Acetate Hydrochloride Research Articles

Pharmacokinetics and Bioequivalence Studies of Roxatidine Acetate Hydrochloride Sustained-Release Capsule in Healthy Chinese Subjects.

This study aimed to evaluate the bioequivalence between a generic roxatidine acetate hydrochloride (RAH) sustained-release capsule and brand-named formulation (ALTAT) under fasting and fed conditions. An open-label, single-center, randomized 2-period crossover study with a 5-day washout period was conducted. A single oral dose of 75-mg generic RAH sustained-release capsule (test drug) or a commercial capsule (reference drug) was given to healthy volunteers under fasting (n = 36) and fed conditions (n = 36). Blood samples were collected at baseline and during the 24 hours after dosing. The concentrations of roxatidine acetate (ROX) and bioactive metabolite roxatidine in plasma were detected using a validated high-performance liquid chromatography-tandem mass spectrometry method. Pharmacokinetic parameters were analyzed with noncompartmental methods. As prodrug, RAH was dehydrochloric acid to ROX in body and further rapidly converted to roxatidine. Such a rapid metabolism resulted in ROX that was hardly detected in plasma. Active metabolism roxatidine was therefore used to evaluate the pharmacokinetic process. The major pharmacokinetic parameters of roxatidine including peak plasma concentration, area under the plasma concentration-time curve from time 0 to time t, and area under the plasma concentration-time curve from time 0 to infinity were similar between the 2 preparations under fasting and fed conditions. The generic RAH sustained-release capsule is bioequivalent to the reference drug under fasting and fed conditions in healthy Chinese subjects.

New Potential of Roxatidine Acetate Hydrochloride on Atopic Dermatitis Mouse Model, Human Keratinocytes, and Human Skin Equivalent Model.

Atopic dermatitis (AD) is a complex inflammatory skin disorder, characterized by a complicated pathophysiology and a wide range of clinical phenotypes. Roxatidine acetate chloride (RXA) is a precursor of Roxatidine and a histamine H2 receptor antagonist, used for the treatment of gastric ulcers. In this study, we aimed to examine whether RXA had anti-AD effects and determine the underlying molecular mechanism of RXA. The anti-AD effects were examined in Dermatophagoides farinae body (Dfb)-induced AD mouse model, tumor necrosis factor (TNF)-α/interferon (IFN)-γ-stimulated HaCaT keratinocytes, and human skin equivalent model using ELISA, histological analysis, immunohistochemistry, Western blot, and immunofluorescence. Results showed that RXA treatment significantly alleviated Dfb-induced AD skin symptoms and clinical severity in mice by decreasing the levels of immunoglobulin E, histamine, and inflammatory cytokines. RXA effectively inhibited the expression of adhesive molecules and recovered the filaggrin expression in Dfb-induced AD skin lesions and TNF-α/IFN-γ-stimulated HaCaT keratinocytes. Additionally, RXA significantly upregulated the expression of aryl hydrocarbon receptor and sirtuin1. The anti-AD effects of RXA were associated with suppressed nuclear factor kappa cascade. Overall, our results suggest that RXA may be a potential anti-AD candidate owing to its inhibitory effect against skin inflammation and protection of the skin barrier function in AD.

Study on improved protocol for the synthesis of propacetamol hydrocloride

(4-Acetamidophenyl) 2-(diethylamino) acetate hydrochloride (propacetamol) is a prodrug of pacetaminophenol (paracetamol). Propacetamol is usually administered intravenously and has a rapid analgesic effect. Moreover, propacetamol is water soluble and is used in postoperative care when the patients cannot take oral or rectal p-acetaminophenol. Studies on propacetamol synthesis on laboratory scale as well as industrial scale with safe, simple and economic procedures are crucial. Over the last few years, a number of studies have been demonstrating the advantages of replacing the traditional heating methods with microwave irradiation. The improved procedure for synthesizing (4-acetamidophenyl) 2-(diethylamino) acetate hydrochloride with N-(4- hydroxyphenyl) acetamide as the starting material is described in this study. Reaction conditions including molar ratio, solvent, catalyst and reaction time were evaluated in order to enhance the synthesis performance. The structure of products obtained after each reaction were determined by using HPLC, MS and NMR methods. The results show a simple process and short reaction time for synthesis of propacetamol from p-acetaminophenol as the starting material. Additionally, the quality and purity of final products meet pharmaceutical standards and high total reaction yield is achieved through the application of microwaves with the suitable catalysts and organic solvents.

TAS-303, a Novel Selective Norepinephrine Reuptake Inhibitor that Increases Urethral Pressure in Rats, Indicating Its Potential as a Therapeutic Agent for Stress Urinary Incontinence.

Stress urinary incontinence (SUI) is characterized by involuntary leakage associated with exertion, effort, sneezing, coughing, or lifting. Duloxetine, a serotonin norepinephrine reuptake inhibitor, is approved for the treatment of patients with SUI in some European countries, but not in the United States. There is currently no globally approved pharmacological drug for the treatment of patients with SUI. Therefore, a new pharmacological treatment option is required. TAS-303 [4-piperidinyl 2,2-diphenyl-2-(propoxy-1,1,2,2,3,3,3-day7 )acetate hydrochloride] is a novel small-molecule selective norepinephrine reuptake inhibitor that displays significant norepinephrine transporter (NET) inhibitory activity toward the serotonin or dopamine transporters. In this report, we describe the pharmacological properties of TAS-303 and its effects on urethral function, using preclinical in vitro and in vivo studies. Radioligand-binding studies showed that TAS-303 selectively and potently inhibited [3H]norepinephrine binding to the human NET. Oral administration of TAS-303 (3 mg/kg) significantly increased norepinephrine levels in the plasma, whereas it did not significantly affect epinephrine, dopamine, and serotonin levels. TAS-303 (0.3, 1, and 3 mg/kg) dose-dependently increased basal urethral pressure in normal rats and leak point pressure in vaginal distention rats, exhibiting a maximal effect comparable to duloxetine. In the forced swimming test, TAS-303 (100 mg/kg) showed no significant effects on immobility time in rats, raising the possibility that this agent would have minimal central nervous system side effects at an effective dose for urethral function. These results demonstrate that TAS-303 has therapeutic potential for the treatment of patients with SUI.

Roxatidine attenuates mast cell-mediated allergic inflammation via inhibition of NF-\u03baB and p38 MAPK activation

Roxatidine is an active metabolite of roxatidine acetate hydrochloride which is a histamine H2-receptor antagonist that is used to treat gastric and duodenal ulcers. In this study, we investigated the anti-allergic inflammatory effects and the underlying molecular mechanism of roxatidine in phorbol 12-myristate 13-acetate and calcium ionophore (PMACI)-stimulated human mast cells-1 (HMC-1), compound 48/80-induced anaphylactic animal model and chemical allergen-induced contact hypersensitivity (CHS) models. Roxatidine suppressed the mRNA and protein expression of inflammatory cytokines such as TNF-α, IL-6, and IL-1β in PMACI-stimulated HMC-1 and compound 48/80-induced anaphylactic mice. In addition, roxatidine attenuated PMACI-induced nuclear translocation of NF-κB and the phosphorylation of MKK3/6 and MK2, which are both involved in the p38 MAPK pathway. Furthermore, we observed that roxatidine suppressed the activation of caspase-1, an IL-1β converting enzyme, in PMACI-stimulated HMC-1 and compound 48/80-induced anaphylactic mice. In CHS model, roxatidine significantly reduced ear swelling, increased number of mast cells, production levels of cytokines and migration of dendritic cells. Our findings provide evidence that the anti-allergic inflammatory properties of roxatidine are mediated by the inhibition of NF-κB and caspase-1 activation, p38 MAPK pathway and mast cell-derived cytokine production. Taken together, the in vitro and in vivo anti-allergic inflammatory effects suggest a possible therapeutic application of roxatidine in allergic inflammatory diseases.

Adduct of dimedone and 1,1,2-tribenzoylethylene. Keto-enol tautomerism and reactions with N-nucleophiles

Condensation of dimedone with 1,1,2-tribenzoylethylene provided pentaketone, where the position of the keto-enol equilibrium in the dibenzoylmethane fragment depended on external factors. In reactions with N-nucleophiles the pentaketone behaves as 1,4-diketone, affording with ammonium acetate, methylamine, and hydroxylamine hydrochloride functional derivatives of 4,5,6,7-tetrahydroindole, and with hydrazine hydrate, a pyridazine derivative.

SIMULTANEOUS DETERMINATION OF PREDNISOLONE ACETATE AND MOXIFLOXACIN HYDROCHLORIDE IN BULK AND IN EYE DROP USING RP–HPTLC

A simple, rapid, and precise RP-HPTLC method for analysis of Prednisolone acetate and Moxifloxacin hydrochloride in their eye drop dosage forms has been developed and validated. Chromatography was performed on silica gel 60 RP-18F254S plates with Methanol:Water:Triethylamine 7:3:0.3 (v/v) as mobile phase. Detection was performed at 274 nm. The Rf values for Prednisolone acetate and Moxifloxacin hydrochloride were found to be 0.50 ± 0.02 and 0.72 ± 0.02, respectively. Regression plots revealed good linear relationships in the concentration ranges 600–3600 ng/band for Prednisolone acetate and 300–1800 ng/band for Moxifloxacin hydrochloride. When accuracy was checked by conducting recovery studies the % recoveries were ranging from 100.97% to 102.03% (Prednisolone acetate) and 100.49% to 101.25% (Moxifloxacin hydrochloride), respectively. The amount of Prednisolone acetate and Moxifloxacin hydrochloride estimated in marketed formulation were 99.22% and 101.07%, respectively.

Pharmacokinetics of the H2 Blocker Roxatidine Acetate Hydrochloride in Pediatric Patients, in Comparison with Healthy Adult Volunteers

Clinical studies were conducted to investigate the pharmacokinetics of roxatidine acetate hydrochloride capsules (ALTAT(®) CAPSULES) in children. In a single-dose pharmacokinetic (PK) study in pediatric patients aged between 6 and 14 years with acid-related diseases, 37.5 mg or 75 mg roxatidine capsules were given orally, and blood samples were collected to determine the plasma roxatidine concentrations. Meanwhile, a single-dose PK study in healthy adult volunteers was newly conducted; subjects were given 37.5 mg, 75 mg or 150 mg roxatidine capsules. Differences were present between the PK parameters in pediatric patients and those in healthy adult volunteers. However, the CL/F and Vd/F adjusted by body surface area (BSA) or body weight (BW) were comparable. A close correlation of the C(max) and AUC(0-∞) to the dose per unit BSA (mg/m(2)) or BW (mg/kg) was also shown. In the multiple-dose study in pediatric patients, no roxatidine accumulation in plasma was observed, as was the case with a previous study in adults. These data show that the PK profile of roxatidine in pediatric patients is similar to the profile in healthy adult volunteers when adjusted by BSA or BW.

Cytochrome P450 enzymes involved in the metabolic pathway of the histamine 2 (H2)-receptor antagonist roxatidine acetate by human liver microsomes.

Roxatidine acetate hydrochloride (ROX, 2-acetoxy-N-[3-[m-(1-piperidinylmethyl)phenoxy]propyl]acetamide hydrochloride, CAS 78273-80-0), a histamine 2 (H2)-receptor antagonist, has been clinically applied for the treatment of gastritis, gastric and duodenal ulcers. There is no report on the identification of the metabolic enzyme of M-1 (2-hydroxy-N-[3-[m-(1-piperidinylmethyl)phenoxy]propyl]acetamide), the pharmacologically active metabolite, in humans. In this study, the Cytochrome P450 (CYP or P450) enzymes which participate in the metabolism of ROX were identified using human liver microsomes and S9 fractions. M-1 was converted to M-4 (3-[m-(1-piperidinyl-methyl)phenoxy]propylamine) by the enzyme reaction with the S9 but not with microsomes. M-4 was further metabolized to M-5 (3-[m-(1-piperidinylmethyl)phenoxy]propanol) by microsomes. The metabolism was inhibited by coumarin and anti-CYP2A1 serum. (3-[m-(1-piperidinylmethyl)-phenoxy]propionic acid) and M-3 (m-(1-piperidinylmethyl) phenol) formation from M-5 were inhibited by quinidine and anti-CYP2D6 serum. Moreover, M-5 was converted to M-2 and M-3 by cDNA-expressed CYP2D6. In conclusion, this study shows that microsomal enzymes do not participate in the clearance of the active metabolite M-1, CYP2A6 primarily catalyzes M-5 formation from M-4, and CYP2D6 primarily catalyzes M-2 and M-3 formation from M-5 in humans.

Investigation of the binding of roxatidine acetate hydrochloride with cyclomaltoheptaose (β-cyclodextrin) using IR and NMR spectroscopy

NMR chemical shift changes of the cyclomaltoheptaose (β-cyclodextrin, β-CD) cavity protons as well as roxatidine acetate hydrochloride aromatic ring protons revealed the formation of a RAH–β-CD inclusion complex. Detailed FTIR and NMR spectroscopic (1H NMR, COSY, NOESY, ROESY) studies have been done. The stoichiometry of the complex was determined to be 1:1, and the overall binding constant was also determined by Scott’s method. The NOESY spectrum confirmed the selective penetration of the aromatic ring of RAH into the β-CD cavity in comparison to that of the piperidine ring. The mode of penetration of the guest into the CD cavity and structure of the complex has been established.

The effects of antibiotics and steroids on the carriage of vaginal bacteria into the uterus during insertion of intra-uterine monofilaments in the guinea-pig.

The effects of systemic norethisterone acetate and oxytetracycline hydrochloride on the levels of vaginal microorganisms found in the uterus after the insertion of transcervical, intra-uterine monofilaments in the guinea-pig were determined. The results indicated that bacteria were transferred to the uterus from the vagina during the insertion process and, in the presence of an intra-uterine substrate, persisted for up to 6 months. Daily treatment with norethisterone acetate or oxytetracycline hydrochloride whilst the monofilament was in-situ failed to reduce the bacterial numbers in the uterus. Similarly, daily treatment with oxytetracycline hydrochloride for the 5 days before monofilament insertion had no effect on these bacteria.

Quantification of roxatidine in human plasma by liquid chromatography electrospray ionization tandem mass spectrometry: Application to a bioequivalence study

A sensitive and specific method using a one-step liquid–liquid extraction (LLE) with ethyl acetate followed by high-performance liquid chromatography (HPLC) coupled with positive ion electrospray ionization tandem mass spectrometry (ESI-MS/MS) detection was developed and validated for the determination of roxatidine in human plasma using famotidine as an internal standard (IS). Data acquisition was carried out in multiple reaction monitoring (MRM) mode, by monitoring the transitions m/ z 307.3 → 107.1 for roxatidine and m/ z 338.4 → 189.1 for famotidine. Chromatographic separation was performed on a reverse phase Hydrosphere C 18 column at 0.2 mL min −1 using a mixture of methanol–ammonium formate buffer as mobile phase (20:80, v/v; adjusted to pH 3.9 with formic acid). The achieved lower limit of quantification (LLOQ) was 1.0 ng mL −1 and the standard calibration curve for roxatidine was linear ( r 2 = 0.998) over the studied range (1–1000 ng mL −1) with acceptable accuracy and precision. Roxatidine was found to be stable in human plasma samples under short-, long-term storage and processing conditions. The developed method was validated and successfully applied to the bioequivalence study of roxatidine administrated as a single oral dose (75 mg as roxatidine acetate hydrochloride) to healthy female Korean volunteers.

Propiverine-induced accumulation of nuclear and cytosolic protein in F344 rat kidneys: Isolation and identification of the accumulating protein

Male and female F344 rats but not B6C3F1 mice exposed for 104 weeks to propiverine hydrochloride (1-methylpiperid-4-yl 2,2-diphenyl-2-(1-propoxy)acetate hydrochloride), used for treatment of patients with neurogenic detrusor overactivity (NDO) and overactive bladder (OAB), presented with an accumulation of proteins in the cytosol and nuclei of renal proximal tubule epithelial cells, yet despite this, no increased renal tumor incidence was observed. In order to provide an improved interpretation of these findings and a better basis for human health risk assessment, male and female F344 rats were exposed for 16 weeks to 1000 ppm propiverine in the diet, the accumulating protein was isolated from the kidneys via cytosolic and nuclear preparations or laser-capture microdissection and analyzed using molecular weight determination and mass spectrometry. The accumulating protein was found to be d-amino acid oxidase (DAAO), an enzyme involved in amino and fatty acid metabolism. Subsequent reanalysis of kidney homogenate and nuclear samples as well as tissue sections using western blot and DAAO-immunohistochemistry, confirmed the presence and localization of DAAO in propiverine-treated male and female F344 rats. The accumulation of DAAO only in rats, and the limited similarity of rat DAAO with other species, including humans, suggests a rat-specific mechanism underlying the drug-induced renal DAAO accumulation with little relevance for patients chronically treated with propiverine.

Determination of roxatidine in human plasma by liquid chromatography/electrospray mass spectrometry and application to a clinical pharmacokinetic study

A rapid and sensitive liquid chromatography/mass spectrometry (LC/MS) method was developed and validated for the determination of roxatidine in human plasma. Roxatidine was extracted by single liquid-liquid extraction with tert-butyl methyl ether, and the chromatographic separation was performed on a C8 column. The total analytical run time was relatively short (5 min), and the limit of assay quantification was 2 ng/mL using 0.1 mL of human plasma. Roxatidine and the internal standard, propranolol, were monitored in selected ion monitoring (SIM) mode at m/z 307.3 and 260.3, respectively. The standard curve was linear over a concentration range from 2-500 ng/mL, and the correlation coefficients were >0.999. The mean intra- and inter-day assay accuracy ranged from 103.4-108.8% and 102.3-110.0%, respectively, and the mean intra- and inter-day precision was between 3.3-8.8% and 5.3-6.2%, respectively. The developed assay method was successfully applied to a pharmacokinetic study in human volunteers after oral administration of roxatidine acetate hydrochloride at a dose of 75 mg.

Synthesis of New Heterocyclic System: 1(5)H-1,5-Diazacycl[3.3.2]azine-2,4-dione

A synthesis of hitherto unknown heterocyclic system 1 (5 )H-1,5 -diazacycl[3.3.2]azine-2,4-dione (5) is presented. The cyclocondensation of 2,6-diaminopyridine (1) with maleic anhydride yielded (5-amino-2-oxo-2,3-dihydroimidazo[1,2 -a]pyridin-3-yl)acetic acid (2), which was converted to methyl (5-amino-2-oxo-2,3-dihydroimidazo[l,2-a]pyridin-3-yl) acetate hydrochloride (3). The ester (3) upon treatment with sodium carbonate solution underwent intramolecular cyclization to 2a,3-dihydro-1 (5)H-1,5 -diazacycl[3.3.2]azine-2,4-dione (4), which was oxidized in alkaline condition to provide 5.

Bioprospecting Program-BIOTA: A Rational Search for Drug Discovery from Brazilian Biodiversity

Certainly, the use of natural products has been the single most successful strategy in the discovery of novel medicines, and their importance is evidenced by the new chemical entities (NCE) approved by regulatory authorities around the world in the past decade. The biodiversity found in Brazil makes it a very feasible source of biological active compounds and its preservation is an important goal both for the intrinsic value of this enormous biological resource, and for its huge potential as a source of new drugs. Our collaborative project at Biota-FAPESP has identified antifungal, anticancer, antimalarial and acetylcholinesterase inhibitor compounds from plant species of Cerrado and Atlantic Forest. Among the isolates, the xanthones mangiferin (IC50=32,55µM), muraxanthone (IC50 56.72µM), 2-(2'-O-trans-caffeoyl)-C-β-D-glucopyranosyl-1,3,6,7-tetrahydroxyxanthone (IC50 61.88µM), 2-(2'-O-trans-cinnamoyl)-C-β-D-glucopyranosyl-1,3,6,7-tetrahydroxyxanthone (IC50=46.31µM), 2-(2'-O-trans-coumaroyl)-C-β-D-glucopyranosyl-1,3,6,7-tetrahydroxyxanthone (IC50 55.94µM), 2-(2'-O-benzoyl)-C-β-D-glucopyranosyl-1,3,6,7-tetrahydroxyxanthone (IC50 55.94µM) and muraxanthone (IC50 56.72µM) showed antimalarial activity, using chroroquine as positive control. As acetylcholinesterase inhibitors, piperidine alkaloid acetyl-spectaline (IC50=24.80µM) and their derivatives (2R,3R,6S)-2-methyl-6-(13-oxotetradecyl)piperidin-3-yl acetate hydrochloride (IC50=7.32µM) and tert-butyl (2R,3R,6S)-20methyl-6-(13-oxotetradecyl)-piperidin-3-yl carbamate hydrochlride (IC50=15.10µM) have been considered lead molecules for Alzheimer disease when compared with standard control: galanthamine (IC50=3.10µM).

HIV risk behaviors during pharmacologic treatment for opioid dependence: A comparison of levomethadyl acetate hydrochloride, buprenorphine, and methadone

The efficacies of three opioid substitution medications for reducing HIV risk behaviors in opioid-dependent patients were assessed in a randomized double-blind clinical trial comparing levomethadyl acetate hydrochloride (LAAM), buprenorphine (BUP), and methadone (METH). Individually optimized flexible dosing was used for each group, with weekly possible doses of 255–391 mg of LAAM, 56–112 mg of BUP, and 420–700 mg of METH. An interview regarding specific HIV risk behaviors, including injecting, equipment sharing, and sexual activity, yielded data for pretreatment and four in-study time points for 137 subjects. Declines in risk behaviors during treatment were evident in all groups for most measures of injecting and equipment sharing. Only the METH group showed consistent declines in measures of sexual behaviors. These results demonstrate that all three medications can be highly effective in decreasing HIV risk behaviors when the dose is optimized. Reductions in sexual behaviors for the METH group are consistent with known METH side effects.

Synthesis and Crystal Structure of (9s)-N-methyl-3-azabicyclo[3.3.1] nonan-9-yl (cyclopentyl)(hydroxy)(2-thienyl)Acetate Hydrochloride

(9s)-N-methyl-3-azabicyclo[3.3.1]nonan-9-yl (cyclopentyl)(hydroxy)(2-thienyl)acetate hydrochloride, a more effective muscarinic receptor antagonist, was synthesised and its crystal structure elucidated by X-ray crystallography.

Optimized and Validated Spectrophotometric Methods for the Determination of Roxatidine Acetate Hydrochloride in Drug Formulations Using 2,3-Dichloro-5,6-dicyano-1,4-benzoquinone and p-Chloranilic Acid

Two simple and sensitive spectrophotometric procedures are proposed for the determination of roxatidine in pure form and in tablets. Both methods are based on the charge transfer complexation reaction of the drug with 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) or p-chloranilic acid resulting in colored products. In both cases, the absorbance measurement was made at 530 nm. Beer’s law was obeyed in the concentration ranges 5–65 and 10–260 µg mL−1 with DDQ and p-chloranilic acid, respectively. A series of variables were studied to optimize the reaction conditions. No interference was observed from the common excipients present in the formulations. The described methods were applied successfully for the analysis of roxatidine in pharmaceutical preparations. Statistical comparison of the results with those from our UV reference method shows excellent agreement. Both methods are validated statistically and do differ significantly in accuracy.

Erythrodermic drug eruption due to roxatidine acetate hydrochloride

Erythrodermic drug eruption due to roxatidine acetate hydrochloride