Pseudoephedrine hydrochloride causes hyperactivity in zebrafish via modulation of the serotonin pathway.

This study aimed to explore behavioral changes of embryonic and larval zebrafish caused by pseudoephedrine hydrochloride (PSE) and its underlying mechanism. Zebrafish embryos were exposed to 0.5 µM, 2 µM, and 8 µM PSE at 4 h post-fertilization (4 hpf) or 22-23 hpf. Mortality, hatching rate, coiling frequency, heart rate, behavior changes, and related gene expression were observed at different developmental stages. PSE below 8 µM did not affect zebrafish mortality, hatching rate, and heart rate compared with the control group. For embryos, PSE caused an increase at 16-32 hpf in zebrafish coiling frequency which could be rescued by serotonin antagonist WAY100635. Similarly, PSE caused an increase in the swimming distance of zebrafish larvae at 120 hpf. PSE also elevated the expression of serotonin (5-HT)-related genes 5-htr1ab and tph2 and dopamine-related gene dbh. Behavioral changes in zebrafish embryos and larvae caused by PSE may be closely associated with increased expression of 5-HT and dopamine-related genes. This may be reflected that the behavioral changes in zebrafish are a possible PSE monitoring indicator.

Extended-Release Guaifenesin/Pseudoephedrine Hydrochloride for Symptom Relief in Support of a Wait-and-See Approach for the Treatment of Acute Upper Respiratory Tract Infections: A Randomized, Double-Blind, Placebo-Controlled Study.

BACKGROUND: Despite the well-known fact that antibiotics (AB) are not effective against viruses, many patients ask for - and all too often doctors provide - AB for treating URTIs. Over-prescribing of AB is one of the key causes for the development of bacterial resistance, which the U.S. Centers for Disease Control and Prevention (CDC) calls "one of the world's most pressing public health problems". In addition to the CDC initiated "Get Smart About Antibiotics" campaign, focused on educating doctors the public about the importance of appropriate AB use, other programs tackling this problem include the development of new treatment paradigms. Data published at the Oregon Health & Science University demonstrated that a 'wait-and-see' approach, without an AB prescription for the treatment of acute childhood ear infections, was as quick, safe, and effective in resolving the infections as an AB prescription (Spiro DM, Tay KY, Arnold DH, Dziura JD, Baker MD, Shapiro ED. Wait-and-See Prescription for the Treatment of Acute Otitis Media. JAMA 2006; 296:1235-1241). OBJECTIVE: To try and reduce inappropriate prescribing practices, a wait and see or delayed approach requires patients to return for a prescription if their symptoms persist or worsen. The aim of this study was to determine whether treatment with Mucinex D (Reckitt Benckiser LLC, Parsippany, New Jersey) lowers the use of antibiotics in the treatment of URTIs when compared with placebo. METHODS: Patients aged 18 to 75 years with symptoms of acute URTIs were randomized to 1200 mg guaifenesin/120 mg pseudoephedrine hydrochloride extended-release, bilayer tablets or matching placebo for 7 consecutive days. Eligible patients met physician's criteria for antibiotic therapy but were considered suitable for a wait and see approach (withholding antibiotics for ≥48 hours). Patients recorded symptom ratings via an interactive voice response system. RESULTS: One thousand one hundred eighty-nine patients enrolled; data are presented for the modified intent-to-treat population (n = 1179). At Day 8, significantly fewer patients receiving guaifenesin/pseudoephedrine versus placebo desired antibiotics (4.2% vs 8.0%). No adverse effects were reported due to patients not taking antibiotics. Significant reductions in URTI symptoms were observed for extended-release guaifenesin/pseudoephedrine versus placebo, from Day 1 throughout the study; however, the proportion of patients experiencing overall relief at the Day 4 evening assessment (primary end point) did not reach statistical significance. Treatment-related adverse events were reported in 9.8% and 4.7% of patients receiving guaifenesin/pseudoephedrine and placebo, respectively. CONCLUSIONS: The study found that a wait and see approach was associated with decreased antibiotic use. In addition, the use of a guaifenesin pseudoephedrine combination product provided an effective symptom control compared to a placebo and a well-tolerated first-line strategy for the management of URTIs. This study was not designed to assess the effects of guaifenesin or pseudoephedrine individually. Other limitations include the need for better clinical methods to assess the effectiveness of treatments for acute symptoms of patients with URTIs. ClinicalTrials.gov identifier: NCT01202279.

The simultaneous measurement of quaternary mixture in over-the-counter cold medications using sequential spectrophotometric resolution approach enhanced with in-lab sample enrichment.

A sequential spectrophotometric resolution technique (SSRT) was developed in this study without the use of systematic separation procedures to determine drug of a quaternary combination; caffeine (CAF), pseudoephedrine (PSE), doxylamine succinate (DOX), and paracetamol (PAR). Their presence in a tablet with a gap ratio of 3:3:1:150, respectively, and their overlapping spectra with low absorptivities make their resolution and determination impossible without prior separation. successive ratio subtraction technique (SRST) and constant multiplication method were used to solve these problems. Furthermore, an in-lab sample enrichment technique was applied to increase minor components concentration and consequently their absorbanses (CAF, PSE, and DOX). The D0 absorption spectra were generated by successive ratios followed by subtraction and multiplication of the constants. The maximum absorbances of the drugs tested, namely (CAF, PSE, DOX and PAR) were measured at wavelengths of 272.0, 257.0, 260.0, and 248.0 nm, respectively. The limits of detection (LOD) and limits of quantification (LOQ) were 0.021, 0.124, 0.186, 0.137 and 0.070, 0.414, 0.621, 0.456 (µg/mL), respectively. The linearitiy ranges (µg/mL) were 1.0-22.0, 1.0-24.0, 10.0-90.0 and 1.0-15.0 for CAF, PSE, DOX, and PAR, respectively. The International Conference on Harmonization (ICH) guidelines were applied for method validation, and the results obtained were within the limited parameters. The finding results were compared to official and/or published analytical methods to determine the procedure's reliability. It was noted that there was no actual difference in accuracy and precision between both meyhods. The proposed technique is sensitive, selective and economic;so it can be applied to the simultaneous analysis of these drugs in their commercial tablets and/or in quality-control laboratories.

Application of green first derivative synchronous spectrofluorometric method for quantitative analysis of fexofenadine hydrochloride and pseudoephedrine hydrochloride in pharmaceutical preparation and spiked human plasma.

Fexofenadine hydrochloride and pseudoephedrine hydrochloride are prescribed in a combined dosage form for the treatment of allergic rhinitis. In the present work, a sensitive synchronous fluorescence spectroscopic method was applied in conjunction with first derivative for quantitative estimation of fexofenadine hydrochloride and pseudoephedrine hydrochloride in pure form, pharmaceutical tablets and spiked human plasma. Fexofenadine hydrochloride showed its conventional emission spectrum at 294 nm when excited at 267 nm. On the other hand, pseudoephedrine hydrochloride showed its conventional emission spectra at 286 nm when excited at 261 nm. The fluorescence intensities were greatly enhanced by the use of sodium dodecyl sulphate as a micellar surfactant. Application of the synchronous mode to measure the fluorescence spectra of the above drugs provided sharp narrowing bands, but the overlap was not completely resolved. Derivatization of the synchronous spectra to the first order completely resolved the overlap of the fluorescence spectra and allowed simultaneous quantitative determination of the drugs under study. Fexofenadine hydrochloride and pseudoephedrine hydrochloride could be determined from their first-order synchronous spectra at 286 and 294 nm, respectively, without interfering with each other. The method showed linearity with an excellent correlation coefficient in the concentration range of 100-1500 ng/mL for Fexofenadine hydrochloride and 50-1000 ng/mL for pseudoephedrine hydrochloride. The method was successfully applied for the simultaneous determination of the studied drugs in pharmaceutical formulation, with mean percent recoveries for Fexofenadine hydrochloride and pseudoephedrine hydrochloride of 99.49 ± 0.931 and 98.67 ± 0.634, respectively, and in spiked human plasma, with mean percent recoveries for Fexofenadine hydrochloride and pseudoephedrine hydrochloride of 95.21 ± 1.938 and 94.89 ± 1.763, respectively. Furthermore, the greenness of the described method was assessed using four different tools namely, the national environmental method index, the analytical eco-scale, the green analytical procedure index and the AGREE evaluation method. The proposed method seemed to be superior to the reported HPLC method with respect to the metrics of the greenness characters.

Development and evaluation of pseudoephedrine hydrochloride abuse-deterrent formulations using thermal modified rice starch.

There is a continued global effort to prevent the spread of prescription drug abuse. In particular, chemical structure of pseudoephedrine hydrochloride (PSE), an over-the-counter medication, is very similar to that of methamphetamine (MET). The aim of this study was to develop abuse-deterrent formulations (ADF) of PSE by using thermal modified starch (TMR). PSE is a water-soluble drug, but it is intended to inhibit extraction from the extraction medium in excess tablets. Starch-based formulations were successfully developed using cross-linking agent and lipid. The extraction (%) of PSE from TMR7-L5 formulation (equivalent to 5 tablets) were 75.3% in DW, 2.7% in ethyl alcohol, and 63.0% in 40% ethyl alcohol (v/v) at 60 °C for 30 min. Moreover, TMR7-L5 formulation delayed drug release compared to the commercial product in in vitro release. In conclusion, the development of ADFs using a starch-based formulation shows novelty and has potential to prevent drug abuse.

A novel fluorimetric method for determination of pseudoephedrine hydrochloride in pharmaceutical formulations and blood serum.

An inexpensive, simple, highly sensitive, and rapid fluorimetric method was developed for the analysis of pseudoephedrine hydrochloride at trace levels. The method is based on the recovery of fluorescence of Rh6G dye due to the interaction of pseudoephedrine hydrochloride with Rh6G-Au NPs complex, which results in the release of Rh6G from the complex and halting fluorescence resonance energy transfer between Rh6G and Au NPs. The intensity of fluorescence was directly proportional to the concentration of the analyte, which was used for its determination. Experimental factors were optimized by response-surface methodology. Under optimum conditions, the calibration curve was linear over the range of 15-150 ng mL-1 and the limit of detection (LOD) was 10 ng mL-1. Percent relative standard deviation (n= 5) for determination of 50 ng mL-1 pseudoephedrine hydrochloride was 3.74%. The method was successfully used for determining the analyte in human blood serum and in pharmaceutical formulations. The possible mechanistic description of the analytical reaction was proposed on the basis of TEM, FT-IR, and fluorescence spectra analysis.

Development of Methamphetamine Abuse-Deterrent Formulations Using Sucrose Acetate Isobutyrate.

The objective of the present research was to investigate application of sucrose acetate isobutyrate (SAIB) in the development of a meth-deterrent formulation in combination with polyethylene oxide (PolyoxTM) and hydroxypropyl methylcellulose. The formulations were prepared by granulating pseudoephedrine hydrochloride, hydroxypropyl methylcellulose, and PolyoxTM with an ethanolic solution of SAIB and compressed into tablets followed by heat curing. The tablets were characterized for surface morphology, crystallinity, drug distribution, hardness, particle size, extraction, and dissolution. Hardness increased insignificantly, surface morphology indicated cracking and crevices, and diffractograms showed an increase and a decrease in drug and PolyoxTM crystallinity, respectively, after heat curing. Pseudoephedrine hydrochloride, PolyoxTM, and SAIB distribution was uniform as indicated by near infrared image. The drug extraction varied from 69.5% to 77.8%, 90.3% to 106.5%, 51.3% to 81.2%, and 48.9% to 72.6% in water, ethanol, 0.1 N HCl, and 0.1 N NaOH, respectively. The dissolution was more than 85% in 9 h from all the formulations. Thus, the addition of SAIB to the formulation decreased the drug extraction in various solvents which has the potential to decrease abuse of pseudoephedrine formulation for methamphetamine synthesis.

Synthesis, characterization and DNA interaction studies of new copper complex containing pseudoephedrine hydrochloride drug.

A new copper(II) complex, [Cu(pse)(phen)Cl2]; in which phen = 1,10-phenanthroline and pse = pseudoephedrine hydrochloride drug; was synthesized and characterized by FT-IR, Mass and UV-Vis spectroscopy in combination with computational methods. Binding interaction of this complex with calf thymus DNA (ct-DNA) has been investigated by absorption, emission, circular dichroism, molecular docking and viscosity measurements. The complex displays significant binding properties of ct-DNA. The results of fluorescence and UV-Vis absorption spectroscopy indicated that, this complex interacted with ct-DNA in a groove-binding mode, and the binding constant was 8 × 104 L mol-1. Competitive fluorimetric studies with Hoechst 33258 have shown that Cu(II) complex exhibit the ability to displace the DNA-bound Hoechst 33258 indicating that it binds to DNA in strong competition with Hoechst 33258 for the groove binding. Furthermore, the complex induces detectable changes in the CD spectrum of ct-DNA and does not induce any changes in DNA viscosity which verified the groove-binding mode. The molecular modeling results illustrated that the complex strongly binds to groove of DNA by relative binding energy of docked structure (-27.61 kJ mol-1).

Fourth-order derivative spectrophotometric method for simultaneous determination of pseudoephedrine and naproxen in pharmaceutical dosage forms.

Combination dosage forms of naproxen sodium and pseudoephedrine hydrochloride are used for symptomatic treatment of cold and sinus disorders. In this study, fourth-order derivative spectrophotometric method was used for simultaneous determination of naproxen sodium and pseudoephedrine hydrochloride. The method was linear over the range of 2-28 µg/ml for pseudoephedrine hydrochloride and 4-200 µg/ml for naproxen sodium. The within-day and between-day coefficient of variation values were less than 5.8% and 2.5% for pseudoephedrine hydrochloride and naproxen sodium, respectively. The application of the proposed method for simultaneous determination of naproxen and pseudoephedrine in dosage forms was demonstrated without any special pretreatment.

Esterification of pseudoephedrine hydrochloride by citric acid in a solid dose pharmaceutical preparation.

Esterification of pseudoephedrine hydrochloride (PSE) by citric acid was observed in a solid dose pharmaceutical preparation at room temperature and accelerated stability condition (40°C/75% relative humidity). The esterification of PSE with citric acid was confirmed by a solid-state binary reaction in the presence of minor level of water at elevated temperature to generate three isomeric esters. The structures of the pseudoephedrine citric acid esters were elucidated using high-resolution mass spectrometry and nuclear magnetic resonance spectroscopy (NMR). Occurrence of esterification in solid state, instead of amidation which is generally more favorable than esterification, is likely due to remaining HCl salt form of solid pseudoephedrine hydrochloride to protect its amino group from amidation with citric acid. In contrast, the esterification was not observed from solution reaction between PSE and citric acid.

Development of a rapid derivative spectrophotometric method for simultaneous determination of acetaminophen, diphenhydramine and pseudoephedrine in tablets.

A mixture of acetaminophen, diphenhydramine hydrochloride and pseudoephedrine hydrochloride is used for the symptomatic treatment of common cold. In this study, a derivative spectrophotometric method based on zero-crossing technique was proposed for simultaneous determination of acetaminophen, diphenhydramine hydrochloride and pseudoephedrine hydrochloride. Determination of these drugs was performed using the (1)D value of acetaminophen at 281.5 nm, (2)D value of diphenhydramine hydrochloride at 226.0 nm and (4)D value of pseudoephedrine hydrochloride at 218.0 nm. The analysis method was linear over the range of 5-50, 0.25-4, and 0.5-5 µg/mL for acetaminophen, diphenhydramine hydrochloride and pseudoephedrine hydrochloride, respectively. The within-day and between-day CV and error values for all three compounds were within an acceptable range (CV<2.2% and error<3%). The developed method was used for simultaneous determination of these drugs in pharmaceutical dosage forms and no interference from excipients was observed.

Pharmacokinetic comparisons of five ephedrine alkaloids following oral administration of four different Mahuang-Guizhi herb-pair aqueous extracts ratios in rats.

ETHNOPHARMACOLOGICAL RELEVANCE: Herba Ephedra (Mahuang in Chinese), is derived from dried Ephedra sinica Stapf stems and has been widely used to treat the common cold, coughs, asthma, and edema for thousands of years. The Mahuang-Guizhi herb-pair is a famous formula composed of Mahuang and Ramulus Cinnamomi (Guizhi in Chinese, the dried twig of Cinnamomum cassia Presl.), used to improve pharmacological effects and reduce toxicity. In order to investigate the influence of Mahuang-Guizhi herb-pair ratios on bioavailability, the plasma pharmacokinetics profiles of five ephedrine alkaloids were compared following oral administration of four different ratios to rats. MATERIALS AND METHODS: Sprague-Dawley rats were randomly assigned to four groups and orally administered Mahuang-Guizhi (ratios 3:0; 3:1; 3:2; 3:4, w/w). Assays for five ephedrine alkaloids (ephedrine, pseudoephedrine, methylephedrine, norephedrine, and norpseudoephedrine) were developed and validated using ultra-high-performance liquid chromatography tandem mass spectrometry coupled with liquid-liquid extraction. RESULTS: Key pharmacokinetic parameters of the five ephedrine alkaloids (maximal plasma concentration, mean residence time, and half-life) were significantly different (p<0.05) after oral administration of Mahuang-Guizhi herb-pair ratios, as compared to those of Mahuang. CONCLUSION: Ephedrine alkaloid pharmacokinetic differences in rat plasma could help explain previous findings of pharmacological and toxicity differences between Mahuang and Mahuang-Guizhi herb-pair preparations. These results could facilitate future studies to increase the efficacy and decrease the toxicity of Mahuang and Guizhi.

High performance thin layer chromatographic method for simultaneous estimation of Ibuprofen and pseudoephedrine hydrochloride.

High performance thin layer chromatographic method is developed for simultaneous estimation of ibuprofen and pseudoephedrine hydrochloride in tablets. Silica gel 60F(254) plates were used as stationary phase and t.butanol: ethyl acetate: glacial acetic acid: water (7:4:2:2 v/v) as mobile phase. Wavelength selected for analysis was 254 nm. Percent estimation of ibuprofen and pseudoephedrine hydrochloride was found to be 99.56% and 98.77%, respectively. Percent recovery for both the drugs was found in the range of 98.27% to 100.91%, respectively.