Trace analysis of 20 antihistamines in milk by ultrahigh performance liquid chromatography coupled with high field quadrupole orbitrap high resolution mass spectrometry followed dispersive micro solid phase extraction.

Ultrahigh-performance liquid chromatography coupled with high-field quadrupole Orbitrap high resolution mass spectrometry was used for the separation and determination of 20 antihistamines, and a dispersive micro solid-phase extraction procedure using high-performance absorbing material was developed as a sample preparation strategy for extracting 20 antihistamines from milk. Instrument conditions and key parameters influencing extraction efficiency were investigated to obtain an optimized method. The limit of detection for 20 antihistamines in milk using this method is 0.05 µg/L to 1.0 µg/L. Recoveries are between 80.7 % and 108.3 %, and the relative standard deviation is less than 15 %. It is suitable for confirmatory monitoring and quantitative analysis of 20 antihistamines in milk. The results show that antihistamines in milk may be noteworthy issues for human health and environmental pollution.

Histamine and cholesterol lowering abilities of lactic acid bacteria isolated from artisanal Pico cheese.

AIMS: This study was designed to select lactic acid bacteria with histamine- and cholesterol-reducing abilities to be used as potential probiotics. METHODS AND RESULTS: Thirty strains of lactic acid bacteria isolated from an artisanal raw milk cheese were screened for their abilities to degrade histamine, reduce cholesterol and hydrolyse bile salts. Strains were also screened for safety and probiotic traits, such as resistance to gastrointestinal conditions, adhesion to Caco-2 cells, resistance to antibiotics and presence of virulence genes. Two Lactobacillus paracasei strains presented high cholesterol- and histamine-lowering abilities, tested negative for the presence of virulence genes and showed susceptibility to most important antibiotics. These strains were also shown to possess desirable in vitro probiotic properties, revealed by tolerance to gastrointestinal conditions and high adhesion to intestinal cells. CONCLUSIONS: Among the screened strains, Lb. paracasei L3C21M6 revealed the best cholesterol and histamine reducing abilities together with desirable probiotic and safety features to be used in food applications. SIGNIFICANCE AND IMPACT OF THE STUDY: The strain L3C21M6 is a good candidate for use as a probiotic with histamine-degrading activity and cholesterol lowering effect. In addition, this strain could be use in dairy foods to prevent histamine food poisoning.

Recent Advances in Chiral Separation of Antihistamine Drugs: Analytical and Bioanalytical Methods.

Chirality is now a key area in the field of research. Researchers are well versed with analytical separations but at the same time, they are unaware of the growth in the field of chiral separation. According to the United States Food and Drug Administration (US FDA) guidelines, it is mandatory to separate chiral drugs before they are marketed. Chiral separation has gained importance in the last 10 years due to the differential biological responses of the enantiomers in chiral environment. Identical physical and chemical properties of the enantiomers pose a major challenge for the separation of chiral compounds. Further, bioanalytical method development is also necessary to throw light on the fate of separated enantiomers in biological environment. High Performance Liquid Chromatography (HPLC) and Capillary Electrophoresis (CE) are the most widely used techniques for such separation. Antihistamines are a class of drugs that are represented by a wide number of chiral compounds. Hence this review focuses on enantioseparation of chiral antihistamine drugs. It begins with a brief discussion about antihistamine drugs, chiral separation and its need for study, followed by a brief overview of the analytical and bio-analytical work carried out on different chiral antihistamine drugs. The analytical and bio-analytical techniques that are used include HPLC, CE and some new techniques.

A fully validated method for the simultaneous determination of 11 antihistamines in breast milk by gas chromatography-mass spectrometry.

Antihistamines are excreted into breast milk in small amounts; however, there are no adequate published studies or data concerning their effects on newborns and safety during breastfeeding. Thus, the development of sensitive and specific methodologies for the determination of antihistamines in breast milk is critical. A simple and sensitive GC-MS method for the simultaneous determination of 11 antihistamines (diphenhydramine, orphenadrine, chlorpheniramine, dimethindene, meclozine, hydroxyzine, loratadine, desloratadine, cetirizine, rupatadine and ebastine) in breast milk was developed and validated. The antihistamines were solid-phase extracted and derivatized with acetic anhydride and n-propanol. Diazepam-d5 , hydroxyzine-d4 and cetirizine-d8 were used as internal standards. Absolute recovery values for all analytes ranged from 70.5 to 120.0%, while the limits of detection and quantification for all analytes were 1.50 and 5.00 ng/mL, respectively. All calibration curves were linear (R2 ≥ 0.990) within the range 5.00-1000.0 ng/mL. Accuracy (Er ) ranged between -7.6 and 7.0%, while precision (RSD) was <12% for all antihistamines. The developed method is suitable for the investigation of antihistamine-related clinical cases, as well as for pharmacokinetic and breastfeeding safety studies.

Formulation of Herbal Fast Disintegrating Tablets and its ex-vivo Study for Anti-histaminic Activity in Guinea Pig Ileum.

OBJECTIVE: The aim of present research work was to develop a herbal fast disintegrating tablet containing Fagonia schweinfurthii Hadidi dried extract and determining its antihistaminic activity using guinea pig ileum. METHOD: The tablets were formulated by wet granulation technique using three different superdisintegrants (croscarmillose, crospovidone and sodium starch glycolate) at three different levels. The tablets were evaluated for various physical properties like hardness, friability weight variation etc. and various mechanical properties like disintegration time, wetting time to select the best superdisintegrant. The selected superdisintegrant was further used as intra as well as extra granulating agent to develop fast disintegrating tablets of Fagonia schweinfurthii Hadidi dried extract. The optimized formulation was subjected to stability study as per the ICH guidelines. Finally, Ex-vivo antihistaminic study was conducted on guinea pig ileum for optimized formulation and compared with marketed tablet containing cetrizine HCl as API (Stanhist-10, Ranbaxy, Pvt. Ltd). RESULTS: Physical properties of all tablet batches were found to be acceptable and comply with various official specifications. The disintegration time and wetting time of optimized formulation (F'3) were found to be 1.15±0.08 and 0.56±0.04 min respectively. Results of Ex-vivo study showed a comparable histamine inhibition between optimized tablet (15%) and marketed tablet formulation (18.8%) in a dose of 5 µg/ml. CONCLUSION: On the basis of in-vitro and Ex-vivo studies, it was concluded that prepared herbal fast disintegrating tablets were stable and had potent antihistaminic activity.

Antiallergic and antihistaminic actions of Ceasalpinia bonducella seeds: Possible role in treatment of asthma.

ETHNOPHARMACOLOGICAL RELEVANCE: Seed kernel of the plant Ceasalpinia bonducella Linn (Caesalpiniacaeae) are used for the treatment of asthma in folk medicine and ancient books. AIM OF STUDY: To assess the pharmacological efficacy of the plant in asthma and to confine and describe the synthetic constituents from the seeds that are in charge of the action. MATERIAL AND METHODS: The viability of petroleum ether, ethanol extract and ethyl acetate fraction from ethanol extract of C. bonducella seeds were screened for the treatment of asthma by various methods viz. effect of test drug on clonidine and haloperidol induced catalepsy, milk-induced leukocytosis and eosinophilia, mast cell stabilizing activity in mice and studies on smooth muscle preparation of guinea pig ileum (in-vitro). Column chromatography of active extract was done to pinpoint the active compound followed by structure elucidation by FTIR, GCMS and NMR spectroscopic methods. RESULTS: Ethyl acetate fraction from ethanol extract of C. bonducella seeds exhibited antihistaminic activity at the dose of 50 and 100 mg/kg, inhibited clonidine-induced catalepsy but not haloperidol-induced catalepsy. Ethyl acetate fraction from ethanol extract significantly inhibited increased leukocyte and eosinophil count due to milk allergen and showed maximum protection against mast cell degranulation by clonidine. The results of guinea pig ileum indicated that the compound 2 methyl, 1 hexadecanol isolated from ethyl acetate fraction of ethanol extract relaxed significantly the ileum muscle strips pre-contracted by which suggests the involvement of ß2-agonists on the relaxation of the tissue. All the results are dose dependent. Active ethyl acetate fraction from ethanol extract showed presence of anti-asthmatic compound, 2-methyl, 1-hexadecanol. CONCLUSION: The ethyl acetate fraction from ethanol extract of seeds of the plant C. bonducella can inhibit parameters linked to asthma disease.

Anticholinergic, antihistaminic, and antiserotonergic activity of n-hexane extract of Zanthoxylum alatum seeds on isolated tissue preparations: An ex vivo study.

OBJECTIVES: The aim of this study was to evaluate anticholinergic, antihistaminic, and antiserotonergic activity of the n-hexane extract of the seeds of Zanthoxylum alatum (ZAHE) on isolated ileum of rat and guinea pig and fundus of rat. MATERIALS AND METHODS: ZAHE was prepared using soxhlet extraction and cumulative concentration response curves were constructed using various doses on the tissues for acetylcholine (ACh), 5-hydroxytryptamine (5-HT), and histamine with or without n-hexane extract. Atropine, ketanserin, and pheniramine maleate were used as antagonists for ACh, serotonin, and histamine, respectively. RESULTS: ZAHE-induced concentration-dependent inhibition of isolated ileum and fundus in rat and ileum of guinea pig. The half maximal effective concentration (EC50) of ACh in the presence of atropine (10-6 M; P < 0.05) and ZAHE (1000 µg/ml; P < 0.01) was significantly higher than EC50of ACh alone. The EC50of 5-HT in the presence of ketanserin (10-5 M; P < 0.01) and ZAHE (1000 µg/ml; P < 0.05) was higher than EC50of 5-HT alone. Similarly, the EC50of histamine in the presence of pheniramine maleate (10-6 M; P < 0.01) and ZAHE (300 µg/ml; P < 0.01 and 1000 µg/ml; P < 0.05) was also significantly higher than EC50of histamine alone. CONCLUSION: From the study, it was observed that ZAHE shows significant anticholinergic, antiserotonergic, and antihistaminic activity. The study provides sufficient evidence that the seeds can be used in gastric disorders, cough, chest infection, etc., as per folklore claims.

Oral mite anaphylaxis mimicking acute asthma

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Biochemical fingerprint and pharmacological applications of Barleria noctiflora L.f. leaves.

Background Antioxidant and antihistamine agents from Barleria noctiflora L.f. as natural source due to the existing modern medicine give various adverse effects to overcome these problems with natural products. MethodsB. noctiflora leaves extract was fractionated with column chromatography; the homogenized fractions were monitored with thin layer chromatography (TLC) and characterized by using UV-visible, FT-IR, 1H NMR, 13C NMR and mass spectrometry spectral studies. The volatile phytoconstituents of B. noctiflora extract were analysed by gas chromatography-mass spectrometry. Phytoconstituents from B. noctiflora leaves extract were screened for their antioxidant and antihistamine potential in vitro (2,2-diphenyl-1-picrylhydrazyl radical scavenging activity, 2,2'-azinobis-3-ethylbenzothiozoline-6-sulfonic acid radical decolouration assay, nitric oxide radical scavenging activity, superoxide radical scavenging activity and hydrogen peroxide radical scavenging activity) and in silico (molecular docking), respectively. Results Antioxidant and antihistamine barlerinoside has been isolated and characterized from the leaves of B. noctiflora L.f. Barlerinoside revealed their free-radical scavenging ability on OH-, OH•, NO-, O2- and H2O2 radicals and found high percentage inhibition against OH- radical at the IC50 value of 50.45±2.52  µg. The methanol (MeOH) extract of B. noctiflora leaves contains cyclotene; N,N-dimethylglycine; tetrahydrocyclopenta [1,3] dioxin-4-one; phenol, 2-methoxy-; benzofuran, 2-methyl-; 1,4:3,6-dianhydro-α-d-glucopyranose; 2-methoxy-4-vinylphenol; 1,3;2,5-dimethylene-l-rhamnitol; levoglucosan and bicyclo[2.2.2]oct-7-ene-2,5-dione as being the major compounds. Among phytoconstituents present in the extract, the hexestrol; 1,2-benzenedicarboxylic acid, bis(2-methylpropyl) ester; 1-(3,6,6-trimethyl-1,6,7,7a-tetrahydrocyclopenta[c]pyran-1-yl) ethanone; megastigmatrienone; furan interacted with histamine H1 receptor and bind at GLU-177 and ASP-178 with high binding energy score -13.95, -13.41, -12.56, -12.03, and -11.72 kcal/mol, respectively, and the expected hydrolysed products of compound-1a and compound-1b from barlerinoside showed -8.91 and -8.68 kcal/mol binding energy against the histamine H1 receptor. This showed that the active ligands exactly bind with active binding site of the protein. ConclusionsWe can conclude that isolated barlerinoside from B. noctflora L.f. has potent antioxidant activity against synthetic free radicals and antihistamine activity against histamine H1 receptor.

Enantioseparation of Six Antihistamines with Immobilized Cellulose Chiral Stationary Phase by HPLC.

A stereoselective high performance liquid chromatography method has been developed for the chiral separation of the enantiomers of six antihistamines, doxylamine, carbinoxamine, dioxopromethazine, oxomemazine, cetirizine and hydroxyzine. The effects of mobile phase additive, column temperature and flow rate on the retention time and resolution were studied. Enantiomeric separation of cetirizine, doxylamine and hydroxyzine were achieved on cellulose tris-(3,5-dichlorophenylcarbamate) immobilized on silica gel chiral stationary phase known as Chiralpak IC (RS = 3.74, RS = 1.85 and RS = 1.74, respectively).

Photodegradation of the antihistamine cetirizine in natural waters.

The photodegradation rate of the anti-histamine cetirizine (Zyrtec®) was investigated in various water matrices. The average observed first-order photodegradation rate coefficient (kobs ), obtained by linear regression of the logarithmic-transformed cetirizine concentrations versus irradiation time in simulated sunlight, was 0.024 h(-1) (n = 6; standard deviation ± 0.004) in deionized water corresponding to a half-life of approximately 30 h. There was no statistical difference in the kobs of cetirizine photodegradation in coastal seawater compared with deionized water or deionized water amended with dissolved chromophoric organic matter. The quantum yield of cetirizine photodegradation decreased dramatically with increasing wavelength and decreasing energy of incoming radiation, with the average value ranging from 5.28 × 10(-4) to 6.40 × 10(-3) in the ultraviolet wavelength range (280-366 nm). The activation energy of cetirizine photodegradation was 10.3 kJ mol(-1) with an observed increase in cetirizine photodegradation as temperature increased. This is a significant environmental factor influencing half-life and an important consideration, given that cetirizine has been detected in wastewater and receiving waters from different locations globally.

Diastereomers of lithospermic acid and lithospermic acid B from Monarda fistulosa and Lithospermum erythrorhizon.

Monardic acids A (1) and B (2), which are (7R,8R) diastereomers of lithospermic acid (LA) and lithospermic acid B, respectively, were isolated from Monarda fistulosa. A (7S,8R) isomer (3) of LA was also isolated from this plant, and a (7R,8S) isomer (7) of LA was obtained from Lithospermum erythrorhizon. The absolute configuration of 1 was confirmed by analysis of its hydrolysates, 7-epiblechnic acid and 2R-3-(3,4-dihydroxyphenyl)-2-hydroxypropanoic acid. The configuration in the dihydrobenzofuran moieties of 2, 3, and 7 was extrapolated by using the phenylglycine methyl ester method and a Cotton effect at approximately 250-260 nm in their electronic circular dichroism spectra. Diastereomers (1-3 and 7) displayed moderate hyaluronidase inhibitory and histamine release inhibitory activities.

Anti-allergic inflammatory effects of cyanogenic and phenolic glycosides from the seed of Prunus persica.

A methanol extract of the seed of Prunus persica (Rosaceae) was found to inhibit histamine release in human mast cells. Activity-guided fractionation of the methanol extract yielded three cyanogenic glycosides (1-3) and other phenolic compounds (4-8). To evaluate their anti-allergic and anti-inflammatory activities, the isolates (1-8) were tested for their inhibitory effects on histamine release and on the gene expressions of tumor necrosis factor (TNF)-alpha and interleukin (IL)-6 in human mast cells. Of these, phenolic glycosides 7 and 8 suppressed histamine release and inhibited the pro-inflammatory cytokines TNF-alpha and IL-6. These results suggest that isolates from P. persica are among the anti-allergic inflammatory principles in this medicinal plant.

Trace analysis of three antihistamines in human urine by on-line single drop liquid-liquid-liquid microextraction coupled to sweeping micellar electrokinetic chromatography and its application to pharmacokinetic study.

A rapid and efficient dual preconcentration method of on-line single drop liquid-liquid-liquid microextraction (SD-LLLME) coupled to sweeping micellar electrokinetic chromatography (MEKC) was developed for trace analysis of three antihistamines (mizolastine, chlorpheniramine and pheniramine) in human urine. Three analytes were firstly extracted from donor phase (4 mL urine sample) adjusted to alkaline condition (0.5 M NaOH). The unionized analytes were subsequently extracted into a drop of n-octanol layered over the urine sample, and then into a microdrop of acceptor phase (100 mM H(3)PO(4)) suspended from a capillary inlet. The enriched acceptor phase was on-line injected into capillary with a height difference and then analyzed directly by sweeping MEKC. Good linear relationships were obtained for all analytes in a range of 6.25 × 10(-6) to 2.5 × 10(-4)g/L with correlation coefficients (r) higher than 0.987. The proposed method achieved limits of detections (LOD) varied from 1.2 × 10(-7) to 9.5 × 10(-7)g/L based on a signal-to-noise of 3 (S/N=3) with 751- to 1372-fold increases in detection sensitivity for analytes, and it was successfully applied to the pharmacokinetic study of three antihistamines in human urine after an oral administration. The results demonstrated that this method was a promising combination for the rapid trace analysis of antihistamines in human urine with the advantages of operation simplicity, high enrichment factor and little solvent consumption.

Optimization using central composite design for antihistamines separation by nonaqueous capillary electrophoresis with electrochemical and electrochemiluminescence detections.

The first detailed examination of non-aqueous capillary electrophoresis with electrochemical and electrochemiluminescence detections (NACE-EC/ECL), separation parameters and their interactions via central composite design was presented. This concept was demonstrated by examining the optimization separation conditions of seven antihistamines (chlorpheniramine, cyproheptadine, diphenhydramine, doxylamine, methapyrilene, terfenadine, and triprolidine) by NACE-EC/ECL. To evaluate the NACE separation quality, the chromatography resolution statistic function (CRS(-1) function) with regard to the resolution and migration time was established as the response variable. The influences of three experimental variables (buffer apparent pH value (pH*), buffer (TBAP) concentration, and separation voltage) on the response were investigated. A set of optimal conditions was obtained from central composite design: 9.2 mM TBAP in ACN (pH* 4.0) and voltage (12.7 kV), and under these optimum conditions, the seven antihistamines could be well separated in less than 10 min. The obtained electropherograms indicated that the dual EC/ECL detection system was indispensable since the six antihistamines (except for triprolidine) displayed both EC and ECL response, whereas triprolidine only displayed the EC response. This work is instructive for investigators in simplifying the NACE-EC/ECL development procedures for multi-component analysis.

Acridanone alkaloid in Baliospermum montanum--evaluation of its effect against anaphylaxis.

Baliospermum montanum leaves yielded 3-hydroxy-2,4-dimethoxy-10-methyl-9-acridanone (1), an alkaloid from the CHCl3 fraction. Spectroscopic analysis was performed to assign the structure of the new compound (1) and its absolute configuration. The compound was evaluated for its effect in anaphylaxis by estimation of the release of histamine in systemic anaphylaxis model. The acridanone alkaloid significantly inhibited the degranulation of mast cells up to 65.22 % and 75.12 % at a dose of 50 and 75 mg/kg, respectively.

Antihistaminic and antiviral activities of steroids of Turbinaria conoides.

The steroids 3,6,17-trihydroxy-stigmasta-4,7,24(28)-triene (A) and 14,15,18,20-diepoxyturbinarin (B) were isolated from the cyclohexane extract of brown alga, Turbinaria conoides (J. Agardh) Kutzing, and have been reported for their antimicrobial activity by us. In this study, the isolated compounds were evaluated for comprehensive antihistaminic, antiviral and cytotoxicity screening. The antihistaminic study was performed using in vitro standard animal models. Evaluation of the potency (EC(50)), affinity (pA(2)) and the maximal response (E(max)) of the histamine alone and in the presence of the compounds were determined. Antiviral activity and cytotoxicity were performed in Crandell-Rees feline kidney (CRFK) cells by a colorimetric formazan-based MTS assay. No significant antiviral activity or cytotoxicity were observed for the compounds in the CRFK cells. Compound A inhibited the histamine-induced concentration at 20 µg mL(-1)(p < 0.05). The most significant inhibition (97%) was observed for compound B (p < 0.01) at the same concentration, which was comparable to that of the positive control chlorpheniramine maleate (10 µg mL(-1)). This potentiality suggests that 14,15,18,20-diepoxyturbinarin (B) can be developed as a new lead antihistaminic agent.

Anti-histaminic potential of fractions from Hedranthera barteri [(Hook F.) Pichon] root in laboratory rodents.

Hedranthera barteri, anti-inflammatory activity, anti-nociceptive activity, anti-histaminic activityL. (HB) is used in the treatment of painful conditions and oedema amongst its folkloric use. The hexane and ethyl acetate fractions of the root of H. barteri were investigated for anti-nociceptive and antiinflammatory properties and probable mechanism of action. Hot plate, tail flick, formalin-induced oedema and acetic acidinduced writhing tests were employed to investigate the anti-nociceptive activity while the anti-inflammatory activity was investigated using carrageenan-induced paw oedema. Anti-histaminic potential of HB root extracts on the rat peritoneal mast cells (RPMCs) was explored through pectrofluorometric method. The root was screened for its phytochemical components. The HB root contains alkaloids,cardenolides and saponins. HXHBR exhibited higher anti-inflammatory potentials (P <0.001). HXHBR dose-dependently (P <0.01) reduced the histamine release from the rat peritoneal mast cells which is comparable with a standard anti-histaminic drug, ketotifen. These results showed that EAHBR and HXHBR possess anti-nociceptive and anti-inflammatory activities, and suggested its mechanism of action through the inhibition of histamine, an inflammatory mediator, usually released during the early phase of allergic responses and chronic phase of inflammatory pain. Flavonoids, alkaloids and/or saponins present in HB root may be responsible for its anti-nociceptive and anti-inflammatory properties.

Effects of Pithecellobium clypearia Benth extract and its main components on inflammation and allergy.

The ethanol extract of Pithecellobium clypearia Benth (PCE) was characterized to be rich in polyphenols by HPLC analysis, and investigated for its anti-inflammatory and anti-allergic activities. In our assay, PCE showed anti-inflammatory activity in both acute and auto-immune inflammation animal models. Administration of PCE can effectively inhibit the croton oil-induced ear edema and capillary permeability, the carrageenin-induced paw edema, and the liver injury caused by propionibacterium acnes plus lipopolysaccharide. PCE was also found to possess anti-allergic activity in inhibiting the DNFB-induced delayed hypersensitivity reaction. Meanwhile, seven main components (1-7) from PCE were studied for their effect on histamine release stimulated by compound 48/80 from rat peritoneal mast cells in vitro. Compound 2 ((-)-epigallocatechin-7-gallate), 3 ((-)-5, 7, 3', 4', 5'-pentahydroxyflavan), and 5 ((-)-tetra hydroxyflavan-7-gallate) showed significant inhibition effect on histamine release.

Conicamin, a novel histamine antagonist from the mediterranean tunicate Aplidium conicum.

In addition to the known 6-bromo-hypaphorine (2) and plakohypaphorine-A (3), the methanol extract of the Mediterranean tunicate Aplidium conicum was shown to contain conicamin, a novel indole alkaloid having histamine-antagonistic activity which structure was determined to be 1 on the basis of the spectral data.