Pharmacokinetics and pharmacodynamics of cumulative single doses of inhaled salbutamol enantiomers in asthmatic subjects.

Objectives of this study were to compare the pharmacokinetics, pharmacodynamics and safety of single cumulative doses of active (R)-salbutamol given either as the single enantiomer or racemic mixture by inhalation to subjects with mild to moderate asthma. This was a double-blind, crossover, cumulative-dose, randomized study where all subjects received either four doses of 1.25 mg of (R)-salbutamol or 2.5 mg of racemic (RS-) salbutamol by nebulization. The pharmacokinetic parameters were determined by noncompartmental analysis and model-fitting. Changes in FEV(1), plasma potassium, plasma glucose, heart rate, and QTc interval were measured. The potassium and glucose data were fitted to indirect response pharmacodynamic models. The heart rate and QTc data were evaluated using data descriptors. No significant differences in pharmacokinetics of (R)-salbutamol given as either (R)- or (RS)-salbutamol were found with AUC values of 11.90 +/- 4.37 and 11. 47 +/- 2.88 ng.h/ml. The t(max)of about 2 h reflected serial dosing rather than delayed absorption. The t(1/2)averaged about 3.5 h. The (S)-salbutamol showed AUC of 48.46 +/- 12.11 ng.h/ml with a t(1/2)of about 5 h. The changes in FEV(1)reached a plateau after an initial increase and did not return to pre-drug values for 10 h. All pharmacodynamic parameters were similar whether (R)- or (RS)-salbutamol was given. The exposure to (R)-salbutamol was identical after inhalation of (R) -and (RS)-salbutamol by subjects with asthma. Several pharmacological responses including FEV(1)were also similar and there were no unique safety concerns with either treatment.

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.

Improved bronchodilation with levalbuterol compared with racemic albuterol in patients with asthma.

BACKGROUND: Racemic albuterol is an equal mixture of (R)-albuterol (levalbuterol), which is responsible for the bronchodilator effect, and (S)-albuterol, which provides no benefit and may be detrimental. OBJECTIVE: We sought to compare 2 doses of a single enantiomer, levalbuterol (0.63 mg and 1.25 mg), and equivalent amounts of levalbuterol administered as racemic albuterol with placebo in patients with moderate-to-severe asthma. METHODS: This was a randomized, double-blind, parallel-group trial. Three hundred sixty-two patients 12 years of age or older were treated with study drug administered by means of nebulization 3 times daily for 28 days. The primary endpoint was peak change in FEV1 after 4 weeks. RESULTS: The change in peak FEV1 response to the first dose in the combined levalbuterol group was significantly greater compared with the combined racemic albuterol group (0.92 and 0.82 L, respectively; P =.03), with similar but nonsignificant results after 4 weeks (0.84 and 0.74 L, respectively). Improvement in FEV1 was similar for levalbuterol 0.63 mg and racemic albuterol 2.5 mg and greatest for levalbuterol 1.25 mg. Racemic albuterol 1.25 mg demonstrated the weakest bronchodilator effect, particularly after chronic dosing. The greatest increase in FEV1 was seen after levalbuterol 1.25 mg, especially in subjects with severe asthma. All active treatments were well tolerated, and beta-adrenergic side effects after administration of levalbuterol 0.63 mg were reduced relative to levalbuterol 1.25 mg or racemic albuterol 2.5 mg. At week 4, the predose FEV1 value was greatest in patients who received levalbuterol or placebo when compared with those who received racemic albuterol. The difference was more evident and was statistically significant in patients who were not receiving inhaled corticosteroids. CONCLUSION: Levalbuterol appears to provide a better therapeutic index than the standard dose of racemic albuterol. These results support the concept that (S)-albuterol may have detrimental effects on pulmonary function.

Pharmacokinetic and pharmacodynamic characteristics and safety of inhaled albuterol enantiomers in healthy volunteers.

The pharmacokinetics and pharmacodynamics of inhaled albuterol given as single or multiple doses of racemate (RS-) or single enantiomers (R-, S-) were determined. In an open-label, three-way crossover, parallel-dose study, 1.25 and 5 mg of (R)- and (S)-albuterol and 2.5 and 10 mg of (RS)-albuterol were given via nebulization to 15 healthy volunteers. The pharmacokinetic parameters of each enantiomer were determined by noncompartmental and model-fitting analyses. Both (R)- and (S)-albuterol showed rapid absorption and biexponential decline, with half-lives (t1/2) averaging 4 and 6 hours, respectively. There were no differences in pharmacokinetics of (R)-albuterol when administered as (R)- or (RS)-albuterol at the 5-mg dose with equivalent relative bioavailability as seen from maximum concentration (Cmax) and area under the concentration-time curve (AUC). The same was true for (S)-albuterol at the 1.25-mg and 5-mg doses. The data from 5-mg doses were considered to be more reliable due to assay sensitivity limitations, and indicated equivalent absorption and disposition of the individual enantiomers. There was no evidence of in vivo racemization, and (R)-albuterol did not interconvert to (S)-albuterol. Plasma potassium, plasma glucose, heart rate, and QTc interval were used in linear and Emax models to assess responses relating to (R)-albuterol concentrations. The Emax for potassium change was 1.32 meq/L, with an EC50 of 0.59 and 0.94 ng/mL after administration of (R)- and (RS)-albuterol, respectively. The slopes and intercepts for glucose and heart rate changes were similar after administration of (R)- and (RS)-albuterol. No concentration-effect relationships were evident for QTc interval or for (S)-albuterol. The extrapulmonary responses of (R)-albuterol and adverse effects were similar for single R-enantiomer or the racemic mixture.

Colour thresholding in video imaging.

The basic aspects of video imaging are reviewed as they relate to measurements of histological and anatomical features, with particular emphasis on the advantages and disadvantages of colour and black-and-white imaging modes. In black-and-white imaging, calculations are based on the manipulation of picture elements (pixels) that contain 0-255 levels of information. Black is represented by the absence of light (0) and white by 255 grades of light. In colour imaging, the pixels contain variation of hues for the primary (red, green and blue) and secondary (magenta, yellow, cyan, pink) colours. Manipulation of pixels with colour information is more computer intense than that for black-and-white pixels, because there are over 16 million possible combinations of colour in a system with a 24-bit resolution. The narrow 128 possible grades of separation in black and white often makes distinction between pixels with overlapping intensities difficult. Such difficulty is greatly reduced by colour thresholding of systems that base the representation of colour on a combination of hue-saturation-intensity (HSI) format.

Safety profile of cefprozil.

The clinical and laboratory safety of cefprozil was analyzed with data from 4,227 patients who received the drug in North American and European clinical efficacy trials. Of these patients, 3,016 adults and children received capsules or tablets, while 1,211 patients (mostly children) were treated with cefprozil suspension. Cefprozil was used in single-daily or twice-daily dosing regimens for treatment of infections of the upper and lower respiratory tracts, sinuses, middle ear, urinary tract, and skin and skin structure. The incidence of adverse clinical events and laboratory abnormalities was similar to that associated with use of other oral cephalosporins. Gastrointestinal adverse effects were the predominant adverse clinical event, although the incidence of diarrhea with cefprozil was much lower than that with cephalosporins that are less well absorbed. The data confirm the safety of cefprozil in both adult and pediatric patients.

Effect of positional environmental domains on the variation of high-performance liquid chromatographic peptide retention coefficients.

While attempting to derive a set of high-performance liquid chromatographic amino acid retention coefficients from a set of 298 related peptide analogues of a 13-amino acid peptide, we found that each position within the peptide would require a different set of retention coefficients to accurately predict peptide retention times. Furthermore, our results show that peptides having the same amino composition but slightly different sequences can have very different retention times. We believe that individual sequence domains and the resulting differences in the solid phase-mobile phase interactions must be taken into account for the accurate prediction of peptide retention times.

The assignment of chain specificities for anti-Ia monoclonal antibodies using L cell transfectants.

The chain specificities of 18 Ak and 26 Ab-reactive anti-Ia monoclonal antibodies have been determined. L cells were transfected with haplotype-matched (A alpha k:A beta k, A alpha b:A beta k) or haplotype-mismatched (A alpha k:A beta b, A alpha b:A beta k) cDNA pairs, lines expressing high levels of surface A complex were selected, and antibody reactivity with a panel of reagents was assessed by cytofluorimetric analysis. Most of the antibodies recognized a determinant specified by one chain, either alpha or (more commonly) beta. A few examples of more complex determinants were also observed. A knowledge of the chain specificities of anti-Ia monoclonal antibodies should prove useful for a variety of studies aimed at dissecting Ia structure-function relationships.

Studies on ABH antigen grouping of ammoniacal extracts of bloodstains by absorption-elution.

The effects of absorption time, titer of antiserum or lectin in the absorption stage, and elution temperature on relative antibody or lectin yield in elutes in the absorption-elution procedure were studied in bloodstains and ammoniacal extracts of bloodstains using conventional grouping reagents. In addition, monoclonal anti-A and anti-B and affinity-purified Ulex europaeus agglutinin I (UEA I) reagents were employed for comparison in these processes. Ammoniacal extracts of bloodstains and dried bloodstains on cotton substrata behaved comparably with respect to the parameters studied. The monoclonal anti-A and anti-B and UEA I reagents studied yielded satisfactory results, comparable in some cases to conventional reagents, with respect to the parameters studied.

Simplified procedure for carrying out simultaneous multiple hydrogen fluoride cleavages of protected peptide resins.

Methods have recently been presented which greatly increase the ability to synthesize large numbers of peptides. These advances make it essential to be able to cleave large numbers of protected peptide resins. Two different procedures are presented for carrying out cleavage of protected peptide resins. The first procedure enables multiple cleavages to be carried out with many existing HF apparatuses, while the second utilizes a new apparatus design. Using these procedures, at least 50 individual cleavages can be carried out per day.