions to allergens. They minimise the nasal secretory response and reduce the sensitivity of local nasal irritant receptors. A potential benefit of topical application is the flushing action of the nasal mucosa, which may reduce allergens and secretions. In addition to seasonal and perennial rhinitis, intranasal corticosteroids have additional benefits when used to reduce inflammation in the treatment of sinusitis and may help in decreasing secondary rhinovirus infections. Furthermore, suboptimal control of asthma can be avoided by treatment of allergic rhinitis with intranasal corticosteroids. In clinical trials, common adverse effects for triamcinolone acetonide include sneezing, dry, mucosa, nasal irritation, sinus discomfort, throat discomfort, epistaxis and headache. Posterior subcapsular cataract formation has not been seen with triamcinolone acetonide. Recent literature evaluating systemic absorption of intranasal corticosteroids have shown surprising results where significant absorption has occurred with intranasal budesonide and fluticasone propionate. Growth and hypothalamic pituitary axis (HPA) function studies have been reviewed, with some intranasal corticosteroids showing changes with continual use. A retrospective study in children receiving daily triamcinolone acetonide for 12 months showed no effect on height and bodyweight. Triamcinolone acetonide at standard dosages (110 or 220microg once or twice a day) does not appear to suppress adrenal gland function and is effective in relieving most symptoms of allergic rhinitis. The International Consensus Conference Proceedings on Rhinitis now currently recommends the use of intranasal corticosteroids as first line therapy, since they have been found to be well tolerated and effective with minimal adverse effects and, specifically, no cognitive impairment. The recommended maximum dose of aqueous triamcinolone acetonide in adults and children is 220microg once a day. The aerosol form may be recommended in children between 7 and 12 years old, up to 440microg once a day or in divided doses. Duration of allergy treatment is generally for the length of each allergy season. If symptoms are perennial, then a reduction of dosage is made to the lowest effective dose with monitoring every 3 months for risk and benefit assessment. Complications to watch for include bleeding, and possible septal perforation and nasal candidiasis, although these are rare.

Role of antileukotriene agents in asthma therapy.

Leukotrienes are proinflammatory mediators with special significance in asthma. Released by numerous cell types, particularly after exposure to allergens, leukotrienes cause a potent contraction of bronchial smooth muscle, resulting in reduced airway caliber. Further, they cause plasma to leak from the vessels, resulting in edema, and enhance the secretion of mucus--both events that increase airway obstruction. Thus, leukotrienes have been a target of basic research in asthma. To date, a number of antileukotriene agents have been developed, and three are currently being used in clinical practice in the United States: zafirlukast and montelukast act by antagonizing the leukotriene receptor, and zileuton inhibits leukotriene synthesis. Studies have shown that these agents improve asthma symptoms, pulmonary function, and patient quality of life. Antileukotriene agents have generally been associated with a low incidence of side effects and good tolerability. Currently recommended for mild-to-moderate, persistent asthma, these agents have enabled patients to reduce their use of corticosteroids.

The safety and efficacy of nebulized levalbuterol compared with racemic albuterol and placebo in the treatment of asthma in pediatric patients.

BACKGROUND: Limited dose-response information is available for nebulized beta2 -agonists, especially in young children. OBJECTIVE: The purpose of this study was to determine the safety and efficacy of increasing doses of nebulized levalbuterol (Xopenex; the pure R-isomer of racemic albuterol) and racemic albuterol compared with placebo in the treatment of asthma in pediatric patients. METHODS: In this randomized, double-blind, crossover study, children (aged 3 to 11 years) with asthma (resting FEV1 50% to 80% of predicted normal [Polgar's] values) were treated with either levalbuterol, racemic albuterol, or placebo. Eligible subjects underwent a screening visit followed by 4 treatment visits. At each treatment visit, serial pulmonary function tests were completed before and after the treatment; plasma was collected to determine enantiomer levels, and safety was evaluated. RESULTS: Five 3- to 5-year-old patients and twenty-eight 6- to 11-year-old patients completed the study, and a total of 87 doses of levalbuterol were administered. In the 6- to 11-year-old group, all doses of levalbuterol were significantly greater than placebo in peak change and percent peak change in FEV1 and area under the FEV1 versus time curve (P <.05). The FEV1 values over the 8-hour study period were similar for levalbuterol 0.31 and 0.63 mg and racemic albuterol 2.5 mg and were greatest after levalbuterol 1.25 mg. Median plasma levels of R-albuterol depended on dose and were 0.4, 0.7, 1.2, and 1.0 after levalbuterol 0.31 mg, 0.63 mg, and 1.25 mg and racemic albuterol 2.5 mg, respectively. All patients in the 2.5-mg racemic albuterol arm had measurable plasma levels of S-albuterol, although S-albuterol levels were undetectable in most patients in the levalbuterol arms. In a few patients who received levalbuterol, S-albuterol levels were detected, which was likely because of the use of racemic albuterol as a concomitant medication. All active treatments were well tolerated. beta-Mediated changes in heart rate, potassium, and glucose were dose dependent for all active treatment groups. CONCLUSION: Levalbuterol caused a significantly greater increase in FEV1 than placebo, and FEV1 values were comparable with or better than those observed with racemic albuterol. beta-Mediated side effects were lower for an equipotent dose of levalbuterol when compared with racemic albuterol. Treatment with levalbuterol resulted in plasma levels that were dose dependent and had an approximate correlation with pharmacodynamic parameters.

Comparative evaluation of therapeutic response to antiasthma drugs: dry powder vs. conventional aerosol delivery systems.

Dry powder inhaler (DPI) delivery systems provide advantages over the metered-dose inhaler (MDI) systems. Of the anti-asthma agents studied, most of the trials have focused on the beta adrenergic agonists with a lesser degree of inhaled cromoglycate and corticosteroids. The results of the studies show either similarities or a lesser effect on pulmonary function for the DPI systems but, in most cases, clinical symptoms are comparable. The trials reported vary in the type of controlled designs, doses, and systems evaluated, hence scrutiny of resultant data should follow assessment of methodology in order to clinically interchange these systems in asthmatic patients.

Microassay for the simultaneous determination of theophylline and dyphylline in serum by high-performance liquid chromatography.

An improved and simplified high-performance liquid chromatographic method is presented for the simultaneous determination of theophylline and dyphylline in serum. The internal standard, beta-hydroxyethyltheophylline (20 microliters of a 100 micrograms/ml solution) is added to 50 microliters of serum. Serum proteins are precipitated by the addition of 30 microliters of 40% trichloroacetic acid solution. The mobile phase consists of a sodium acetate buffer with 6% acetonitrile. Chromatogram run time is 6 min. The sensitivity limit for both compounds is 0.25 micrograms/ml. This method is interference-free from the major metabolites of theophylline and other drugs commonly coadministered with theophylline.

A new simplified assay for the quantitation of theophylline and its major metabolites in urine by high-performance liquid chromatography.

A high-performance liquid chromatographic technique is presented for the simultaneous determination of theophylline, 3-methylxanthine, 1-methyluric acid, 1,3-dimethyluric acid, and caffeine in urine using beta-hydroxyethyl theophylline (BHET) as an internal standard. Following centrifugation of the sample, 2 mL of urine was placed onto a Sep-Pak C18 cartridge (Waters Associates, Milford, MA, USA) that was prepared with 5 mL of methanol followed by 10 mL of distilled water. The compounds were eluted with 2.5 mL of a methanol:water (50:50) mixture. An aliquot of the filtered urine sample (100 microL) was added to 40 microL of an internal standard solution (BHET; 100 micrograms/mL). Distilled water (60 microL) was added to yield a volume of 200 microL. The mixture was vortexed and centrifuged, and 100 microL was injected onto a C8 column maintained at 55 degrees C. Inter- and intraday variability of the assay for all compounds was less than 5.7%. Sensitivity ranged from 0.10 microgram/mL for caffeine to 0.68 microgram/mL for 1-methyluric acid. Drugs commonly coadministered with theophylline did not interfere with the assay.

New simplified microassay for the quantitation of theophylline and its major metabolites in serum by high-performance liquid chromatography.

A high-performance liquid chromatographic technique is presented for simultaneous determination of theophylline, 3-methylxanthine, 1-methyluric acid, 1,3-dimethyluric acid and caffeine in serum using beta-hydroxyethyltheophylline (BHET) as an internal standard. An aliquot of a serum sample (100 microliters) was added to 40 microliters of an internal standard solution (BHET; 100 micrograms/ml) and vortexed. A 20% trichloroacetic acid solution (60 microliters) was then added; the mixture was vortexed, centrifuged and 100 microliters were injected onto a C8 column maintained at 45 degrees C. Inter- and intra-day variability of the assay for all compounds was less than 4.3%. Sensitivity ranged from 10 ng/ml for 1-methyluric acid to 25 ng/ml for theophylline. Drugs commonly coadministered with theophylline did not interfere with the assay.

The effect of amiodarone on theophylline pharmacokinetics in the rat.

Amiodarone is an investigational antiarrhythmic agent which has been implicated in reducing the activity of the hepatic mixed-function oxidase system. To evaluate this effect further, two groups of six male Sprague-Dawley rats each received theophylline (6 mg/kg, iv) preceded by either normal saline or amiodarone HC1 (100 mg/kg, iv). Blood samples were obtained serially for a period of 6 hr and the sera were assayed for theophylline by high-pressure liquid chromatography (HPLC). In rats pretreated with amiodarone, a significant 45% reduction in the mean (± SD) systemic clearance [0.057 (0.010) vs 0.031 (0.004) liter/hr/kg, P < 0.001] and a greater than 100% increase in the mean elimination half-life [2.03 (0.46) vs 4.29 (0.71) hr, P < 0.001] of theophylline were observed. These data demonstrate an acute inhibitory effect of amiodarone on the hepatic microsomal enzyme system.

The effect of phenobarbital on theophylline disposition in children with asthma.

The disposition of theophylline was examined in seven children with asthma on two occasions before and on one occasion after chronic phenobarbital dosing (2 mg/kg/day). There was little intrapatient variability in apparent theophylline clearance between the two baseline assessments (0.081 versus 0.073 L/hr/kg). After 19 days of phenobarbital therapy, there was a significant increase in apparent theophylline clearance (0.104 versus 0.077 L/hr/kg), accompanied by a 30% decrease in the mean steady-state serum theophylline concentration (12.0 versus 8.4 micrograms/ml). The inducing effect of phenobarbital on theophylline metabolism may require theophylline dosage adjustment in patients with asthma who receive both drugs concurrently to maintain a given average steady-state theophylline concentration.

Cimetidine versus famotidine: the effect on the pharmacokinetics of theophylline in rats.

The effects of cimetidine and a new, potent H2-antagonist, famotidine, on the single dose pharmacokinetics of theophylline were examined in rats. Male Sprague-Dawley rats (6 rats/group) received an i.v. dose of theophylline (6 mg/kg) alone and in conjunction with an i.v. dose of famotidine (10 mg/kg) or cimetidine (10 mg/kg). Venous blood samples were collected serially for seven hours after theophylline infusion and analyzed for theophylline concentration by HPLC. Concomitant famotidine administration did not alter any of the pharmacokinetic parameters of theophylline (AUC0- infinity; 38.1 +/- 8.7 vs. 38.8 +/- 6.3 micrograms.hr.ml-1), while cimetidine demonstrated a significant reduction in theophylline systemic clearance (0.11 +/- 0.02 vs. 0.16 +/- 0.02 L/hr/kg; p less than 0.001), a 40% prolongation of half-life (2.8 +/- 0.9 vs. 2.0 +/- 0.5 hr), with no change in the volume of distribution (0.39 +/- 0.1 vs. 0.41 +/- 0.13 L/kg). These results suggest that in contrast to cimetidine, famotidine, a non-imidazole H2-receptor antagonist, does not interfere with theophylline disposition in the rat.

Morphine inhibition of theophylline clearance.

The effects of morphine on the single dose pharmacokinetics of theophylline were examined in two groups (6 rats/group) of male Sprague-Dawley rats after the administration of theophylline (6.25 mg/kg) alone and in conjunction with a 5 mg /kg I.V. dose of morphine sulfate. Concomitant morphine administration resulted in a 55 % reduction in theophylline clearance (0.14 ± 0.04 vs. 0.31 ± 0.061 · h(-1) kg(-1); p. < 0.0005). The reduction in theophylline clearance with morphine administration was accompanied by a significant prolongation in theophylline half-life (3.5 ± 1.5 vs. 1.4 ± 0.35 h; p < 0.02). No changes in the volume of distribution of theophylline occurred with co-administration of morphine. The mechanism of this pharmacokinetic interaction may be partially related to competition between theophylline and morphine for enzymes which metabolize these compounds.

Tobramycin sulfate elimination in premature infants.

The elimination pharmacokinetics of tobramycin sulfate was studied in 25 newborn infants of birth weight 0.7 to 4.7 kg during 31 treatment episodes. The peak serum concentrations after a 2.5 mg/kg dose were usually within the therapeutic range of 5 to 10 micrograms/ml; however, the serum predose trough values were elevated above the theoretical safe limit of 2 micrograms/ml. Because of the prolonged serum elimination half-lives, a calculated extended dosage interval, sometimes greater than 24 hours, was necessary to obtain a predose trough of less than or equal to 2 micrograms/ml. The serum elimination half-lives inversely correlated with gestational age, extrauterine age, birth weight, and creatinine clearance. The very low ratio of tobramycin renal clearance to creatinine renal clearance was virtually constant and indicated a probable tubular reabsorption of tobramycin. A general dosage schedule based on birth weight was derived from the data. An alternative formula was derived to enable prediction of the tobramycin elimination half-life based on a combination of birth weight, gestational age, and extrauterine age for an infant younger than 7 days of age.

Theophylline pharmacokinetics in the young infant.

The pharmacokinetics of theophylline were investigated in 13 infants, 4 to 18 months of age. An inverse relationship was found between theophylline half-life and age. Volume of distribution did not differ from that reported by other authors in similarly aged infants. Our data suggest that childhood clearance rates of elimination can be achieved by 6 months of age. The decreased theophylline elimination observed in the smaller infant indicates that the usual pediatric dosing recommendations cannot be used routinely. Until more specific data are available in the infant under 6 months, the authors reaffirm individualization of theophylline dosage to maintain therapeutic levels and avoid toxicity.

Drug therapy in the treatment of minimal brain dysfunction.

The pharmacotherapy of minimal brain dysfunction (MBD) is reviewed. Studies using central nervous system (CNS) stimulants (amphetamines and methylphenidate, deanol, pemoline, caffeine), antidepressants (imipramine and desipramine), anticonvulsants (phenytoin and primidone), antianxiety agents (chlordiazepoxide, hydroxyzine, meprobamate), antipsychotic agents (phenothiazines, thioxanthenes, butyrophenones) and miscellaneous agents (benztropine, thyrotropin-releasing hormone, megavitamins) are discussed. When drugs are indicated, the CNS stimulants are the agents of choice in the treatment of MBD. The use of tricyclic antidepressants in MBD is regarded as investigational and warrants careful monitoring to minimize toxicities. Anticonvulsants have been ineffective in controlling behavior problems; however, phenytoin may be helpful in auditory perception problems. Anti-anxiety and antipsychotic agents are not as desirable as the CNS stimulants for treatment since they do not decrease distractibility or increase attention spans.