Mepyramine Research Articles

Influence of the H1 Antihistamine Mepyramine on the Antibacterial Effect of Florfenicol in Pigs.

The effect of florfenicol against Escherichia coli (E. coli) was investigated in vivo to confirm results of an in vitro study of Bruer et al. (2019), which has shown positive effects of various antibacterial agents in combination with the antihistamine mepyramine (MEP). Therefore, pigs were treated in three different settings: An untreated control group, 10 mg/kg florfenicol (FFC) and 10 mg/kg FFC in combination with 20 mg/kg MEP. E. coli were isolated from faecal samples and analyzed in growth quantity and resistance to FFC. The FFC medication induced an increased number of resistant E. coli strains isolated from faecal samples. The number of colonies detected after cultivation of animal samples treated with 10 mg/kg FFC was higher than the number of colonies after treatment with 10 mg/kg FFC in combination with of FFC and MEP. Furthermore, the effect of both compounds was examined on bacterial susceptibility of Pasteurella multocida in vitro, where the combination of FFC with MEP resulted in a diminished minimum inhibitory concentration. We confirmed the development of bacterial resistance in the intestine as non-target tissue caused by the use of the antibacterial agent florfenicol. Moreover, the combination of FFC with an antihistamine like MEP offers a possibility to enhance the efficacy of an antibacterial treatment and modifies the effect on gut microbiota.

The Neuroprotective Effects of Histamine H3 Receptor Antagonist E177 on Pilocarpine-Induced Status Epilepticus in Rats.

Epilepsy is a multifaceted neurological disorder which severely affects neuronal function. Some patients may experience status epilepticus (SE), a life-threatening state of ongoing seizure activity linked to cognitive dysfunction, necessitating an immediate intervention. The potential of histamine H3 receptors in several neuropsychiatric diseases including epilepsy is well recognized. In the current study, we aimed to explore the effect of H3R antagonist E177 on prevention and termination of pilocarpine (PLC)-induced SE in rats as well as evaluating the effects of E177 on the levels of oxidative stress in hippocampus tissues. The results showed that the survival rate of animals pretreated with E177 (5 and 10 mg/kg, intraperitoneal (i.p.)) was significantly increased during the first hour of observation, and animals were protected from SE incidence and showed a prolonged average of latency to the first seizure when compared with animals pretreated with PLC (400 mg/kg, i.p.). Moreover, the protective effect of E177 (10 mg/kg) on SE was partially reversed when rats were co- administered with H3R agonist R-(α)-methylhistamine (RAM) and with the H2R antagonist zolantidine (ZOL), but not with the H1R antagonist pyrilamine (PYR). Furthermore, pretreatment with E177 (5 and 10 mg/kg) significantly decreased the abnormal levels of malondialdehyde (MDA), and increased levels of glutathione (GSH) in the hippocampal tissues of the treated rats. However, E177 failed to modulate the levels of catalase (CAT), superoxide dismutase (SOD), or acetylcholine esterase activity (AChE). Our findings suggest that the newly developed H3R antagonist E177 provides neuroprotection in a preclinical PLC-induced SE in rats, highlighting the histaminergic system as a potential therapeutic target for the therapeutic management of SE.

Multivariate approaches for the development of quality control in-situ fiber optics dissolution methods for fixed-dose combination tablets

The purpose of this research was to develop a fiber optic (FO) dissolution method for quantification of multiple actives in combination pharmaceutical tablets. FO dissolution allows direct API quantification in the vessel, obviating the need for error-prone facets of traditional dissolution methods. However, FO dissolution is potentially challenged by overlapping UV spectra, matrix effects, UV-active excipients, API interactions with excipients and media, and undissolved components attenuating the UV signal. These obstacles might render FO dissolution method development more complex than LC-end dissolution. The case study in this manuscript has the added complexity of a triple combination product (Midol), where acetaminophen, caffeine, and pyrilamine maleate exhibit similar release kinetics, share largely overlapping UV spectra and span an order of magnitude difference in concentration. Single-wavelength quantification required unique features for the actives of interest, which were not available for the formulation of interest without preprocessing. The methods employed for the quantification of actives were a partial least squares multivariate calibration and a peak area calibration, both using prepared mixtures as reference data. The selected combination tablet demonstrated collinear API release; therefore, individual quantification required a design of experiments for mixture design. The advantages of FO dissolution will be discussed in the context of the formulation under investigation. Additionally, some general guidelines will be suggested for the development of other FO methods.

Validated ultra-performance liquid chromatographic and thin-layer chromatographic–densitometric methods for the determination of paracetamol, pamabrom, and pyrilamine maleate

Two chromatographic methods were developed for the simultaneous determination of paracetamol, pamabrom, and pyrilamine maleate in bulk and combined pharmaceutical dosage form. The first method is a...

Anticonvulsant evaluation of novel non-imidazole histamine H3R antagonists in different convulsion models in rats

Novel non-imidazole histamine H3 receptor (H3R) antagonists (2–8) were developed and assessed for in-vitro antagonist binding affinities at the human histamine H1–H4R. These novel H3R antagonists (2–8) were examined in-vivo for anticonvulsant effects in three different convulsion models in male adult rats. Compound 6 significantly and dose-dependently exhibited decreased duration of tonic hind limb extension (THLE) in the maximal electroshock (MES)- and fully protected animals against pentylenetetrazole (PTZ)-induced convulsion, following acute systemic administration (5, 10, and 20 mg/kg, i.p.). Contrary, all compounds 2–8 showed moderate protection in the strychnine (STR)-induced convulsion model following acute pretreatment (10 mg/kg, i.p.). Moreover, the acute systemic administration of H3R antagonist 6 (10 mg/kg, i.p.) significantly prolonged latency time for MES convulsions. Furthermore, the anticonvulsant effect observed with compound 6 in MES-model was entirely abrogated when rats were co-injected with the brain penetrant H1R antagonist pyrilamine (PYR) but not the brain penetrant H2R antagonist zolantidine (ZOL). However, PYR and ZOL failed to abolish the full protection provided by the H3R antagonist 6 in PTZ- and STR-models. No mutagenic or antiproliferative effects or potential metabolic interactions were shown for compound 6 when assessing its antiproliferative activities and metabolic profiling applying in-vitro methods. These findings demonstrate the potential of non-imidazole H3R antagonists as novel antiepileptic drugs (AEDs) either for single use or in addition to currently available epilepsy medications.

Mepyramine overdose

Mepyramine overdose

Development and Validation of Green Spectrophotometric Methods for Simultaneous Determination of Paracetamol, Pamabrom and Pyrilamine Maleate in Bulk and Pharmaceutical Dosage Form

Development and Validation of Green Spectrophotometric Methods for Simultaneous Determination of Paracetamol, Pamabrom and Pyrilamine Maleate in Bulk and Pharmaceutical Dosage Form

Simultaneous Determination of Acetaminophen, Pamabrom and Pyrilamine Maleate in Pharmaceutical Formulations Using Stability Indicating HPLC Assay Method

A simple, specific and accurate stability indicating RPHPLC method was developed for the determination of acetaminophen, pamabrom and pyrilamine maleate simultaneously in pharmaceutical dosage forms. Successful separation of all the components was enacted within 10 min using C18 column with mobile phase of methanol and acidified water (pH 1.8) in the ratio of (27: 73 v/v respectively). Flow rate of the mobile phase was 1.5 mL/min with detection at 300 nm. The method was validated in accordance with ICH guidelines. Response was a linear function of concentration over the range of 50- 150 􀈝g/mL for acetaminophen, 2.5-7.5 􀈝g/ mL for pamabrom and 1.5-4.5 􀈝g/mL for pyrilamine maleate. The method resulted in excellent separation of all the analytes along with their stress induced degradation products with acceptable peak tailing and good resolution. It is therefore can be applied successfully for simultaneous determination of acetaminophen, pamabrom and pyrilamine maleate in pharmaceutical formulations and their stability studies.

Novel potentiometric sensors for pyrilamine maleate

The fabrication and electrochemical response characteristics of four novel potentiometric sensors for determination of pyrilamine maleate (PyraH) were described. The sensors include polymeric membrane electrodes (PME1, PME2) and carbon paste electrodes (CPE1, CPE2). The fabricated sensors were based on the ion-pair of pyrilamine with sodium tetraphenylborate (NaTPB) and ammonium reineckate (NH4RN) using dibutyl phthalate (DBP) as plasticizing solvent. The sensors showed linear, stable and near-Nernstian slopes of 56.4 ± 0.4, 54.2 ± 0.2, 58.8 ± 0.3 and 57.9 ± 0.4 mV decade−1 at 25 ± 0.1 °C and detection limits of 2.0 × 10−5, 1.8 × 10−5, 1.0 × 10−5 and 9.5 × 10−6 mol L−1 for PME1, PME2, CPE1 and CPE2 sensors, respectively. The response time was less than 10 and 8 s for polymeric membrane and carbon paste sensors. The proposed sensors displayed good selectivity for pyrilamine with respect to a number of common inorganic and organic species. The thermal temperature coefficients of the investigated sensors were 0.9508, 0.7012, 0.9450 and 0.6497 mV °C−1. Modified carbon paste sensors showed lower detection limits, higher thermal stability and faster response time than those of polymeric membrane sensors. The proposed sensors displayed useful analytical characteristics for determination of pyrilamine in pharmaceutical preparation and biological fluids (Human urine and plasma).

Non-imidazole-based histamine H3 receptor antagonists with anticonvulsant activity in different seizure models in male adult rats.

A series of twelve novel non-imidazole-based ligands (3–14) was developed and evaluated for its in vitro binding properties at the human histamine H3 receptor (hH3R). The novel ligands were investigated for their in vivo protective effects in different seizure models in male adult rats. Among the H3R ligands (3–14) tested, ligand 14 showed significant and dose-dependent reduction in the duration of tonic hind limb extension in maximal electroshock (MES)-induced seizure model subsequent to acute systemic administration (5, 10, and 20 mg/kg, intraperitoneally), whereas ligands 4, 6, and 7 without appreciable protection in MES model were most promising in pentylenetetrazole (PTZ) model. Moreover, the protective effect observed for ligand 14 in MES model was lower than that observed for the reference drug phenytoin and was entirely abrogated when rats were co-administered with the brain-penetrant H1R antagonist pyrilamine (PYR) but not the brain-penetrant H2R antagonist zolantidine (ZOL), demonstrating that histaminergic neurotransmission by activation of postsynaptically located H1Rs seems to be involved in the protective action. On the contrary, PYR and ZOL failed to abrogate the full protection provided by 4 in PTZ model and the moderate protective effect by 14 in strychnine (STR) model. Moreover, the experimental and in silico estimation of properties such as metabolism was performed for five selected test compounds. Also, lipophilicity using planar reversed-phase thin-layer chromatography method was included for better understanding of the molecular properties of the tested compounds. Additionally, the absorption, distribution, metabolism, and elimination and toxicity parameters were evaluated for the most promising compounds 2, 4, 6, 7, and 14 utilizing in vitro methods. These interesting results highlight the potential of H3R ligands as new antiepileptic drugs or as adjuvants to available epilepsy medications.

Effect of Conjugated Bile Salt Taurodeoxycholic Acid (TDCA) on Mice Colonic Motor Activity

Background & Aims: There is an ongoing discussion concerning the role of bile salts on the gastrointestinal motility. Therefore, Taurodeoxycholic acid (TDCA) was studied to investigate the effect of TDCA on mice colonic motility and to examine this mechanism of action in presences histamine antagonist (pyrilamine maleate salt, H1) and serotonin agonist (5-hydroxytryptamine hydrochloride, 5-HT). Methods: Dose response curve of TDCA was performed using different doses of TDCA (0.3, 30, 50, 100, 200, 300 and 500 µM). Peristaltic motor complexes (PMCs) amplitudes and intervals of contractions were recorded. TDCA inhibitory effect (300 µM) on PMCs was studied with presence with H1 (10 µM) and 5-HT (25 µM). Results: TDCA inhibits intestine motility through increasing PMC intervals and decreasing PMC amplitudes with doses of 100, 200, 300 and 500 µM compared to the control values ( P < 0.03, 0.03, 0.01, 0.01 respectively). H1 antagonist (10 μM) induced significant reducing in the PMC intervals (137.2 ± 13 S) compared to the control values (255.8 ± 31 S, P < 0.04) while there was no response of 5-HT agonist (25 µM) on interval or amplitude of PMCs regardless applying of TDCA (300 µM). Conclusion: TDCA directly inhibited colon motility may be due to slowing intestinal transit time. These finding is not revealed with presences of histamine antagonist and serotonin agonist. Keywords: TDCA, antagonist, agonist, colon, motility.

Aminergic Regulation of Anoxic Coma in Locusta migratoria

Cortical spreading depression (CSD), a phenomenon underlying stroke and head trauma, involves the depolarization of neurons in one localized area that rapidly propagates to and depolarizes surrounding cells. CSD is characterized by a sudden increased concentration of extracellular potassium ions (K+), which is also generated by cellular stressors like anoxia. The purpose of this study is to examine the role of biogenic amines in the time to succumb and time to recover from anoxic coma in Locusta migratoria, a locust which is regularly exposed to anoxia in its natural environment and survive by entering a reversible coma (a spreading‐depression like event). Locusts were first immersed in water for 30 minutes and the time to succumb, ventilate, and stand upright were measured. There were 5 treatment groups with each one paired to a control group using saline injections: 1) octopamine (OA) and its antagonist epinastine (EP), 2) dopamine (DA) and its antagonist haloperidol, 3) serotonin (5‐HT) and its antagonist mianserin, 4) tyramine (TA) and its antagonist yohimbine, and 5) histamine (HA) and its antagonist pyrilamine maleate salt. Results indicated that EP‐injected locusts took significantly longer to succumb, ventilate, and stand upright compared to controls. Mianserin‐injected locusts also took significantly longer to succumb, ventilate, and stand upright.

Extraction and Performance Evaluation of Salvia hispanica Mucilage as Natural Disintegrants for Optimization of Pyrilamine Maleate Fast Dissolving Tablets

Extraction and Performance Evaluation of Salvia hispanica Mucilage as Natural Disintegrants for Optimization of Pyrilamine Maleate Fast Dissolving Tablets

Morphine modulates the effects of histamine H1 and H3 receptors on seizure susceptibility in pentylenetetrazole-induced seizure model of mice

Histamine regulates release of neurotransmitters such as dopamine, serotonin, gamma-aminobutyric acid (GABA), glutamate and also is involved in several functions in central nervous system (CNS). It has been shown that histamine participates in disorders like seizure. It has been well documented that morphine dose-dependently induces anti or proconvulsant effects. In the current study, we firstly showed that morphine (1mg/kg) exerts anticonvulsant effects which significantly reversed by naltrexone administration. Secondly, we determined seizure threshold for H1 and H3 receptors agonists and antagonists in mouse model of pentylenetetrazole (PTZ)-induced clonic seizures. Our results showed that activation of H1 receptors by 2-(2-Pyridyl)-ethylamine exerts anticonvulsant properties while inhibition of H1 receptors by pyrilamine maleate induced proconvulsant effects. Furthermore, we showed that immepip dihydrobromide, a H3 receptor agonist, increased seizure susceptibility to PTZ whereas thioperamide, a H3 receptor antagonist increased seizure threshold. We also revealed that pretreatment with morphine potently reversed the effects of histaminergic system on seizure threshold suggesting the involvement of opioid system in alteration of seizure threshold by histaminergic drugs.

The dual-acting H3 receptor antagonist and AChE inhibitor UW-MD-71 dose-dependently enhances memory retrieval and reverses dizocilpine-induced memory impairment in rats

Both the histamine H3 receptor (H3R) and acetylcholine esterase (AChE) are involved in the regulation of release and metabolism of acetylcholine and several other central neurotransmitters. Therefore, dual-active H3R antagonists and AChE inhibitors (AChEIs) have shown in several studies to hold promise to treat cognitive disorders like Alzheimer's disease (AD). The novel dual-acting H3R antagonist and AChEI 7-(3-(piperidin-1-yl)propoxy)-1,2,3,9-tetrahydropyrrolo[2,1-b]quinazoline (UW-MD-71) with excellent selectivity profiles over both the three other HRs as well as the AChE's isoenzyme butyrylcholinesterase (BChE) shows high and balanced in vitro affinities at both H3R and AChE with IC50 of 33.9nM and hH3R antagonism with Ki of 76.2nM, respectively. In the present study, the effects of UW-MD-71 (1.25–5mg/kg, i.p.) on acquisition, consolidation, and retrieval in a one-trial inhibitory avoidance task in male rats were investigated applying donepezil (DOZ) and pitolisant (PIT) as reference drugs. Furthermore, the effects of UW-MD-71 on memory deficits induced by the non-competitive N-methyl-d-aspartate (NMDA) antagonist dizocilpine (DIZ) were tested. Our results indicate that administration of UW-MD-71 before the test session dose-dependently increased performance and enhanced procognitive effect on retrieval. However neither pre- nor post-training acute systemic administration of UW-MD-71 facilitated acquisition or consolidation. More importantly, UW-MD-71 (2.5mg/kg, i.p.) ameliorated the DIZ-induced amnesic effects. Furthermore, the procognitive activity of UW-MD-71 in retrieval was completely reversed and partly abrogated in DIZ-induced amnesia when rats were pretreated with the centrally-acting H2R antagonist zolantidine (ZOL), but not with the CNS penetrant H1R antagonist pyrilamine (PYR). These results demonstrate the procognitive effects of UW-MD-71 in two in vivo memory models, and are to our knowledge the first demonstration in vivo that a potent dual-acting H3R antagonist and AChEI is effective in improving retrieval processes in the one-trial inhibitory avoidance task and provide evidence to such compounds to treat cognitive disorders.

Mepyramine

Mepyramine

The novel non-imidazole histamine H3 receptor antagonist DL77 reduces voluntary alcohol intake and ethanol-induced conditioned place preference in mice

It has become clear that histamine H3 receptors (H3R) have been implicated in modulating ethanol intake and preference in laboratory animals. The novel non-imidazole H3R antagonist DL77 with excellent selectivity profile shows high in-vivo potency as well as in-vitro antagonist affinity with ED50 of 2.1±0.2mg/kg and pKi=8.08, respectively. In the present study, and applying an unlimited access two-bottle choice procedure, the anti-alcohol effects of the H3R antagonist, DL77 (0, 3, 10 and 30mg/kg; i.p.), were investigated in adult mice. In this C57BL/6 line, effects of DL77 on voluntary alcohol intake and preference, as well as on total fluid intake were evaluated. Results have shown that DL77, dose-dependently, reduced both ethanol intake and preference. These effects were very selective as both saccharin and quinine, used to control for taste sensitivity, and intakes were not affected following DL77 pre-application. More importantly, systemic administration of DL77 (10mg/kg) during acquisition inhibited ethanol-induced conditioned-place preference (EtOH-CPP) as measured using an unbiased protocol. The anti-alcohol activity observed for DL77 was abrogated when mice were pretreated with the selective H3R agonist R-(α)-methyl-histamine (RAMH) (10mg/kg), or with the CNS penetrant H1R antagonist pyrilamine (PYR) (10mg/kg). These results suggest that DL77 has a predominant role in two in vivo effects of ethanol. Therefore, signaling via H3R is essential for ethanol-related consumption and conditioned reward and may represent a novel therapeutic pharmacological target to tackle ethanol abuse and alcoholism.

Effects of antihistamines on the function of human α7-nicotinic acetylcholine receptors

Effects of the histamine H1 receptor (H1R) antagonists (antihistamines), promethazine (PMZ), orphenadrine (ORP), chlorpheniramine (CLP), pyrilamine (PYR), diphenhydramine (DPH), citerizine (CTZ), and triprolidine (TRP) on the functional properties of the cloned α7 subunit of the human nicotinic acetylcholine receptor expressed in Xenopus oocytes were investigated. Antihistamines inhibited the α7-nicotinic acetylcholine receptor in the order PYR>CLP>TRP>PMZ>ORP≥DPH≥CTZ. Among the antihistamines, PYR showed the highest reversible inhibition of acetylcholine (100µM)-induced responses with IC50 of 6.2µM. PYR-induced inhibition was independent of the membrane potential and could not be reversed by increasing the concentration of acetylcholine. Specific binding of [125I] α-bungarotoxin, a selective antagonist for α7-nicotinic acetylcholine receptor, was not changed in the presence of PYR suggesting a non-competitive inhibition of nicotinic receptors. In line with functional experiments, docking studies indicated that PYR can potentially bind allosterically with the α7 transmembrane domain. Our results indicate that the H2–H4 receptor antagonists tested in this study (10µM) showed negligible inhibition of α7-nicotinic acetylcholine receptors. On the other hand, H1 receptor antagonists inhibited the function of human α7-nicotinic acetylcholine receptor, with varying potencies. These results emphasize the importance of α7-nicotinic acetylcholine receptor for future pharmacological/toxicological profiling.

Anticonvulsive effect of nonimidazole histamine H3 receptor antagonists.

To determine the potential of histamine H3 receptor (H3R) ligands as new antiepileptic drugs (AEDs), aromatic ether, and diether derivatives (1-12) belonging to the nonimidazole class of ligands, with high in-vitro binding affinity at human H3R, were tested for their in-vivo anticonvulsive activity in the maximal electroshock (MES)-induced and pentylenetetrazole (PTZ)-kindled seizure models in rats. The anticonvulsive effects of a systemic injection of 1-12 on MES-induced and PTZ-kindled seizures were evaluated against the reference AED phenytoin (PHT) and the structurally related H3R antagonist/inverse agonist pitolisant (PIT). Among the most promising ligands 2, 4, 5, and 11, there was a significant and dose-dependent reduction in the duration of tonic hind limb extension (THLE) in MES-induced seizure subsequent to administration of 4 and 5 [(5, 10, and 15 mg/kg, intraperitoneally (i.p.)]. The protective effects observed for the 1-(3-(3-(4-chlorophenyl)propoxy)propyl)-3-methylpiperidine derivative 11 at 10 mg/kg, i.p. were significantly greater than those of PIT, and were reversed by pretreatment with the central nervous system penetrant H1R antagonist pyrilamine (PYR) (10 mg/kg). Moreover, the protective action of the reference AED PHT, at a dose of 5 mg/kg (without considerable protection in the MES model), was significantly augmented when coadministered with derivative 11 (5 mg/kg, i.p.). Surprisingly, pretreatment with derivative 7 (10 mg/kg, i.p.), an ethylphenoxyhexyl-piperidine derivative without considerable protection in the MES model, potently altered PTZ-kindled seizure, significantly prolonged myoclonic latency time, and clearly shortened the total seizure time when compared with control, PHT, and PIT. These interesting results highlight the potential of H3R ligands as new AEDs or as adjuvants to available AED therapeutics.

Ultra-Fast Determination of Scopolamine, Orphenadrine, Mepyramine, Caffeine, Dipyrone, and Ascorbic Acid by Capillary Electrophoresis with Capacitively Coupled Contactless Conductivity Detection

In this paper, we present a simple and low-cost capillary electrophoresis method for ultra-fast determination of active ingredients present in three different pharmaceutical formulations: (i) scopolamine (SCO) and dipyrone (DIP); (ii) orphenadrine (ORP), caffeine (CAF) and DIP; (iii) mepyramine (MEP), CAF, DIP, and ascorbic acid (AA). The proposed method is based on capillary electrophoresis with capacitively coupled contactless conductivity detection (CE-C4D). The samples can be analyzed in a single run ( 0.993) was obtained from 0.10 to 0.50 mmol L-1 for SCO, from 0.25 to 1.25 mmol L-1 for ORP and MEP, from 0.50 to 2.50 mmol L-1 for DIP and CAF, and from 1.00 to 3.00 mmol L-1 for AA. The limits of detection were 0.02, 0.05, 0.03, 0.04, 0.02, and 0.06 mmol L-1 for SCO, DIP, ORP, CAF, MEP, and AA, respectively. In addition, the proposed method also provided adequate intra (< 4%) and inter-day (< 14%) precision values, as well as satisfactory recovery values for spiked pharmaceutical samples (from 92% to 103%).