Lead Optimization of Butyrolactone I as an Orally Bioavailable Antiallergic Agent Targeting FcγRIIB.

Food allergy (FA) poses a growing global food safety concern, yet no effective cure exists in clinics. Previously, we discovered a potent antifood allergy compound, butyrolactone I (BTL-I, 1), from the deep sea. Unfortunately, it has a very low exposure and poor pharmacokinetic (PK) profile in rats. Therefore, a series of structural optimizations toward the metabolic pathways of BTL-I were conducted to provide 18 derives (2-19). Among them, BTL-MK (19) showed superior antiallergic activity and favorable pharmacokinetics compared to BTL-I, being twice as potent with a clearance (CL) rate of only 0.5% that of BTL-I. By oral administration, Cmax and area under the concentration-time curve (AUC0-∞) were 565 and 204 times higher than those of BTL-I, respectively. These findings suggest that butyrolactone methyl ketone (BTL-BK) could serve as a drug candidate for the treatment of FAs and offer valuable insights into optimizing the druggability of lead compounds.

Recent Advancement and Novel Application of Natural Polyphenols for the Treatment of Allergy Asthma: From Phytochemistry to Biological Implications.

Allergic diseases, primarily IgE-mediated, exert a substantial global health burden. A pivotal role in allergic reactions is played by mast cells, with histamine serving as a central mediator. Within this context, plant-based polyphenols, abundantly present in vegetables and fruits, show promising potential for allergy prevention. These natural compounds, particularly flavonoids, possess anti-inflammatory and anti-allergic properties, influencing dendritic cells, modulating macrophages, and fostering the proliferation of B cells and T cells. The potent anti-allergic effects of flavonoids are attributed to their ability to reduce the production of signaling factors, suppress cytokine production, and regulate signal transduction and gene expression in mast cells, basophils, and T cells. Notably, their benefits extend beyond allergy prevention, as they hold promise in the prevention and treatment of autoimmune illnesses such as diabetes, rheumatoid arthritis, and multiple sclerosis. In the context of allergic reactions and autoimmune diseases, polyphenols exhibit immunomodulatory effects by inhibiting autoimmune T cell proliferation and downregulating pro-inflammatory cytokines. In recent times, flavonoids, being the most prevalent polyphenols in food, have garnered significant attention from researchers due to their potential health advantages. This review compiles the latest scientific research to highlight the impact of flavonoids on allergic illnesses and their potential as a beneficial dietary component.

Chlorogenic Acid-Loaded Mesoporous Silica Nanoparticles Modified with Hexa-Histidine Peptides Reduce Skin Allergies by Capturing Nickel.

Nickel-induced contact dermatitis is a severe allergic reaction to objects or environments that contain nickel. Many nanomaterials have been developed to reduce skin allergies by capturing nickel, but few agents are effective and safe. In this work, mesoporous silica nanoparticles (MSN) were synthesized and decorated with hexa-histidine peptides (denoted as MSN-His6), making it a strong nickel chelator. Subsequently, a dietary polyphenol, chlorogenic acid, was loaded into the mesopores of MSN (denoted as MSN-His6@CGA), realizing the potential of its anti-inflammatory properties. In vitro and in vivo experiments revealed that the synthesized MSN-His6@CGA nanoparticles exhibited more stable and stronger chelation, better biocompatibility, and ideal allergy-relieving ability, whether for environmental metal contamination or for allergic contact dermatitis caused by prolonged nickel exposure. Thus, the application of mesoporous silica-based nanoparticles may represent an ideal approach to alleviate skin allergies by capturing nickel, which would benefit people who suffer from metal-induced contact dermatitis.

Alleviation effects of Rubus coreanus Miquel root extract on skin symptoms and inflammation in chronic atopic dermatitis.

Atopic dermatitis (AD) is an inflammatory skin disease characterized by chronic inflammatory dermatitis with immunological manifestations. The aim of this study was to investigate the effects of polyphenol-containing Rubus coreanus Miquel root extract on skin allergy and AD. The protective effects of R. coreanus root ethanol extract against AD were investigated using the human keratinocyte cell line HaCaT, human mast cell line HMC-1, and the 2,4-dinitrochlorobenzene (DNCB)-induced AD-like skin NC/Nga mouse model. Treatment with R. coreanus root ethanol extracts reduced ß-hexosaminidase and histamine release from HMC-1 cells stimulated with compound 48/80 compared to treatment with R. coreanus fruit ethanol extract. Furthermore, topical application of R. coreanus root ethanol extract dramatically reduced the severity of skin symptoms and the thickening and swelling of the dorsal skin and ear in DNCB-treated NC/Nga mice. The protein and mRNA expression of several cytokines (IL-4, IL-5, IL-12, IFN-γ, TNF-α, and TARC) and IgE was significantly lowered upon application of the R. coreanus root ethanol extract. The promising candidate for the active ingredient of R. coreanus root polyphenols was revealed to be ellagic acid. These findings clearly indicate that the R. coreanus root polyphenols show strong anti-allergic effects and suppress the symptoms of AD. Therefore, polyphenol-containing R. coreanus root ethanol extract could be a novel therapeutic candidate for the treatment of allergy and AD.

Synthesis and evaluation of new potential anti-pseudo-allergic agents.

Pseudo-allergic reactions frequently occur following clinical drug use and sometimes even cause mortal danger. Mas-related G-protein-coupled receptor member X2 (MRGPRX2) is a novel receptor that mediates pseudo-allergy and is an important target in the treatment of allergies. However, to date, there are no synthetic small-molecule inhibitors that prevent anaphylactoid reactions through this pathway. Our preliminary research suggested that B10-S and mubritinib effectively inhibited LAD2 cells. Therefore, two novel derivatives were synthesized by integrating the active substructures of B10-S and mubritinib, according to the molecular docking results. The antiallergic inhibitory effects of the two compounds were preliminarily evaluated in vitro using ß-hexosaminidase release, histamine release, and intracellular Ca2+ mobilization assays, and their binding sites on MRGPRX2 were analyzed by molecular docking. Both substances inhibited ß-hexosaminidase and histamine release in LAD2 cells and decreased intracellular Ca2+ by inhibiting MRGPRX2 in MRGPRX2-HEK293 cells treated with C48/80 in a dose-dependent manner. The docking results suggested that the molecules could competitively bind to the active site on MRGPRX2 and Glu141, which were combined by C48/80. Our study indicated that the two compounds have potential anti-allergic properties, which may provide evidence that will facilitate the development of synthetic molecules with anti-pseudo-allergic activity for clinical use in the future.

Juzentaihoto Exerts Anti-Allergic Effects by Inhibiting Effector T-Cell Activation and Inducing and/or Activating Regulatory T Cells in a Murine Model of Contact Hypersensitivity.

BACKGROUND: Juzentaihoto (JTT) is a Kampo prescription that has been used clinically for treating skin diseases such as atopic dermatitis in Japan. We have previously studied the anti-allergic effects of JTT on 2,4,6-trinitrochlorobenzene (TNCB)-induced contact hypersensitivity (CHS) in mice and demonstrated that it significantly suppresses ear swelling in a dose-dependent manner. However, the mechanism underlying the anti-allergic actions of JTT is obscure. METHODS: We investigated the mechanism underlying the anti-allergic effects of JTT using a TNCB-induced murine CHS model and adoptive cell transfer experiments. RESULTS: We showed that the anti-allergic effects of JTT are due to inhibition of effector T-cell activation and induction and/or activation of regulatory T cells. Furthermore, ex vivo experiments confirmed the effect of JTT on the activation of effector T cells and regulatory T cells, as interferon-γ production decreased, whereas interleukin (IL)-10 production increased, in the cultured lymphocytes obtained from 5% TNCB-sensitized mice treated with anti-CD3ε and anti-CD28 monoclonal antibodies. Flow cytometry showed that the CD4+CD25+Foxp3+, CD4+CD25+Foxp3-, and CD8+CD122+ cell population increased after oral administration of JTT. Finally, the anti-allergic effect of JTT by inducing and/or activating regulatory T cells (Tregs) was confirmed to be mediated by IL-10 through in vivo neutralization experiments with anti-IL-10 monoclonal antibodies. CONCLUSION: We suggested that JTT exerts anti-allergic effects by regulating the activation of effector T cells and Tregs involved in murine CHS model.

Anti-Allergic Effect of Low Molecular Weight Digest from Abalone Viscera on Atopic Dermatitis-Induced NC/Nga.

Abalone viscera (AV) is one of the byproducts of the seafood processing industry. The low molecular weight (<5 kDa) peptides (LMW-AV) obtained from gastrointestinal digestion of AV could suppress allergenic responses on activated HMC-1 human mast cells in our previous study. Regarding the allergenic response of LMW-AV, in the present study, we further investigated the potential of oral administration of LMW-AV against atopic dermatitis (AD) in a dermatitis-induced model stimulated with Dermatophagoides farinae. The results demonstrated that the LMW-AV reduced a number of clinical symptoms, such as the severity of the dermatitis and serum immunoglobulin E levels. Moreover, LMW-AV could inhibit the expression of chemokines and cytokines. The histological analysis indicated that the LMW-AV has suppressed the eosinophil count and the mast cell infiltration into the upper dermis. The results suggest that LMW-AV can be considered as a promising candidate for AD treatment.

Anti-Food Allergic Alkaloids from the Lotus Seed Pot.

Lotus seed pod (LSP) has been used as traditional herbal cuisine to modulate immunity. From the AcOEt-soluble extract of LSP, one new aporphine alkaloid, N-[2-(2H-phenanthro[3,4-d][1,3]dioxol-5-yl)ethyl]acetamide (nelunucine A, 1) was obtained along with 19 known ones. Their structures were established by detailed analysis of the 1D-, 2D-NMR, and HR-ESI-MS data. N-Nornuciferine (9) and lirinidine (10) showed potent in vitro anti-food allergic activity with IC50 values of 40.0 and 55.4 µM, respectively, compared to 91.4 µM for loratadine, the positive control.

Anti-allergic property of 4,8-sphingadienine stereoisomers in vivo and in vitro model.

4,8-Sphingadienines (SD), metabolites of glucosylceramides (GlcCer), are sometimes determined as key mediators of the biological activity of dietary GlcCer, and cis/trans geometries of 4,8-SD have been reported to affect its activity. Since regulating excessive activation of mast cells seems an important way to ameliorate allergic diseases, this study was focused on cis/trans stereoisomeric-dependent inhibitory effects of 4,8-SD on mast cell activation. Degranulation of RBL-2H3 was inhibited by treatment of 4-cis-8-trans- and 4-cis-8-cis-SD, and their intradermal administrations ameliorated ear edema in passive cutaneous anaphylaxis reaction, but 4-trans-8-trans- and 4-trans-8-cis-SD did not. Although the activation of mast cells depends on the bound IgE contents, those stereoisomers did not affect IgE contents on RBL-2H3 cells after the sensitization of anti-TNP IgE. These results indicated that 4-cis-8-trans- and 4-cis-8-cis-SD directly inhibit the activation of mast cells. In conclusion, it was assumed that 4,8-SD stereoisomers with cis double bond at C4-position shows anti-allergic activity by inhibiting downstream pathway after activation by the binding of IgE to mast cells.

An integrated strategy for the identification and screening of anti-allergy components from natural products based on calcium fluctuations and cell extraction coupled with HPLC-Q-TOF-MS.

Allergic diseases are a significant public health problem worldwide. Traditional Chinese medicines (TCMs) with reported anti-allergy effects may be important sources for the development of new anti-allergy drugs. Thus, establishing an analytical method that can simultaneously identify and screen anti-allergic compounds in TCMs is important. The increased concentrations of intracellular calcium ions resulting in mast cell degranulation releasing active mediators play a key role in allergic diseases, which can be used as a potential index to identify anti-allergic herbs and compounds. In this study, we provide a new strategy that was applied to screening natural anti-allergic compounds based on fluorescence calcium ion (Ca2+) fluctuation integrated with cell extract and high-performance liquid chromatography-mass spectrometry (HPLC-MS). A low-cost, convenient fluorescence detection Ca2+ signaling method was established and successfully applied to identify three herbs. Then, the method was integrated with biospecific cell fishing and HPLC-MS to screen potential active components that have the effect of stabilizing the cell membrane of rat basophilic leukemia granulocytes (RBL-2H3). Seven components, namely, albiflorin and paeoniflorin from Radix Paeoniae Alba, ononin and formononetin from Radix Astragali, cimifugin, 4'-O-ß-D-glucosyl-5-O-methylvisamminol, and prim-O-glucosylcimifugin from Radix Saposhnikoviae were fished. These seven compounds have the effect of inhibiting cell Ca2+ influx. 4'-O-ß-D-Glucosyl-5-O-methylvisamminol, prim-O-glucosylcimifugin, paeoniflorin, ononin, and formononetin significantly inhibit the release of ß-hexosaminidase, which is equivalent to the positive drug. In conclusion, the integrated strategy of fluorescence detection calcium ion kinetic method binding with biospecific cell fishing was an effective mode to identify and screen natural anti-allergic compounds.

Antiallergic Activity of 6-Deoxy-2-O-methyl-6-(N-hexadecanoyl)amino-l-ascorbic Acid.

Allergy is an excessive immune response to a specific antigen. Type I allergies, such as hay fever and food allergies, have increased significantly in recent years and have become a worldwide problem. We previously reported that an ascorbic acid derivative having palmitoyl and glucosyl groups, 2-O-α-d-glucopyranosyl-6-O-hexadecanoyl-l-ascorbic acid (6-sPalm-AA-2G), showed inhibitory effects on degranulation in vitro and on the passive cutaneous anaphylaxis (PCA) reaction in mice. In this study, several palmitoyl derivatives of ascorbic acid were synthesized and a structure-activity relationship study was performed to discover more potent ascorbic acid derivatives with degranulation inhibitory activity. 6-Deoxy-2-O-methyl-6-(N-hexadecanoyl)amino-l-ascorbic acid (2-Me-6-N-Palm-AA), in which a methyl group was introduced into the hydroxyl group at the C-2 position of ascorbic acid and in which the hydroxyl group at the C-6 position was substituted with an N-palmitoyl group, exhibited much higher inhibitory activity for degranulation in vitro than did 6-sPalm-AA-2G. 2-Me-6-N-Palm-AA strongly inhibit the PCA reaction in mice at lower doses than those of 6-sPalm-AA-2G. These findings suggest that 2-Me-6-N-Palm-AA may be a promising therapeutic candidate for allergic diseases.

Design of peptides with high affinity binding to a monoclonal antibody as a basis for immunotherapy.

About half of the US population is sensitized to one or more allergens, as found by a National Health and Nutrition Examination Survey (NHANES). The most common treatment for seasonal allergic responses is the daily use of oral antihistamines, which can control some of the symptoms, but are not effective for nasal congestion, and can be debilitating in many patients. Peptide immunotherapy is a promising new approach to treat allergic airway diseases. The small size of the immunogens cannot lead to an unwanted allergic reaction in sensitized patients, and the production of peptides with sufficient amounts for immunotherapy is time- and cost-effective. However, it is not known what peptides are the most effective for an immunotherapy of allergens. We previously produced a unique monoclonal antibody (mAb) E58, which can inhibit the binding of multiple groups of mAbs and human IgEs from patients affected by the major group 1 allergens of ragweed (Amb a 1) and conifer pollens (Jun a 1, Cup s 1, and Cry j 1). Here, we demonstrated that a combined approach, starting from two linear E58 epitopes of the tree pollen allergen Jun a 1 and the ragweed pollen allergen Amb a 1, and residue modifications suggested by molecular docking calculations and peptide design could identify a large number of high affinity binding peptides. We propose that this combined experimental and computational approach by structural analysis of linear IgE epitopes and peptide design, can lead to potential new candidates for peptide immunotherapy.

Anti-Inflammatory, Antiallergic, and COVID-19 Main Protease (Mpro) Inhibitory Activities of Butenolides from a Marine-Derived Fungus Aspergillus terreus.

In December 2020, the U.K. authorities reported to the World Health Organization (WHO) that a new COVID-19 variant, considered to be a variant under investigation from December 2020 (VUI-202012/01), was identified through viral genomic sequencing. Although several other mutants were previously reported, VUI-202012/01 proved to be about 70% more transmissible. Hence, the usefulness and effectiveness of the newly U.S. Food and Drug Administration (FDA)-approved COVID-19 vaccines against these new variants are doubtfully questioned. As a result of these unexpected mutants from COVID-19 and due to lack of time, much research interest is directed toward assessing secondary metabolites as potential candidates for developing lead pharmaceuticals. In this study, a marine-derived fungus Aspergillus terreus was investigated, affording two butenolide derivatives, butyrolactones I (1) and III (2), a meroterpenoid, terretonin (3), and 4-hydroxy-3-(3-methylbut-2-enyl)benzaldehyde (4). Chemical structures were unambiguously determined based on mass spectrometry and extensive 1D/2D NMR analyses experiments. Compounds (1-4) were assessed for their in vitro anti-inflammatory, antiallergic, and in silico COVID-19 main protease (Mpro) and elastase inhibitory activities. Among the tested compounds, only 1 revealed significant activities comparable to or even more potent than respective standard drugs, which makes butyrolactone I (1) a potential lead entity for developing a new remedy to treat and/or control the currently devastating and deadly effects of COVID-19 pandemic and elastase-related inflammatory complications.

Surfactin exerts an anti-cancer effect through inducing allergic reactions in melanoma skin cancer.

Surfactin is a mast cell degranulator, that increases the immune response via the degranulation of mast cells. Recently, numerous studies reported that allergic reactions play an important role in the reduction of melanoma development. So, this study aimed to investigate the anti-cancer effects of surfactin in a melanoma skin cancer in vivo model and a melanoma cell line, B16F10. Oral administration of surfactin significantly increased survival rate and reduced tumor growth and tumor weight on melanoma skin cancer in vivo model. Surfactin significantly increased infiltration of mast cells and levels of histamine. Surfactin significantly enhanced levels of IgE and immune-enhancing mediators, such as interferon-γ, interleukin (IL)-2, IL-6, IL-12, and tumor necrosis factor-α in serum and melanoma tissues. Activities of caspase-3, 8, and 9 were significantly enhanced by oral administration of surfactin. In vitro model, surfactin significantly increased B16F10 cell death via activation of caspase-3, 8, and 9 in a dose-dependent manner. Overall, our results indicate that surfactin has a significant anti-cancer effect on melanoma skin cancer through indirectly or directly inducing apoptosis of B16F10 melanoma cells. Also, these findings suggest that it will contribute to a novel perception into the role of allergic reactions in melanoma.

Mechanistic Studies of the Antiallergic Activity of Phyllanthus amarus Schum. & Thonn. and Its Compounds.

Phyllanthus amarus Schum. & Thonn. (Phyllanthaceae) is a medicinal plant that is commonly used to treat diseases such as asthma, diabetes, and anemia. This study aimed to examine the antiallergic activity of P. amarus extract and its compounds. The antiallergic activity was determined by measuring the concentration of allergy markers release from rat basophilic leukemia (RBL-2H3) cells with ketotifen fumarate as the positive control. As a result, P. amarus did not stabilize mast cell degranulation but exhibited antihistamine activity. The antihistamine activity was evaluated by conducting a competition radioligand binding assay on the histamine 1 receptor (H1R). Four compounds were identified from the high performance liquid chromatography (HPLC) analysis which were phyllanthin (1), hypophyllanthin (2), niranthin (3), and corilagin (4). To gain insights into the binding interactions of the most active compound hypophyllanthin (2), molecular docking was conducted and found that hypophyllanthin (2) exhibited favorable binding in the H1R binding site. In conclusion, P. amarus and hypophyllanthin (2) could potentially exhibit antiallergic activity by preventing the activation of the H1 receptor.

Depolymerized sulfated galactans from Eucheuma serra ameliorate allergic response and intestinal flora in food allergic mouse model.

The ameliorative effect of depolymerized sulfated polysaccharides from Eucheuma serra (DESP) on ovalbumin (OVA)-caused induced food allergy was investigated in this work. Results showed that OVA stimulated the secretion of allergy-related cytokines (OVA-specific IgE, mMCP-1, IgA, TNF-α) and led to diarrhea, intestinal epithelial damage, and intestinal microflora dysbiosis in sensitized mice. After the administration of DESP, however, the anaphylactic symptoms (shortness of breath, hypothermia, diarrhea), along with the allergy-related cytokines, were effectively suppressed. Moreover, the reduced intestinal inflammation was discovered in the DESP-treated group. Additionally, 16S rRNA sequencing of fecal samples was performed, and gene count and α-diversity analysis revealed that DESP improved microbial community richness. Taxonomic composition analysis showed that DESP modulated the proportion of Firmicutes and Bacteroidetes/Proteobacteria. Particularly, DESP increased probiotics (Lactobacillaceae, Bifidobacteriaceae and Prevotellaceae) and decreased pathogenic bacteria (Helicobacteraceae and Desulfovibrionaceae). These findings, therefore, suggest that DESP may ameliorate food allergy through the regulation of intestinal microbiota.

An Omalizumab Biobetter Antibody With Improved Stability and Efficacy for the Treatment of Allergic Diseases.

The critical role of IgE in allergic diseases is well-documented and clinically proven. Omalizumab, a humanized anti-IgE antibody, was the first approved antibody for the treatment of allergic diseases. Nevertheless, omalizumab still has some limitations, such as product instability and dosage restriction in clinical application. In this study, we attempted to develop an omalizumab biobetter antibody with the potential to overcome its limitations. We removed two aspartic acid isomerization hotspots in CDRs of omalizumab to improve antibody candidate's stability. Meanwhile, several murine amino acids in the framework region of omalizumab were replaced with human source to reduce the potential immunogenicity. Yeast display technology was then applied to screen antibody candidates with high binding affinity to IgE. Moreover, YTE mutation in Fc fragment was introduced into the candidates for extending their serum half-life. A lead candidate, AB1904Am15, was screened out, which showed desired biophysical properties and improved stability, high binding affinity and elevated potency in vitro, prolonged half-life in human FcRn transgenic mouse, and enhanced in vivo efficacy in cynomolgus monkey asthma model. Overall, our study developed a biobetter antibody of omalizumab, AB1904Am15, which has the potential to show improved clinical benefit in the treatment of allergic diseases.

Inhibitory Effects of Green Asparagus Extract, Especially Phospholipids, on Allergic Responses in Vitro and in Vivo.

Asparagus (Asparagus officinalis L.) is one of the widely consumed vegetables. To investigate the mechanism underlying the anti-allergic responses of asparagus, we extracted different fractions from asparagus and measured their inhibitory effects on ß-hexosaminidase release in RBL-2H3 cells in vitro and an atopic dermatitis NC/Nga mouse model in vivo. The lipid fractions from asparagus were extracted with 50% ethanol, separated using chloroform by liquid-liquid phase separation, and fractionated by solid-phase extraction. Among them, acetone fraction (rich in glycolipid) and MeOH fraction (rich in phospholipid) markedly inhibited ß-hexosaminidase release from RBL-2H3 cells. In NC/Nga mice treated with picryl chloride, atopic dermatitis was alleviated following exposure to the 50% EtOH extract, acetone fraction, and methanol fraction. The inhibitory effects of asparagus fractions in vivo were supported by the significant decrease in serum immunoglobulin E (IgE) levels. The phospholipid fractions showed significantly better inhibitory effects, and phosphatidic acid from this fraction showed the best inhibitory effect on ß-hexosaminidase release. In mice challenged with ovalbumin (OVA), oral administration of asparagus extract and its fractions decreased the OVA-specific IgE level and total IgE, indicating that these effects may be partly mediated through the downregulation of antigen-specific IgE production. Taken together, the present study shows for the first time that asparagus extract and its lipid fractions could potentially mitigate allergic reactions by decreasing degranulation in granulocytes. Our study provides useful information to develop nutraceuticals and functional foods fortified with asparagus.

The role of algal fucoidans in potential anti-allergic therapeutics.

Allergic diseases are among the commonest causes of chronic ill-health and are rapidly rising the prevalence and complexity. Although the current drugs are efficacy for treatment of allergic diseases, however the extensive clinical use of these drugs has led to the diverse and undesirable side effects. Thus, the extensive studies of alternative anti-allergic agents from natural products are essential for a long-term purpose. Marine environment covers a huge source of extremely potential secondary metabolites for drug discovery. Among them, fucoidans from brown seaweeds have been evidenced to possess various biological activities and health benefit effects. Notably, a great deal of interest has been expressed regarding anti-allergic activity of fucoidans. Consequently, this contribution presents an overview of potential anti-allergic therapeutics of fucoidans from brown seaweeds to emphasize its functions in prevention as well as treatment of allergic diseases.

QbD based Eudragit coated Meclizine HCl immediate and extended release multiparticulates: formulation, characterization and pharmacokinetic evaluation using HPLC-Fluorescence detection method.

This study is based on the QbD development of extended-release (ER) extruded-spheronized pellets of Meclizine HCl and its comparative pharmacokinetic evaluation with immediate-release (IR) pellets. HPLC-fluorescence method was developed and validated for plasma drug analysis. IR drug cores were prepared from lactose, MCC, and PVP using water as granulating fluid. Three-level, three-factor CCRD was applied for modeling and optimization to study the influence of Eudragit (RL100-RS100), TEC, and talc on drug release and sphericity of coated pellets. HPLC-fluorescence method was sensitive with LLOQ 1 ng/ml and linearity between 10 and 200 ng/ml with R2 > 0.999. Pharmacokinetic parameters were obtained by non-compartmental analysis and results were statistically compared using logarithmically transformed data, where p > 0.05 was considered as non-significant with a 90% CI limit of 0.8-1.25. The AUC0-t and AUC0-∞ of ER pellets were not significantly different with geometric mean ratio 1.0096 and 1.0093, respectively. The Cmax of IR pellets (98.051 ng/ml) was higher than the ER pellets (84.052 ng/ml) and the Tmax of ER pellets (5.116 h) was higher than the IR pellets (3.029 h). No significant food effect was observed on key pharmacokinetic parameters of ER pellets. Eudragit RL100 (6%) coated Meclizine HCl pellets have a potential therapeutic effect for an extended time period.