Intravenous Cetirizine Versus Intravenous Diphenhydramine for the Treatment of Acute Urticaria: A Phase III Randomized Controlled Noninferiority Trial.

STUDY OBJECTIVE: Acute urticaria is a frequent presentation in emergency departments (EDs), urgent care centers, and other clinical arenas. Treatment options are limited if diphenhydramine is the only intravenous antihistamine offered because of its short duration of action and well-known adverse effects. We evaluate cetirizine injection, the first second-generation injectable antihistamine, for acute urticaria in this multicenter, randomized, noninferiority, phase 3 clinical trial. METHODS: Adult patients presenting to EDs and urgent care centers with acute urticaria requiring an intravenous antihistamine were randomized to either intravenous cetirizine 10 mg or intravenous diphenhydramine 50 mg. The primary endpoint was the 2-hour pruritus score change from baseline, with time spent in treatment center and rate of return to treatment centers as key secondary endpoints. Frequency of sedation and anticholinergic adverse effects were also recorded. RESULTS: Among 262 enrolled patients, the 2-hour pruritus score change from baseline for intravenous cetirizine was statistically noninferior to that for intravenous diphenhydramine (-1.6 versus -1.5; 95% confidence interval -0.1 to 0.3), and in favor of cetirizine. Treatment differences also favored cetirizine for mean time spent in treatment center (1.7 versus 2.1 hours; P=.005), return to treatment center (5.5% versus 14.1%; P=.02), lower change from baseline sedation score at 2 hours (0.1 versus 0.5; P=.03), and adverse event rate (3.9% versus 13.3%). CONCLUSION: Intravenous cetirizine is an effective alternative to intravenous diphenhydramine for treating acute urticaria, with benefits of less sedation, fewer adverse events, shorter time spent in treatment center, and lower rates of revisit to treatment center.

On-demand continuous-flow production of pharmaceuticals in a compact, reconfigurable system.

Pharmaceutical manufacturing typically uses batch processing at multiple locations. Disadvantages of this approach include long production times and the potential for supply chain disruptions. As a preliminary demonstration of an alternative approach, we report here the continuous-flow synthesis and formulation of active pharmaceutical ingredients in a compact, reconfigurable manufacturing platform. Continuous end-to-end synthesis in the refrigerator-sized [1.0 meter (width) × 0.7 meter (length) × 1.8 meter (height)] system produces sufficient quantities per day to supply hundreds to thousands of oral or topical liquid doses of diphenhydramine hydrochloride, lidocaine hydrochloride, diazepam, and fluoxetine hydrochloride that meet U.S. Pharmacopeia standards. Underlying this flexible plug-and-play approach are substantial enabling advances in continuous-flow synthesis, complex multistep sequence telescoping, reaction engineering equipment, and real-time formulation.

[Determination of ambroxol and clenbuterol in human plasma by LC-MS/MS method].

Ambroxol and clenbuterol were extracted from human plasma samples by liquid-liquid extraction, ambroxol was separated on a Zorbax XDB-C18 column and detected by tandem mass spectrometry with an atmospheric pressure chemical ionization interface after oral administration of a compound preparation. Clenbuterol was separated on a Zorbax XDB-C8 column and detected by tandem mass spectrometry with an electrospray ionization interface. Diphenhydramine is used as the internal standard. The linear concentration ranges of the calibration curves for ambroxol and clenbuterol were 0.080 - 400 microg x L(-1) and 5.0 - 5 000 ng x L(-1), respectively. The lower limits of quantification were 0.080 microg x L(-1) for ambroxol and 5.0 ng x L(-1) for clenbuterol, individually. The inter-day and intra-day precision (RSD) across three validation run over the entire concentration range was below 7.5%, and the accuracy (RE) was within +/- 2.5% for both ambroxol and clenbuterol. The methods were used to determine the pharmacokinetic parameters of ambroxol and clenbuterol in human plasma after oral administration of a compound preparation containing 60 mg ambroxol hydrochloride and 40 microg clenbuterol hydrochloride. The method was proved to be highly sensitive, selective and suitable for the pharmacokinetic study of different compound preparations containing ambroxol and clenbuterol.

[Determination of risperidone in human plasma by liquid chromatography-tandem mass spectrometry].

AIM: To develop and validate a liquid chromatographic-tandem mass spectrometric (LC-MS/MS) method for the determination of risperidone in human plasma. METHODS: Risperidone and the internal standard, diphenhydramine, were isolated from plasma by liquid-liquid extraction with etherdichloromethane (3:2, v/v) , then chromatographed on a Zorbax Extend-C18 column (150 mm x 4.6 mm ID, 5 microm) using a mobile phase consisted of acetonitrile-water-formic acid (40:60: 0.5, v/v), at a flow rate of 0.7 mL x min(-1). A Finnigan TSQ tandem mass spectrometer equipped with atmospheric pressure chemical ionization source was used as detector and was operated in the positive ion mode. Selected reaction monitoring (SRM) using the precursor product ion combinations of m/z 411-->191 and m/z 256-->167 were used to quantify risperidone and diphenhydramine (IS) , respectively. RESULTS: The linear concentration range of the calibration curve for risperidone was 0.025 - 50 microg L(-1). The lower limit of quantification was 0.025 microg x L(-1). The intra- and inter-day relative standard deviation (RSD) across three validation running over the entire concentration range was less than 7.1%. The accuracy was within +/- 3.8%. Each sample was chromatographed within 2.7 min. CONCLUSION: The method was proved to be rapid, sensitive and suitable for pharmacokinetic investigations of risperidone.

Simultaneous determination of flupirtine and its major active metabolite in human plasma by liquid chromatography-tandem mass spectrometry.

A rapid, selective and sensitive HPLC-tandem mass spectrometry method was developed and validated for simultaneous determination of flupirtine and its active metabolite D-13223 in human plasma. The analytes and internal standard diphenhydramine were extracted from plasma samples by liquid-liquid extraction, and chromatographed on a C18 column. The mobile phase consisted of acetonitrile-water-formic acid (60:40:1, v/v/v), at a flow rate of 0.5 ml/min. Detection was performed on a triple quadrupole tandem mass spectrometer by selected reaction monitoring (SRM) mode via atmospheric pressure chemical ionization (APCI). The method has a limit of quantitation of 10 ng/ml for flupirtine and 2 ng/ml for D-13223, using 0.5-ml plasma sample. The linear calibration curves were obtained in the concentration range of 10.0-1500.0 ng/ml for flupirtine and 2.0-300.0 ng/ml for D-13223. The intra- and inter-run precision (RSD), calculated from quality control (QC) samples was less than 7.2% for flupirtine and D-13223. The accuracy as determined from QC samples was less than 5% for the analytes. The overall extraction recoveries of flupirtine and D-13223 were determined to be about 66% and 78% on average, respectively. The method was applied for the evaluation of the pharmacokinetics of flupirtine and active metabolite D-13223 in volunteers following peroral administration.

Controlled trial of H1 antagonists in the treatment of chronic idiopathic urticaria.

The efficacy of astemizole, diphenhydramine, and hydroxyzine hydrochloride in the treatment of chronic idiopathic urticaria was evaluated in this 3-month double-blind, randomized, parallel group study. Thirty-six adult patients were randomly assigned, 13 to the astemizole group (10 mg daily), 12 to the diphenhydramine group (25 mg t.i.d.), and 11 to the hydroxyzine hydrochloride group (25 mg t.i.d.). Demographic data were statistically similar for all variables assessed in the three treatment groups. Seven (58%) of the diphenhydramine patients withdrew before the end of the study, six because of lack of efficacy and one because of drowsiness. Two (18%) of the hydroxyzine hydrochloride patients withdrew, one because of lack of efficacy and one because of drowsiness. Two patients (15%) in the astemizole group withdrew, one because of adverse reaction, and the other because of lack of efficacy. Mean total symptom scores and mean individual symptom scores were lower in the astemizole group than in the other two groups. Wheal area measurements (0.1 mg/mL histamine challenge) decreased more in the astemizole and hydroxyzine hydrochloride groups than in the diphenhydramie group (P = .02). With regard to symptoms, 12/13 patients in the astemizole group improved clinically during their treatment period, versus 8/11 in the hydroxyzine hydrochloride group and 5/12 in the diphenhydramine group. The mean time to first observed therapeutic effect (maintained for three consecutive days) was 5.5 days in the astemizole group, 10.9 days in the hydroxyzine hydrochloride group, and 7.2 days in the diphenhydramine group. In this study, astemizole was as effective as hydroxyzine in patients treated for chronic idiopathic urticaria.

Use of SE-30 as a stationary phase for the gas-liquid chromatography of drugs.

The dimethyl silicone elastomer SE-30 has been chosen as the preferred liquid phase for the gas-liquid chromatographic analysis of drugs, and retention index data have been compiled for 480 drugs and commonly occurring chemicals such as plasticisers. The inter-laboratory variation in measurement of retention indices has been measured for three drugs in eleven laboratories and the standard deviations were between 20 and 15 retention index units.