Tripelennamine Research Articles

Green micellar factorial design optimized first derivative synchronous spectrofluorimetric method for tripelennamine and diphenhydramine determination in pharmaceutical gel.

A green micellar synchronous spectrofluorimetric method was developed and validated for simultaneous determination of tripelennamine hydrochloride and diphenhydramine in bulk and combined pharmaceutical formulation. Synchronous fluorescence of tripelennamine hydrochloride and diphenhydramine was determined using Δλ = 60 nm. The first derivative of synchronous fluorescence was computed to resolve overlap in the synchronous fluorescence spectra. Tripelennamine hydrochloride was quantified at 375 nm, whereas diphenhydramine was quantified at 293 nm; each is the zero-crossing point of the other. As diphenhydramine exhibited weak native fluorescence, micelle enhancement upon incorporation of sodium dodecyl sulfate was considered. Two-level full factorial design was carried out to optimize experimental parameters. Optimum conditions involved using SDS (2% w/v) along with Teorell and Stenhagen buffer (pH9). The method was found to be linear over the range 0.2-4.5 and 0.2-5μg/mL for tripelennamine and diphenhydramine, respectively, with limits of detection 0.211 and 0.159 μg/mL. The method was successfully applied for simultaneous determination of tripelennamine hydrochloride and diphenhydramine in laboratory-prepared gel containing all possible excipients with mean percent recoveries ±SD 100.59 ±0.79 and 98.99 ±0.98 for tripelennamine hydrochloride and diphenhydramine, respectively. The proposed method was proved to be eco-friendly using different greenness assessment tools.

Analytical determination of ethylenediamine impurity in tripelennamine hydrochloride by gas chromatography-mass spectrometry using phthalaldehyde as the derivatizing agent.

In the pharmaceutical industry, effective risk management and control strategies for potential genotoxic impurities are of paramount importance. The current study utilized GC-MS to evaluate a precise, linear, and accurate analytical method for quantifying ethylenediamine present in tripelennamine hydrochloride using phthalaldehyde as a derivatizing agent. When phthalaldehyde is sonicated for 10 min at room temperature, it reacts with ethylenediamine to form (1z,5z)-3,4-dihydrobenzo[f][1,4]diazocine. This approach minimizes matrix interference issues and resolves sample preparation difficulties encountered during ethylenediamine identification in GC-MS. In this method, helium serves as the carrier gas, while methanol acts as the diluent. The stationary phase consists of a DB-5MS column (30 m × 0.25 mm × 0.25 μm) with a flow rate of 1.5 mL/min. The retention time of (1z,5z)-3,4-dihydrobenzo[f][1,4]diazocine was determined to be 6.215 min. The method validation demonstrated limits of detection and quantification for (1z,5z)-3,4-dihydrobenzo[f][1,4]diazocine at 0.4 and 1.0 ppm, respectively, with a linearity range spanning from 1 to 30 ppm concentration with respect to the specification level. System suitability, precision, linearity, and accuracy of the current method were assessed in accordance with guidelines, yielding results deemed suitable for the intended use.

Green micellar liquid chromatographic method for simultaneous determination of antihistaminic drugs tripelennamine hydrochloride and diphenhydramine in pharmaceutical gel.

A new green micellar liquid chromatographic method has been developed and validated for the simultaneous determination of diphenhydramine (DPH) and tripelennamine hydrochloride (TRP) using a micellar mobile phase consisting of 1mM Tween 20 in phosphate buffer pH 4:isopropanol (85:15, %v/v). The method was linear in the range of 4-150 and 5-120μg/mL for TRP and DPH, respectively. The method was successfully applied for the simultaneous determination of DPH and TRP in a laboratory-prepared gel containing all possible excipients with mean percent recoveries±standard deviation of 100.346±1.265 and 100.754±1.117 for TRP and DPH, respectively. The method was validated according to the International Conference on Harmonization guidelines. The method is confirmed to have excellent greenness.

Electrochemical Detection of Tripelennamine Hydrochloride Voltammetrically at Glassy Carbon Electrode

Tripelennamine hydrochloride (TPA) primarily acts as first generation antihistamine psychoactive or H1 receptor antagonist and an antipruritic drug. In the present study, the voltammetric behavior of TPA was studied using glassy carbon electrode with pH ranging from 4.2 to 10.4. Cyclic voltammetry (CV) and Differential pulse voltammetric (DPV) techniques have beenemployed in order to elucidate an irreversible electrodic reaction with maximum anodic peak current at pH 7.0. Surface area of the electrode was calculated and was found to be 0.0202 cm². Scan rate variation shows that electrodic reaction involves electron transfer with diffusion controlled mass transfer process. The heterogeneous electron transfer rate constant (k⁰) was obtained to be 1.332× 10³ s^-1. A linear relationship between peak current and TPA concentrations was obtained from 0.9×10^-7 M to 10.0 × 10^-5 M by using DPV and limit of detection of 9.7 × 10^-8 M was estimated. In addition, a sensitive voltammetric method was developed, and it was successfully applied for TPA determination in pharmaceutical sample and human urine samples.The present method was also applied for the determination of TPA in pharmaceutical samples, with satisfactory recoveries from 95.32 % to 100.12 %.

Electro‐oxidation and Determination of Tripelennamine Hydrochloride at MWCNT‐CTAB Modified Glassy Carbon Electrode

AbstractAn electrochemical method for the determination of tripelennamine hydrochloride (TPA) using cetyltrimethylammoniumbromide‐multiwalled carbon nanotubes modified glassy carbon electrode (MWCNT‐CTAB/GCE) was developed. Because of good electrical conductivity of MWCNT and catalytic behavior of CTAB, new electrode significantly enhances the sensitivity for the detection of TPA. Parameters such as amount of modifier suspension, scan rate, pH of measure solution, heterogeneous rate constant were investigated. The electrode exhibits a linear potential response in the range of 1.0×10−8 M to 3.0×10−6 M with a detection limit of 2.38× 10−9 M. The modified electrode was successfully applied to the determination of TPA in pharmaceutical and real samples.

PH-Dependent Complexation of Histamine H1 Receptor Antagonists and Human Serum Albumin Studied by UV Resonance Raman Spectroscopy

UV resonance Raman spectroscopy was used to characterize the binding of three first-generation histamine H(1) receptor antagonists-tripelennamine (TRP), mepyramine (MEP), and brompheniramine (BPA)-to human serum albumin (HSA) at pH 7.2 and pH 9.0. Binding constants differ at these pH values, which can be ascribed to the different extent of protonation of the ethylamino side chain of the ligands. We have recently shown [Tardioli et al. J. Raman Spectrosc. 2011, 42, 1016-1024] that for the solution conformation of TRP and MEP the side chain plays an important role by allowing an internal hydrogen bond with the aminopyridine nitrogen in TRP and MEP. Results presented in this paper suggest that the existence of such molecular structures has serious biological significance on the binding affinity of those ligands to HSA. At pH 7.2, only the stretched conformers of protonated TRP and MEP bind in HSA binding site I. Using UV absorption data, we derived binding constants for the neutral and protonated forms of TRP to HSA. The neutral species seems to be conjugated to a positive group of the protein, affecting both the tryptophan W214 and some of the tyrosine (Y) vibrations. BPA, for which the structure with an intramolecular hydrogen bonded side chain is not possible, is H bound to the indole ring nitrogen of W214, of which the side chain rotates over a certain angle to accommodate the drug in site I. We propose that the protonated BPA is also bound in site I, where the Y150 residue stabilizes the presence of this compound in the binding pocket. No spectroscopic evidence was found for conformational changes of the protein affecting the spectroscopic properties of W and Y in this pH range.

Structure elucidation of fluorescent H1 antihistamines by ultraviolet resonance Raman spectroscopy: solvent structures of tripelennamine and mepyramine

AbstractUltraviolet Resonance Raman (UVRR) spectroscopy—a Raman technique that combines high sensitivity with high selectivity and does not suffer from background fluorescence—is applied to the fluorescent H1 antihistamines tripelennamine (TRP) and mepyramine (MEP) in aqueous solution to elucidate their molecular structure as a function of pH. In a previous investigation of these compounds (C. Tardioli, G. Gooijer G. van der Zwan, J. Phys. Chem. B, 113, (2009), 6949), the presence of gauche conformers caused by intramolecular interaction of the protonated alkylamine tail with the pyridine nitrogen was assumed to explain the pH dependence of the fluorescence properties. In order to validate this assumption, use is made of the resonant excitation of the aminopyridine chromophore in TRP and MEP. In that way, structural information associated with the vibrations of that moiety can be obtained, and the changes it undergoes upon protonation can be monitored. Assignment of the vibrations was achieved with the help of a number of other compounds, and quantum chemical calculations. N,N‐Dimethylaminopyridine (2DMP) and its mono‐protonated form (2DMPH+) were investigated, since this molecule was shown to have optical properties closely resembling those of the aminopyridine moiety in TRP and MEP. Assignment of the vibrations of 2DMP was accomplished by comparison with the resonance Raman spectra of two other reference structures, 2‐aminopyridine and dimethylaniline—for which ordinary Raman data are available—and by Gaussian calculations. UVRR spectra of TRP and MEP could be readily interpreted on the basis of vibrational assignments of the parent chromophores, i.e. 2DMP and 2DMPH+. Vibrations of the aminopyridine chromophore in TRP and MEP at neutral pH, where the aminoalkyl chain is protonated, are modified when compared to the vibrational pattern recorded for a fully neutral molecule in alkaline solution. This implies an electronic redistribution in the ring originating from internal hydrogen bonding between the aminoalkyl tail and the aminopyridine chromophore. Copyright © 2010 John Wiley & Sons, Ltd.

Effects of antihistamines on fenfluramine-induced depletion of indoles in the brain of rats.

Various effects of chlorpheniramine (CPA), diphenhydramine (DIPH), tripelennamine (TRIP), and pyrilamine (PYRI) on fenfluramine (FEN)-induced depletion of serotonin in the brain of rats were observed to be dependent on body temperature. Levels of 5-HT and 5-HIAA in the frontal cortex, hippocampus, and striatum of rats treated with FEN (10 mg/kg, once or twice daily x 4 days) decreased to approximately 30% (P < 0.01) that of controls with no significant changes after CPA, DIPH, TRIP, and PYRI. Treatment with FEN plus CPA (5, 10, 20 mg/kg) and FEN plus DIPH (20 mg/kg), but not FEN plus TRIP (20 mg/kg) and FEN plus PYRI (20 mg/kg), increased brain serotonin levels 2- to 3-fold more than those treated with FEN plus saline. Treatment with FEN plus CPA and FEN plus DIPH, but not FEN plus TRIP and FEN plus PYRI, decreased rectal temperature with no significant change after FEN. The antihistamines alone decreased temperature at a 1-hour period and enhanced FEN-induced reduction in body weight. Possible mechanisms of the different effects of antihistamines on FEN-induced depletion of serotonin are discussed.

The discriminative stimulus effects of tripelennamine in humans.

Twenty volunteers were trained to discriminate between 75 mg tripelennamine (TP) and placebo. During the first four sessions, the drugs were identified prior to ingestion by letter code. During the next six sessions, the procedure was the same except the capsules were not identified. At the end of the 3-h session, participants indicated which capsule they believed they received using the letter codes. When correct, they received a monetary bonus. If they were correct on five sessions, they entered the third phase which had ten additional training and 12 test sessions. During tests, participants received capsules that contained other drugs, including diphenhydramine (50 and 75 mg), chlorpheniramine (4 and 6 mg), diazepam (5 and 10 mg), d-amphetamine (5 and 10 mg), as well as tripelennamine (25, 50 and 75 mg) and placebo. Thirteen participants learned the discrimination and nine entered the third phase. Except for placebo, most participants identified the test compounds as TP and labeled them as sedatives. TP produced significant changes on several subjective and physiological measures. The test compounds produced varied effects which were neither clearly dose-related nor related to the identification as TP or placebo. These results indicate that tripelennamine can function as a discriminative stimulus, but with little evidence of pharmacological specificity.

Subchronic Studies of Tripelennamine in Fischer 344 Rats

The purpose of this study was to determine the subchronic toxicity of the antihistamine tripelennamine and to allow selection of appropriate doses for chronic studies. Male and female Fischer 344 rats were administered tripelennamine hydrochloride in the feed at dose levels of 0, 300, 600, 1200, 2400, and 6000 ppm (as the free amine) for 14 days or at dose levels of 0, 150, 300, 600, 1200, and 2400 ppm for 90 days. In the 14-day study, all of the animals in the 6000 ppm groups died. All others survived until killed. Final body weights of treated groups were reduced from 3% to 25%. Cytoplasmic vacuolization of the liver was observed. In the 90-day study, a dose-dependent reduction in body weight gain was produced by tripelennamine, with a 10% reduction in final body weight occurring between 300 and 600 ppm. Reductions in various organ weights were found to be correlated with reduced final body weights. Tripelennamine produced cytoplasmic vacuolization or fatty change in the liver, cytomegaly and granular basophilic cytoplasm in the parotid salivary gland, and vacuolar degeneration of the bronchial epithelium of the lung. Based on the results of this study, it was determined that 400 ppm tripelennamine administered ad libitum in the feed to both male and female Fischer 344 rats would be an appropriate highest dose for a 2-year carcinogenicity study.

Subchronic Studies of Tripelennamine in B6C3F1 Mice

The subchronic toxicity of tripelennamine hydrochloride was determined to provide data for selecting dose levels for a 2-year study in mice. Male and female B6C3F1 mice were administered the drug in their feed at dose levels of 0, 150, 300, 600, 1200, and 2400 ppm (calculated as free amine) for 14 days or 0, 300, 600, 1200, 2400, and 4800 ppm for 90 days. Little toxicity was observed in the 14-day study. In the 90-day study, final body weights of males and females of the 4800 ppm groups were reduced 14% and 4%, respectively. Clinical observations and necropsy findings were unremarkable in the 90-day study. Decreased heart weight/brain weight ratios in males and increased liver weight/brain weight ratios in females were seen at dose levels as low as 600 ppm. Histologically, changes consisting of cytomegaly, karyomegaly, and cytoplasmic vacuolization of the liver, mild to severe cytomegaly and necrosis of parotid salivary gland acinar cells, and a mild degree of vacuolar degeneration of the bronchial epithelium of the lung were observed. The results indicate that an oral dose level of 2000 ppm tripelennamine would not be life-shortening in male or female B6C3F, mice in a 2-year study.

N+-Glucuronidation of aliphatic tertiary amines, a general phenomenon in the metabolism of H1-antihistamines in humans

1. Representative drugs of the various structural classes of H1 antihistamines were chosen for study. The drugs chosen (class name in parentheses) were chlorpheniramine maleate and pheniramine maleate (alkylamines), diphenhydramine hydrochloride and doxylamine succinate (ethanolamines), pyrilamine maleate and tripelennamine hydrochloride (ethylenediamines), promethazine hydrochloride (phenothiazine), cyclizine lactate (piperazine) and terfenadine (miscellaneous). In each case oral dose(s) were administered over no more than 6 h to two healthy volunteers and the total urine collected for 36 h. 2. Metabolites from urine were separated by h.p.l.c. and individually collected prior to mass spectrometric analysis in the fast atom bombardment mode. The structure of each metabolite identified as a quaternary ammonium-linked glucuronide metabolite was confirmed by direct comparison of its mass spectrum and chromatographic behaviour with that of a synthetic authentic compound. 3. For eight of the nine drugs studied, metabolism by the N(+)-glucuronidation pathway was observed in each of the volunteers. Terfenadine was the exception. 4. The amount of each N(+)-glucuronide in the urine was estimated by h.p.l.c. analysis. The mean proportion of dose excreted as the metabolite was 14.3%, 6.5% and 4.0% for cyclizine, tripelennamine and diphenhydramine, respectively. Promethazine was the only case where the N(+)-glucuronide accounted for less than 1.0% of the administered dose in both volunteers examined.

A comparative in vitro metabolic study of methaphenilene and pyribenzamine.

1. In vitro metabolism of methaphenilene (MFN) and pyribenzamine (PBZ) was compared to that of methapyriline (MPH) in rat, because chronic treatment with MPH causes cancer in rats, whereas MFN and PBZ cause no cancer. 2. G.l.c. and mass spectrometry were used to identify 7 metabolites of MFN and 6 of PBZ in extracts of rat liver microsome incubations. 3. Quantification of the metabolic pathways revealed that N-oxide formation is considerably more important for both MFN and PBZ than for MPH, and only MPH forms an amide as a metabolic product. 4. Quantitative balance studies show that a lower recovery is apparent for metabolic experiments with MPH than for either MFN or PBZ under all conditions examined, indicating that significant metabolic pathways for MPH exist which are not being measured under these conditions.

Abuse of Pentazocine-Naloxone Combination

The combination of pentazocine hydrochloride and tripelennamine hydrochloride (T's and blues) has been abused as a heroin substitute. In response to this abuse, the formulation of pentazocine has been changed to include naloxone hydrochloride, a short-acting narcotic antagonist, in the tablet (Talwin Nx). Two cases of abuse of the new pentazocine and naloxone formulation along with tripelennamine are reported. Potential reasons for the failure of naloxone to block the effects of pentazocine are discussed.

Dermal reactivity to histamine, serotonin and bradykinin in relation to allergic skin reactions of the horse.

The reactivity of horse skin to intradermal inoculation of histamine, serotonin and bradykinin was investigated, and the resulting reactions compared with those produced in the same horses by a 1% whole-body extract of Culicoides. Both histamine and bradykinin produced large reactions, but there was no significant correlation between the dermal responsiveness to insect allergen and either histamine or bradykinin. Two anti-histamine drugs (promethazine hydrochloride and tripelennamine hydrochloride) were effective in reducing the reaction produced by the insect extract.

Liquid Chromatographic Determination of Organic Nitrogenous Bases in Dosage Forms: A Progress Report

A liquid chromatographic (LC) method has been developed as a general procedure for the assay of the salts of organic nitrogenous bases in a variety of dosage forms. The method uses a nitrile-bonded reverse phase column, a methanol-0.003M ammonium acetate (90 + 10) mobile phase, and photometric detection at 254 nm. The sample is dissolved in the mobile phase and an aliquot is injected through a 20 microL injection loop. Average recovery values for duplicate assays were chlorpheniramine maleate injection 97.8%, chlorpheniramine maleate tablets 99.1%, cyclizine hydrochloride tablets 100.0%, doxylamine succinate tablets 103.3%, mesoridazine besylate tablets 100.4%, pentazocine hydrochloride tablets 103.0%, promethazine hydrochloride injection 98.4%, protriptyline hydrochloride tablets 101.2%, pyrilamine maleate tablets 97.8%, pyrimethamine tablets 100.0%, tripelennamine citrate elixir 100.0%, and tripelennamine hydrochloride tablets 97.2%. Results by this method were in good agreement with those obtained by the USP XX method. This study, which is being continued, will be expanded to include additional drugs.

Trace determination of the antihistamines tripelennamine hydrochloride, thenyldiamine hydrochloride, and chlorothen citrate in admixture in animal feed, human urine, and wastewater by high-pressure liquid chromatography and use of a fluorescence detector

Tripelennamine hydrochloride, thenyldiamine hydrochloride, and chlorothen citrate have been used as antihistamines and for the treatment of asthma and bronchitis. Toxicological evaluation of these drugs was scheduled as part of a structure-activity relationship study of antihistamines in rats and mice, because of the paucity of such information. Prerequisite for the evaluation was the development of analytical chemical procedures to certify the concentration, homogeneity, and stability of the drugs in dosed feed, to monitor the urine of laboratory personnel to signal their possible exposure to the drugs, and to monitor the wastewater to ensure that the test agents were not discharged into the environment. A high-pressure liquid chromatographic procedure with fluorescence detection was developed for determination of the three antihistamines in admixture in animal feed, human urine, and wastewater at levels of 500, 10 and 10 ng g , respectively. Data on the partition values and use of a silica gel column to aid in the clean-up of sample extracts from the three substrates are reported for the three test agents. Extraction efficiencies and data concerning the stability of tripelennamine hydrochloride and thenyldiamine hydrochloride in animal feed are presented. Description of a new route for synthesis of chlorothen citrate and ancillary data concerning the gas chromatographic analysis for the three drugs in admixture in animal feed at levels as low as 10 μg g are also reported.

Inhibition of bone resorption in tissue culture by H1-receptor antagonists.

Mouse bone culture studies show that several representative H1-receptor antagonists, promethazine hydrochloride, pyrilamine maleate, tripelennamine hydrochloride, and diphenhydramine hydrochloride, inhibit parathyroid extract-stimulated bone resorption. The H2-receptor antagonists, metiamide and cimetidine, are ineffective. In view of the finding that histamine and histamine agonists did not stimulate bone resorption, it is unlikely that histamine receptors are involved in mediating parathyroid extract-stimulated bone resorption. Because H1-receptor antagonists bind to phospholipids and have been shown to influence membrane structure and function, it is suggested that they inhibit bone resorption by a mechanism that depends on their membrane-stabilizing effect.

Lethality of pentazocine and tripelennamine combinations in mice housed individually and in groups

Lethality of 80 mg/kg pentazocine alone; 40 mg/kg tripelennamine 20 mg/kg tripelennamine in combination with 40, 60, and 80 mg/kg pentazocine; and 40 mg/kg tripelennamine in combination with 10, 20, and 40 mg/kg pentazocine was determined in mice housed individually and in groups. Results indicate that the lethality of pentazocine and tripelennamine combinations in mice is (1) dose-dependent, (2) potentiated relative to either drug alone, and (3) greater in group-housed than in individually-housed animals.

The effects of cocaine, chlorpheniramine and tripelennamine on the cardiac responses to sympathetic nerve stimulation

The effects of cocaine (COC), chlorpheniramine (CHL), and tripelennamine (TRI) on the cardiac responses to sympathetic neural stimulation were compared in open-chest, anesthetized dogs. The amplitudes of the chronotropic responses were not significantly altered by any of these drugs. Similarly, the amplitudes of the inotropic responses were not affected significantly by either COC or TRI, but they were increased moderately by CHL. All three drugs prolonged the inotropic and especially the chronotropic responses. CHL and TRI, and addition to being antihistaminics, are inhibitors of the neuronal uptake of norepinephrine. Therefore, the similarity of the effects of CHL, TRI, and COC on the cardiac responses to sympathetic stimulation is probably ascribable to their inhibitory activities on the neuronal uptake mechanism.