piperidines and diphenidol

Meniere's disease is a common inner ear disease with an incidence of 15 to 50 per 100,000 population. Since Meniere's disease is thought to be triggered by an immune insult to the inner ear, we examined intraendolymphatic sac application of steroids as a new therapeutic strategy for intractable Meniere's disease.. Prospective randomized controlled study.. Between 1996 and 2005, we enrolled and assigned 197 intractable Meniere's patients to three groups in a randomized controlled trial: Group I (G-I)- patients who underwent endolymphatic sac drainage and steroid-instillation; Group II (G-II)-those who underwent endolymphatic sac drainage without steroid-instillation; and Group III (G-III)-those who declined endolymphatic sac drainage. Definitive spells and hearing in all three groups were determined for 2 to 7 years after treatment.. According to the 1995 American Academy of Otolaryngology-Head and Neck Surgery (AAO-HNS) criteria, 2-year results demonstrated that vertigo was completely controlled in 88.0% of patients in G-I (n = 100), 85.1% of patients in G-II (n = 47), and 8.0% in G-III (n = 50). Statistically, G-I = G-II>G-III. Hearing was improved in 49.0% of patients in G-I, 31.9% in G-II, and 6.0% in G-III (G-I>G-II>G-III). Results after 7 years showed that vertigo was completely controlled in 78.8% of patients in G-I, 79.2% in G-II, and 25.0% in G-III (G-I = G-II>G-III). Hearing improved in 36.5% of patients in G-I, 8.3% in G-II, and 0.0% in G-III (G-I>G-II = G-III).. From non-surgical observation in G-III for at least 7 years after treatment, steroids instilled into endolymphatic sac in G-I patients significantly improved hearing in intractable Meniere's patients, more so than endolymphatic sac drainage without steroids in G-II patients.

Topics: Anti-Inflammatory Agents; Antidepressive Agents; Dexamethasone; Diazepam; Dimenhydrinate; Diuretics; Endolymphatic Sac; Female; Follow-Up Studies; Histamine H1 Antagonists; Humans; Male; Meniere Disease; Middle Aged; Piperidines; Prospective Studies

Diphenidol was determined by an HPLC method developed in our laboratory. It was validated and proved to be linear in the 40-400 ng/ml range. Accuracy for quality-control samples for intra and inter day assays ranged from 96.1-98.9% and 98.8-101.4%, respectively. This method was applied to a multi-dose bioequivalence study. No serious side effects were observed in the multi-dose design. Pharmacokinetic parameters (mean+/-standard error [S.E.]) of Cavg (ng/ml) and AUCtau (ngh/ml) for reference and test products were 139.54+/-12.66 versus 148.60+/-16.51 and 551.07+/-53.53 versus 588.78+/-69.02, respectively. Log-transformed values were compared by analysis of variance (ANOVA) followed by the classical 90% confidence interval (CI 90%) test and Schuirmann's test. Confidence limits ranged from 91.48-116.18% for Cmax and from 91.24-117.65% for AUCtau. These results suggest that the analytical method was linear, precise, and accurate for our purpose, and that both assayed formulations were bioequivalent.

Topics: Adult; Antiemetics; Chromatography, High Pressure Liquid; Data Interpretation, Statistical; Female; Humans; Mexico; Piperidines; Reproducibility of Results; Spectrophotometry, Ultraviolet; Therapeutic Equivalency

The antiarrhythmic activity of diphenidol, an antiemetic, has been demonstrated both in electrophysiologic studies of patiens and in experimental arrhythmias in animals. Accordingly, 18 patients with tachyarrhythmias were treated with intravenous diphenidol in doses of 0.5 to 1.5 mg/kg. In six patients with atrial arrhythmias, there was no notable effect. Similarly, 12 patients with premature ventricular contractions were treated and studied. In six of them, ectopic beats were abolished, at least transiently; in three the number of ventricular premature contractions decreased; in two there was no effect; and in one, the number of premature beats was increased. Of the total number of 18 patients, 14 suffered adverse effects related to the central nervous system. These adverse effects were of such severity as to suggest that further studies with diphenidol as an antiarrhythmic are not warranted.

Topics: Aged; Arrhythmias, Cardiac; Butanols; Central Nervous System; Clinical Trials as Topic; Confusion; Digitalis Glycosides; Dyspnea; Electrocardiography; Electrophysiology; Hemodynamics; Humans; Injections, Intravenous; Middle Aged; Piperidines; Placebos

In 24 patients with Ménière's disease, chemotherapy using Diphenidol (1,1-diphenyl-4-piperidino-l-butanol hydrochloride), a non-phenothiazinic antiemetic agent, was carried out using the double-blind technique in the cross-over design. The prevalence and intensity of symptoms at the three stages were recorded every three weeks according to fixed scales which were graded: vertigo, unsteadiness, tinnitus, nausea, headache, and shoulder stiffness. The hearing was measured by tone audiometry. Equilibrium function tests were also performed every three weeks and these included the electronystagmographical procedure to determine caloric response and the ARG-Tilt tests. Both symptoms and the results of equilibrium function tests, showed a higher incidence of improvement during the period of Diphenidol administration than during that of placebo. The difference was statistically significant with respect to vertigo, dizziness or unsteadiness, and general condition subjectively, as well as caloric response and ARG-Tilt tests. The Diphenidol effect consisted of an improvement of imbalance, both in the peripheral and in the central vestibular system through its neural and circulatory action. Only 8% of the patients dropped out and no side effects were observed in this series. Both the feasibility of the graded symptom scales and the utility of each parameter obtained from the equilibrium function tests are discussed in connection with testing of the drug in various stages of the disease.

Topics: Audiometry; Clinical Trials as Topic; Eye Movements; Hearing; Humans; Meniere Disease; Piperidines; Placebos; Postural Balance; Vestibular Function Tests

A gas chromatography-mass spectrometry (GC-MS) method for the determination of difenidol hydrochloride in biological specimens has been developed. The method exhibited excellent recovery (> 90%) and precision (RSD < 10%), and the LOD was 0.05 μg/mL or μg/g, which met the requirements of bioanalytical method. Through the animal model of the forensic toxicokinetics, the dynamic distribution, postmortem redistribution (PMR) and stability in specimen preservation process of difenidol in animals were studied. The experimental results showed that after intragastric administration, the difenidol's concentrations in the heart-blood and various organs increased over time except stomach, and then decreased gradually after reaching the peaks of concentration. The toxicological kinetics equation and toxicokinetic parameters were established by processing the data of the mean drug concentration of difenidol changing with time. In PMR experiment, the concentrations of difenidol in some organs closer to the gastrointestinal tract (heart-blood, heart, liver, lung, kidney, and spleen) changed significantly at different time points. But the concentration of difenidol in brain tissues which were far away from the gastrointestinal tract and muscles with larger overall mass was relatively stable. PMR of difenidol was therefore confirmed. Thus, the effect of PMR on the concentration of difenidol in the specimens should be considered in cases involving difenidol poisoning or death. Furthermore, the stability of difenidol in heart-blood samples from poisoned rats was investigated at various time points and under different preservation conditions (20 °C, 4 °C, - 20 °C and 20 °C (1% NaF)) for a period of two months. Difenidol was stable and did not decompose in the preserved blood. Therefore, this study provided the experimental basis for the forensic identification of the cases of difenidol hydrochloride poisoning (death). PMR has been verified by practical lethal cases.

Topics: Animals; Autopsy; Forensic Medicine; Piperidines; Rats; Toxicokinetics

To explore the characteristics of postmortem examination, chemical examination and scene investigation of deaths caused by oral diphenidol hydrochloride poisoning, and so as to provide a reference for proper settlement and prevention of such deaths.. The data of 22 deaths caused by oral diphenidol hydrochloride poisoning in a city from January 2018 to August 2020 were collected, including case details, scene investigations, autopsies, chemical examinations and digital evidence. Thirty-one cases of deaths caused by oral diphenidol hydrochloride poisoning reported in previous literature were also collected.. In the 53 oral diphenidol hydrochloride poisoning death cases, 50 cases were suicide, 2 cases were accidental, while 1 case was undetermined. Fifty-two cases were found in the medical records or crime scene investigation reports with doses ranging from 775 mg to 12 500 mg, and 23 deceased were detected with postmortem blood concentrations ranging from 2.71 mg/L to 83.1 mg/L. Clinical symptoms were recorded in 6 patients, including conscious disturbance and convulsion. Among the 45 cases which were performed with external examination, 23 cases autopsied.. Most of the deceased of oral diphenidol hydrochloride poisoning were suicide. No significant correlation was found between dose and blood concentration through the retrospective analysis of cases.

Topics: Autopsy; Humans; Piperidines; Poisoning; Retrospective Studies; Suicide

陈某，男，27岁，因工作、感情、生活等压力厌世。某日陈某独自骑摩托车旅行，于3月15日入住某民宿，并先后于实体药店和网上平台购买药物。3月22日民宿到期，房东联系不上陈某，敲门不应，遂报警。民警上门查探时发现房门为反锁状态，强行破门后发现陈某已死亡。为明确死亡原因，对其进行法医学鉴定。.

Topics: Chlorides; Ethanol; Humans; Piperidines; Poisoning; Potassium Chloride

Clinically, there is a kind of patients with positional vertigo or dizziness, which occurs when they turn left or right, look down or up, lie down or sit up. With a long duration and varying frequency, it is not consistent with the manifestations of benign paroxysmal positional vertigo (BPPV). In addition, the persistent geotropic direction-changing positional nystagmus (PG-DCPN) was observed in a supine head-roll test.. With no apparent trigger for visual rotation and a sense of self instability, an 81-year-old female patient had suffered from vertigo for 3 days. The vertigo occurred every day, lasting several minutes each time, and associated with head movements and changes in body position. In a supine head-roll test, it appeared persistent geotropic direction-changing positional nystagmus for a long time, without latency, fatigability and in the presence of 3 zero planes.. Light cupula.. Difenidol hydrochloride 25 mg orally 3 times/day for 2 weeks and betahistine hydrochloride 12 mg orally 3 times/day for 1 month were administered.. After 1 month of treatment, the patient's vertigo symptoms disappeared. And in the supine head-roll test, the persistent geotropic direction-changing positional nystagmus disappeared.. We report the characteristics of nystagmus produced in a typical patient with light cupula during the supine head-roll test. After reviewing the relevant literatures, we believe that a simpler method can be used to identify canalolithiasis and cupula disease, to distinguish light and heavy cupula, and to determine the pathological semicircular canal to which the lesion belongs.

Topics: Aged, 80 and over; Betahistine; Female; Humans; Nystagmus, Pathologic; Nystagmus, Physiologic; Piperidines; Supine Position; Vestibular Function Tests

Diphenidol (DPN) is a nonphenothiazinic antivertigo and antiemetic drug that has been widely used in clinical practice in China because of its good antivertigo curative effect, minimal side effects and high safety. In recent years, there have been some cases of sporadic suicide and accidental poisoning related to DPN. Hence, a validated method for the determination of DPN in biological samples by ultra-high-performance liquid chromatography-tandem mass spectrometry (UPLC-MS-MS) was developed. The method is characterized by the use of a simple, fast and inexpensive liquid-liquid extraction (LLE) for sample preparation, a rapid run time (5 min) and a low required sample volume (0.1 mL or 0.1 g). The lower limits of quantitation (LLOQs) were 0.05 ng/mL and 0.3 ng/g for blood and liver tissue, respectively. The method was shown to be linear over a concentration range of 0.05-200 ng/mL (blood) and 0.3-400 ng/g (liver). The accuracy was in the range of 92.77-112.75%. The relative standard deviations of the intraday and interday imprecisions were in the range of 3.22% to 12.17%, and the recoveries were in the range of 58.75-95.27%. Furthermore, the method was successfully applied to the detection and quantification of DPN in 15 real forensic cases. The postmortem concentration range of heart blood was 0.87-99 μg/mL.

Topics: Chromatography, High Pressure Liquid; Chromatography, Liquid; Humans; Piperidines; Tandem Mass Spectrometry

In recent years, diphenidol [1,1-diphenyl-4-piperidino-1-butanol] has been one of the drugs that appears in suicide cases, but there are few research data on its metabolic pathways and main metabolites. Metabolite identification plays a key role in drug safety assessment and clinical application. In this study, in vivo and in vitro samples were analyzed with ultra-high-performance liquid chromatography-quadrupole/electrostatic field orbitrap high-resolution mass spectrometry. Structural elucidation of the metabolites was performed by comparing their molecular weights and product ions with those of the parent drug. As a result, 10 Phase I metabolites and 5 glucuronated Phase II metabolites were found in a blood sample and a urine sample from authentic cases. Three other Phase I metabolites were identified in the rat liver microsomes incubation solution. The results showed that the main metabolic pathways of diphenidol in the human body include hydroxylation, oxidation, dehydration, N-dealkylation, methylation, and conjugation with glucuronic acid. This study preliminarily clarified the metabolic pathways and main metabolites of diphenidol. For the development of new methods for the identification of diphenidol consumption, we recommend using M2-2 as a marker of diphenidol entering the body. The results of this study provide a theoretical basis for the pharmacokinetics and forensic scientific research of diphenidol.

Topics: Animals; Antiemetics; Chromatography, High Pressure Liquid; Humans; Male; Mass Spectrometry; Microsomes, Liver; Piperidines; Rats; Rats, Sprague-Dawley; Species Specificity

Umami taste is one of the five basic tastes (sweet, umami, bitter, sour, and salty), and is elicited by l-glutamate salts and 5'-ribonucleotides. In chickens, the elucidation of the umami taste sense is an important step in the production of new feedstuff for the animal industry. Although previous studies found that chickens show a preference for umami compounds in long-term behavioral tests, there are limitations to our understanding of the role of the umami taste sense in chicken oral tissues because the long-term tests partly reflected post-ingestive effects. Here, we performed a short-term test and observed agonists of chicken umami taste receptor, l-alanine and l-serine, affected the solution intakes of chickens. Using this method, we found that chickens could respond to umami solutions containing monosodium l-glutamate (MSG) + inosine 5'-monophosphate (IMP) within 5 min. We also demonstrated that chickens were successfully conditioned to avoid umami solution by the conditioned taste aversion test. It is noted that conditioning to umami solution was generalized to salty and sweet solutions. Thus, chickens may perceive umami taste as a salty- and sweet-like taste. In addition, we found that umami taste receptor candidates were differentially expressed in different regions of the chicken oral tissues. Taken together, the present results strongly suggest that chickens have a sense of umami taste and have umami taste receptors in their oral tissue.

Topics: Analysis of Variance; Animals; Animals, Newborn; Avoidance Learning; Chickens; Dose-Response Relationship, Drug; Gene Expression Regulation; Glutamic Acid; Inosine Monophosphate; Piperidines; Receptors, G-Protein-Coupled; RNA, Messenger; Taste; Taste Perception; Time Factors

Recent studies have shown that human bitter taste receptors (TAS2Rs) are not only expressed in mucous epithelial cells of the tongue, but also in epithelial cells of the colon, stomach and upper respiratory tract. These cell types come in close contact with external bitter compounds by ingestion or breathing. In the present work we addressed the question whether bitter taste receptors might also be expressed in cornified epithelial cells of the skin. Here, we show for the first time the expression of TAS2R1 and TAS2R38 in human skin. Double staining of HaCaT cells and primary keratinocytes demonstrated the colocalization of TAS2R1 and TAS2R38 with the adaptor protein α-gustducin that is essential for signal transduction upon ligand binding. To test if TAS2Rs in keratinocytes are functional, we stimulated HaCaT cells with diphenidol, a clinically used bitter-tasting antiemetic, or amarogentin, the bitterest plant substance, that binds TAS2Rs, including TAS2R1 and TAS2R38. Diphenidol and amarogentin induced calcium influx. Furthermore, in keratinocytes diphenidol and amarogentin stimulated the expression of the differentiation markers keratin 10, involucrin and transglutaminase. Therefore, apart from the known role in mucous membranes of the gastrointestinal tract, TAS2Rs are expressed in the epidermis and might play a role in keratinocyte differentiation.

Topics: Adult; Animals; Cell Line; Cells, Cultured; Humans; Iridoids; Keratinocytes; Mice; NIH 3T3 Cells; Piperidines; Receptors, G-Protein-Coupled; Tongue

The impact of coadministration of transcutaneous electrical nerve stimulation (TENS) and diphenidol is not well established. Here we estimated the effects of diphenidol in combination with TENS on mechanical allodynia and tumor necrosis factor-α (TNF-α) expression. Using an animal chronic constriction injury (CCI) model, the rat was estimated for evidence of mechanical sensitivity via von Frey hair stimulation and TNF-α expression in the sciatic nerve using the ELISA assay. High frequency (100Hz) TENS or intraperitoneal injection of diphenidol (2.0μmol/kg) was applied daily, starting on postoperative day 1 (POD1) and lasting for the next 13 days. We demonstrated that both high frequency TENS and diphenidol groups had an increase in mechanical withdrawal thresholds of 60%. Coadministration of high frequency TENS and diphenidol gives better results of paw withdrawal thresholds in comparison with high frequency TENS alone or diphenidol alone. Both diphenidol and coadministration of high frequency TENS with diphenidol groups showed a significant reduction of the TNF-α level compared with the CCI or HFS group (P<0.05) in the sciatic nerve on POD7, whereas the CCI or high frequency TENS group exhibited a higher TNF-α level than the sham group (P<0.05). Our resulting data revealed that diphenidol alone, high frequency TENS alone, and the combination produced a reduction of neuropathic allodynia. Both diphenidol and the combination of diphenidol with high frequency TENS inhibited TNF-α expression. A moderately effective dose of diphenidol appeared to have an additive effect with high frequency TENS. Therefore, multidisciplinary treatments could be considered for this kind of mechanical allodynia.

Topics: Analgesics; Animals; Combined Modality Therapy; Constriction, Pathologic; Hyperalgesia; Male; Pain Threshold; Physical Stimulation; Piperidines; Rats, Sprague-Dawley; Sciatic Nerve; Touch; Transcutaneous Electric Nerve Stimulation

Clarification of the mechanism of the sense of taste in chickens will provide information useful for creating and improving new feedstuffs for chickens, because the character of the taste receptors in oral tissues affects feeding behavior in animals. In this study, we focused on the sensitivity to bitterness in chickens. We cloned one of the bitter taste receptors, T2R1, from the chicken palate, constructed several biosensor-cells expressing chicken T2R1 (cT2R1), and determined a highly sensitive biosensor of cT2R1 among them. By using Ca(2+) imaging methods, we identified two agonists of cT2R1, dextromethorphan (Dex) and diphenidol (Dip). Dex was a new agonist of cT2R1 that was more potent than Dip. In a behavioral drinking study, the intake volumes of solutions of these compounds were significantly lower than that of water in chickens. These aversive concentrations were identical to the concentrations that could activate cT2R1 in a cell-based assay. These results suggest that the cT2R1 activities induced by these agonists are linked to behavioral sensitivity to bitterness in chickens.

Topics: Animals; Behavior, Animal; Calcium; Chickens; Cloning, Molecular; Dextromethorphan; Piperidines; Receptors, G-Protein-Coupled; Taste

Diphenidol hydrochloride (DPN), a nonphenothiazinic antiemetic agent used primarily in patients with Meniere disease and labyrinthopathies to treat vomiting and vertigo, is considered to be a relatively safe drug. Since it was first approved in the United States in 1967, this drug has been widely used in Latin America and Asia and has contributed to sporadic suicidal and accidental poisonings in mainland China and Taiwan. However, its toxic or lethal concentration ranges have not yet been determined. We report a case of a 23-year-old female who suffered from DPN poisoning that resulted in death. At autopsy, there were no typical pathological findings, except for cerebral edema with high acetylcholinesterase expression. Postmortem analysis of DPN revealed 45 µg/ml in heart blood, 39 µg/ml in femoral vein blood, 141 µg/g in the liver, and 53 mg in the gastric contents. These concentrations indicated that the cause of death was DPN poisoning. The circumstances indicated that the manner of death was suicide. We also present a retrospective study, in which we review and summarize the literature from 1998 to 2014 and describe 16 cases of poisoning, including information from autopsy reports and postmortem drug concentrations. In forensic practice, drug residues at the scene, patients with convulsions and disturbance of consciousness, and rapidly occurring deaths, should draw attention to the possibility of this drug. Toxicological analysis and the exclusion of other diseases may ultimately be used to confirm DPN poisoning.

Topics: Antiemetics; Brain Edema; Female; Gastrointestinal Contents; Humans; Liver; Molecular Structure; Piperidines; Retrospective Studies; Suicide; Young Adult

The core@shell Fe3O4@Au nanoparticles (NPs) functionalized with exchangeable self-assembled monolayers have been developed for mode switching magnetic solid-phase extraction (MSPE) using high performance liquid chromatography with ultraviolet detection. The adsorbents were synthesized by chemical coprecipitation to prepare magnetic cores followed by sonolysis to produce gold shells. Functionalization of Fe3O4@Au NPs surface was realized through self-assembly of commercially available low molecular weight thiol-containing ligands using gold shells as intermediate platform and the dynamic nature of Au-S chemistry allowed substituent of one thiol-containing ligand with another simply by thiol exchange process. The resultant adsorbents were characterized by transmission electronic microscopy, Fourier transform infrared spectroscopy, elemental analysis, contact angle measurement, and vibrating sample magnetometry. To evaluate the versatile performance of the developed MSPE adsorbents, they were applied for normal-phase SPE followed by reversed-phase SPE. A few kinds of diphenols and polycyclic aromatic hydrocarbons (PAHs) were employed as model analytes, respectively. The predominant parameters affecting extraction efficiency were investigated and optimized. Under the optimum experimental conditions, wide dynamic linear range (6.25-1600 μg L(-1) for diphenols and 1.56-100 μg L(-1) for PAHs) with good linearity (r(2)≥0.989) and low detection limits (0.34-16.67 μg L(-1) for diphenols and 0.26-0.52 μg L(-1) for PAHs) were achieved. The advantage of the developed method is that the Fe3O4@Au NPs could be reutilized for preconcentrating diverse target analytes in different SPE modes sequentially simply through treatment with desired thiol-containing ligands.

Topics: Adsorption; Chromatography, High Pressure Liquid; Ferrosoferric Oxide; Gold; Magnetite Nanoparticles; Piperidines; Polycyclic Aromatic Hydrocarbons; Solid Phase Extraction; Spectrophotometry, Ultraviolet; Surface Properties; Water Pollutants, Chemical

Diphenidol has been shown to block voltage-gated Na(+) channels, which are associated with specific types of pain. Here, we evaluated the effects of diphenidol on chronic constriction injury (CCI)-evoked allodynia and expression of tumor necrosis factor-α (TNF-α). A peripheral nerve injury was elicited in rats by placing four loosely constrictive ligatures around the sciatic nerve. After intraperitoneal injection of diphenidol, rats were tested for evidence of mechanical allodynia prior to surgery, and on postoperative days 3, 6, 7, 11, 13 and 14. We showed that CCI rats received diphenidol caused dose-dependent increases in mechanical withdrawal threshold. Both diphenidol 2 and 10 μmol/kg groups, but not 0.4 μmol/kg diphenidol, displayed lower TNF-α level in the sciatic nerve than the CCI group (P<0.05) on day 7 after CCI. Our results support the conclusion that systemic diphenidol produced a dose-related inhibition of mechanical allodynia following chronic constriction injury of the sciatic nerve. This antiallodynic effect is related to the decrease of TNF-α expression in the sciatic nerve of CCI rats.

Topics: Analgesics; Animals; Dose-Response Relationship, Drug; Gene Expression Regulation; Hyperalgesia; Male; Peripheral Nerve Injuries; Piperidines; Rats; Sciatic Nerve; Tumor Necrosis Factor-alpha

Bitter-taste receptors (TAS2Rs) have recently been involved in the relaxation of mouse and guinea pig airways, and increased expression of TAS2Rs was shown in blood leucocytes from asthmatic children. We sought to identify and characterize the TAS2Rs expressed in isolated human bronchi and the subtypes involved in relaxation.. Human bronchi were isolated from resected lungs and TAS2R transcripts were assessed with RT-qPCR. Relaxation to TAS2R agonists was tested in organ bath in the presence or absence of pharmacological modulators of the signalling pathways involved in bronchial relaxation.. We detected the expression of TAS2R transcripts in human bronchi. The non-selective agonists chloroquine, quinine, caffeine, strychnine and diphenidol produced a bronchial relaxation as effective and potent as theophylline but much less potent than formoterol and isoproterenol. Denatonium, saccharin and colchicine did not produce relaxation. Receptor expression analysis together with the use of selective agonists suggest a predominant role for TAS2R5, 10 and 14 in bitter taste agonist-induced relaxation. The mechanism of relaxation was independent of the signalling pathways modulated by conventional bronchodilators and may be partly explained by the inhibition of phosphatidylinositol-3-kinases.. The TAS2Rs may constitute a new therapeutic target in chronic obstructive lung diseases such as asthma.

Topics: Adult; Aged; Aged, 80 and over; Bronchi; Bronchoconstriction; Bronchodilator Agents; Caffeine; Chloroquine; Female; Humans; Male; Middle Aged; Piperidines; Receptors, Cell Surface; Receptors, G-Protein-Coupled; Signal Transduction; Strychnine; Taste

OCT2 is the entry step for organic cation (OC) secretion by renal proximal tubules. Although many drugs inhibit OCT2 activity, neither the mechanistic basis of their inhibition nor their transport status is generally known. Using representatives of several structural classes of OCT2-inhibitory ligands described recently (Kido Y, Matsson P, Giacomini KM. J Med Chem 54: 4548-4558, 2011), we determined the kinetic basis of their inhibition of 1-methyl-4-phenylpyridinium (MPP) transport into Chinese hamster ovary cells that stably expressed hOCT2. The "cluster II" inhibitors (which contain known OCT2 substrates) metformin and cimetidine interacted competitively with MPP. However, other cluster II compounds, including tetraethylammonium (TEA), diphenidol and phenyltoloxamine, were mixed-type inhibitors of MPP transport (i.e., decreasing J(max) and increasing K(t)). A cluster III (neutral steroid) representative, adrenosterone, and a cluster I (large, flexible cation) representative, carvedilol, displayed noncompetitive inhibitory profiles. Competitive counterflow (CCF) was used to determine whether the inhibitory ligands served as substrates of hOCT2. Carvedilol (cluster I) and adrenosterone (cluster III) did not support CCF, consistent with the prediction that members of these structural classes are likely to be nontransported inhibitors of OCT2. The cluster II representatives MPP, metformin, cimetidine, and TEA all supported CCF, consistent with independent assessments of their OCT2-mediated transport. However, the other cluster II representatives, diphenidol and phenyltoloxamine, failed to support CCF, suggesting that neither compound is transported by OCT2. An independent assessment of diphenidol transport (using liquid chromatography with tandem mass spectroscopy) confirmed this observation. The results underscore the caution required for development of predictive models of ligand interaction with multidrug transporters.

Topics: 1-Methyl-4-phenylpyridinium; Androstenes; Animals; Benzhydryl Compounds; Carbazoles; Carvedilol; CHO Cells; Cimetidine; Cricetinae; Cricetulus; Humans; Inhibitory Concentration 50; Kinetics; Ligands; Metformin; Organic Cation Transport Proteins; Organic Cation Transporter 2; Piperidines; Propanolamines; Tetraethylammonium

Difenidol (1,1-diphenyl-4-piperidino-1-butanol hydrochloride) is an effective drug for the treatment of vertigo and dizziness. This drug is known to improve the blood flow in vertebral arteries, though the precise mechanism underlying this action remains unclear. In the present study, we investigated the effect of difenidol on voltage-gated calcium channel Ca(v)1.2 and α(1)-adrenoceptor subtypes that regulate the intracellular calcium concentration ([Ca(2+)](i)), as well as their possible involvement in the action of difenidol on vertebral artery relaxation and blood flow in dogs. In vitro binding assays demonstrated that difenidol at micromolar concentrations bound to the α(1A)-, α(1B)- and α(1D)-adrenoceptor subtypes. Difenidol inhibited the phenylephrine-induced increase in [Ca(2+)](i) in Chinese hamster ovary cells expressing human α(1A)-, α(1B)- or α(1D)-adrenoceptor subtypes with similar IC(50) values in the low micromolar range. In an electrophysiological assay, difenidol inhibited L-type calcium channel (Ca(v)1.2 subunit). In dogs, i.v. difenidol preferentially enhanced vertebral over femoral arterial blood flow. Phenylephrine and potassium induced contraction of dog vertebral arterial rings, and difenidol inhibited this action. Inhibition of phenylephrine-induced contraction by difenidol was mimicked by the α(1)-adrenoceptor antagonist phentolamine, the α(1A)-adrenoceptor antagonist RS 17,053 (N-[2-(2-cyclopropylmethoxyphenoxy)ethyl]-5-chloro-α,α-dimethyl-1H-indole-3-ethanamine hydrochloride) and the α(1D)-adrenoceptor antagonist BMY 7378 (8-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-8-azaspiro[4,5]decane-7,9-dione dihydrochloride). In addition, the L-type calcium channel blocker nifedipine, like difenidol, attenuated the potassium-induced contraction. These findings suggest that the difenidol-induced increase in vertebral arterial blood flow may be due to vascular relaxation mediated by mixed blocking actions at α(1)-adrenoceptors and voltage-gated calcium channel Ca(v)1.2.

Topics: Adrenergic alpha-1 Receptor Antagonists; Animals; Blood Flow Velocity; Calcium Channel Blockers; Calcium Channels, L-Type; CHO Cells; Cricetinae; Cricetulus; Dogs; HEK293 Cells; Humans; Male; Piperidines; Rats; Receptors, Adrenergic, alpha-1; Vertebral Artery; Vertigo

Although diphenidol has long been deployed as an anti-emetic and anti-vertigo drug, its mechanism of action remains unclear. In particular, little is known as to how diphenidol affects neuronal ion channels. Recently, we showed that diphenidol blocked neuronal voltage-gated Na(+) channels, causing spinal blockade of motor function, proprioception and nociception in rats. In this work, we investigated whether diphenidol could also affect voltage-gated K(+) and Ca(2+) channels.. Electrophysiological experiments were performed to study ion channel activities in two neuronal cell lines, namely, neuroblastoma N2A cells and differentiated NG108-15 cells.. Diphenidol inhibited voltage-gated K(+) channels and Ca(2+) channels, but did not affect store-operated Ca(2+) channels.. Diphenidol is a non-specific inhibitor of voltage-gated ion channels in neuronal cells.

Topics: Animals; Antiemetics; Calcium Channels; Cell Differentiation; Cell Line, Tumor; Electrophysiological Phenomena; Mice; Neuroblastoma; Piperidines; Potassium Channels, Voltage-Gated

The aim of this study was to evaluate the effect of diphenidol on blocking Na(+) currents and spinal anesthesia. We used the patch-clamp method to examine if diphenidol blocked Na(+) currents. Lidocaine, a common used local anesthesia, was used as control. We also evaluated the potencies and durations of diphenidol and lidocaine on spinal blockades of motor function, proprioception, and nociception in rats. Lidocaine exhibited a concentration- and state-dependent effect on tonic blockade of voltage-gated Na(+) currents in mouse neuroblastoma N2A cells (IC(50) of 8.1 and 138.9 microM at holding potentials of -70 and -100 mV, respectively). Diphenidol was more potent (IC(50) of 0.77 and 62.6 microM at holding potentials of -70 and -100 mV, respectively). However, unlike lidocaine, block of Na(+) currents by diphenidol lacked use-dependence. We also found that diphenidol acted like lidocaine and produced dose-related spinal blockades of motor function, proprioception and nociception. Although diphenidol had similar potencies of spinal anesthesia compared with lidocaine it produced a much longer duration of spinal blockades than lidocaine. Our results demonstrated that intrathecal diphenidol produced a long duration and similar potency on spinal anesthesia compared with lidocaine in rats. The anesthetic effect of diphenidol could be in part due to its blockade of Na(+) currents.

Topics: Anesthetics, Local; Animals; Cell Line, Tumor; Dose-Response Relationship, Drug; Lidocaine; Male; Membrane Potentials; Mice; Motor Activity; Neurons; Pain; Piperidines; Proprioception; Rats; Rats, Sprague-Dawley; Sodium; Spinal Cord; Time Factors

In this paper, we report a sensitive method for ECL detection for CE based on generation of gold nanostructures at the surface of Pt electrode by electrodeposition. Difenidol hydrochloride was used as a model analyte. With the increase of electrodeposition amount, the morphology of gold nanostructures changed from discrete nanoflowers to dense nanoparticle array. Interestingly, the variation of deposition amount also greatly affected the ECL intensity of difenidol. The ECL intensity increased remarkably with deposition amount and reached the maximum value at the deposition amount of 7.0 x 10(-8)C; further increasing the deposition amount, however, caused the ECL intensity to decrease. Other conditions, including applied potential, injection time and voltage, buffer pH, were also optimized in detail. Under the optimized conditions, the linear response range of difenidol is from 1.0 x 10(-8) to 5.0 x 10(-5) M, and the detection limit was 4.0 x 10(-9) M (S/N=3). The RSDs of ECL intensity and migration time were 2.0 and 1.6%, respectively (n=5, at 7.5 microM difenidol). Compared with using bare electrode, the detection sensitivity was significantly improved by ca. two orders of magnitude. Notably, the nanogold was prepared at the surface of electrode and no nanogold was added to the electrophoretic buffer or detection cell, thus causing no interference to the separation. Finally, the proposed method was successfully applied to the analysis of difenidol in tablets and urine samples. With high sensitivity and good reproducibility, this method provides a promising platform for the determination of pharmaceuticals that have a tertiary amine group such as difenidol.

Topics: Electrochemical Techniques; Electrodes; Electrophoresis, Capillary; Electroplating; Gold; Humans; Hydrogen-Ion Concentration; Luminescent Measurements; Metal Nanoparticles; Piperidines; Platinum

Pharmacokinetics of diphenidol (DPN) is limited due to the lack of analytical methodology. Here, a micro-assay for DPN quantification was developed, by coupling ultra-performance liquid chromatography with tandem mass spectrometry. The procedure involved plasma precipitation and injection of supernatant into UPLC with an Acquitytrade mark C18 column. Detection was in positive electrospray, following transitions of m/z 310.3 --> 292.3 and m/z 275.3 --> 230.2 for DPN and chlorphenamine (internal standard), respectively. The method was linear with a range of 4-400 ng/mL, and a 2 min run time. This method was applied in a switchability trial, where both formulations of DPN were bioequivalent.

Topics: Administration, Oral; Chromatography, Liquid; Humans; Microchemistry; Piperidines; Reproducibility of Results

Enzymatic syntheses of cefaclor by immobilized penicillin acylase under kinetic control were carried out. According to the initial reaction rate ratio of synthesis to hydrolysis (Vs/Vh), penicillin acylase from Alcaligenes faecalis was chosen as the suitable catalyst for the synthesis of cefaclor. The reaction conditions, such as temperature, pH, and substrate concentration were investigated based on their Vs/Vh values. In the process of preparing cefaclor, in situ product removal (ISPR) and acyl donor feeding were used to achieve high yield. At the optimal conditions, the yield of cefaclor was 90%. In addition, the product were separated and purified, the total yield of cefaclor was 61%.

Topics: Alcaligenes; Catalysis; Cephalosporins; Enzymes, Immobilized; Penicillins; Piperidines

Novel 2-carbonyl analogues of diphenidol (1) - bearing lipophylic 1-substituents (2) - were synthesized starting from previously investigated diphenidol derivatives acting as M(2)-selective muscarinic antagonists. These compounds were tested for receptor binding affinity versus human muscarinic M(1)-M(5) receptors stably expressed in CHO-K1 cells. Their activity in functional assays carried out on CHO-K1 cells expressing human M(4) receptors (CHO-hM(4)) and on classical models of M(1)-M(3) receptors, in guinea pig and rabbit tissue preparations, was also evaluated. Compound 2d showed an affinity of pK(i) = 7.73 at the human M(4)-receptor subtype with selectivity ratios ranging from 31-fold (M(4)/M(5)) to 60-fold (M(4)/M(2)). Interestingly this compound, in CHO-hM(4) cells, blocked the inhibition of forskolin-activated cAMP accumulation produced by carbachol (IC(50)= 61 nM) whereas it was a weak muscarinic antagonist in functional tests carried out in guinea-pig and rabbit tissue expressing M(1) (pK(b) = 5.96), M(2) (pK(b) = 6.43) and M(3) (pK(b) = 6.09) receptors. In conclusion, the modifications performed in this work on reference compounds led us to obtain surprisingly a M(4) selective antagonist. Considering the therapeutic indications for M(4) selective antagonists, compound 2d may serve as a novel lead compound for further optimization.

Topics: Animals; CHO Cells; Cricetinae; Cricetulus; Guinea Pigs; Muscarinic Antagonists; Piperidines; Rabbits; Receptor, Muscarinic M4; Structure-Activity Relationship

A series of hydrochloride derivatives 2a-9a and quaternary ammonium derivatives 3b-9b of diphenidol have been synthesized and characterized in receptor binding and cellular functional assays versus human muscarinic M(1)-M(5) receptors expressed in CHO cells. Compound 8b, a methiodide derivative with a bipiperidinyl moiety and a second diphenidol framework, showed a potent and selective M(4) activity as competitive antagonist. Moreover 8b, acting as an allosteric modulator, was able to retard the dissociation rate of [(3)H]-N-methylscopolamine from CHO-M(4) cell membranes exposed to atropine. Taken together, these data suggest that 8b might open new avenues to the discovery of novel multivalent antagonists for the muscarinic receptors.

Topics: Allosteric Regulation; Animals; Binding, Competitive; Cell Membrane; CHO Cells; Cricetinae; Cricetulus; Diamines; Humans; Kinetics; Muscarinic Antagonists; N-Methylscopolamine; Piperidines; Radioligand Assay; Receptor, Muscarinic M4; Staining and Labeling; Structure-Activity Relationship

This paper describes a novel and sensitive method for the estimation of chloroquine phosphate (CQ) using capillary electrophoresis with end-column electrochemiluminescence (ECL) detection. Under the optimized condition, linear calibration curve was obtained for the system over two orders of magnitude with a detection limit of 3x10(-7) M (S/N=3). The relative standard deviations of the ECL intensity and the migration time were 1.4% and 0.05%, respectively (n=6, 5x10(-5) M CQ). Successful separation of chloroquine phosphate, difenidol hydrochloride and clomifene citrate was obtained at pH 7.0. Using the proposed electrochemiluminescence system, a simple method was proposed to study the interaction between chloroquine phosphate and human serum albumin (HSA), and the number of binding sites and binding constant were estimated to be 32.6 and 7.7x10(3) M(-1), respectively.

Topics: Binding Sites; Chloroquine; Clomiphene; Electrochemistry; Electrophoresis, Capillary; Humans; Luminescent Measurements; Organometallic Compounds; Piperidines; Reproducibility of Results; Sensitivity and Specificity; Serum Albumin

A novel and sensitive method for the determination of difenidol hydrochloride has been established using capillary electrophoresis coupled with end-column electrogenerated chemiluminescence (ECL) detection, based on the ECL reaction of tris(2,2'-bypyridine)ruthenium(II) (Ru(bpy)(3)(2+)) with the tertiary amino groups of the difenidol analyte. Parameters that affect separation and detection were optimized. Calibration curve was linear over the range from 1 x 10(-6)M to 6 x 10(-5)M with a detection limit of 1 x 10(-7)M (S/N=3). Separation of difenidol hydrochloride from clomifene citrate and lidocaine was achieved using the proposed method. This method was successfully utilized to the assay of the active ingredients of the "difenidol hydrochloride" tablets and to the investigation on the interaction of difenidol hydrochloride with hemoglobin. The number of binding sites and the binding constant were estimated as (11.2 and 2.5) x 10(3)M(-1), respectively.

Topics: 2,2'-Dipyridyl; Clomiphene; Electrochemistry; Electrophoresis, Capillary; Hemoglobins; Humans; Lidocaine; Luminescent Measurements; Organometallic Compounds; Piperidines; Reproducibility of Results; Ruthenium; Sensitivity and Specificity

Previous studies showed that diphenidol was effective on emetogens-induced pica, eating of non-nutritive substances, in rats, a model analogous to emesis in other species. We evaluated the actual antiemetic activity of diphenidol against four emetic stimuli in the dog and ferret, animals that possess an emetic reflex. In dogs, emetic responses to apomorphine were significantly prevented by diphenidol (3.2 mg/kg, i.v.), whereas diphenidol (3.2 mg/kg, i.v. x 2) showed a weak inhibition to the vomiting evoked by cisplatin. In ferrets, diphenidol (10 mg/kg, i.p.) exhibited a weak antiemetic activity on the emesis induced by copper sulfate and had no activity on emesis by loperamide. On the other hand, CP-122,721, a NK1-receptor antagonist, significantly reduced the emetic episodes to all four stimuli. These results suggest that the prediction of antiemetic activity of compounds in animals lacking an emetic reflex does not always correspond with actual antiemetic activity.

Topics: Animals; Antiemetics; Dogs; Female; Ferrets; Male; Piperidines; Species Specificity; Vomiting

A series of new derivatives, related to diphenidol and to its 2-carbonyl analogue, were designed as antimuscarinic agents. The synthesized compounds were evaluated both as hydrochlorides and as methiodides by functional tests at guinea-pig heart (M(2)), guinea-pig ileum (M(3)) and rabbit vas deferens (putative M(4)). Two derivatives (3a and 5a) showed an M(3)-selective profile similar to that of the reference compounds, though they resulted less potent.

Topics: Animals; Guinea Pigs; Heart; Ileum; In Vitro Techniques; Male; Muscarinic Antagonists; Muscle Contraction; Muscle, Smooth; Piperidines; Receptor, Muscarinic M2; Receptor, Muscarinic M3; Receptor, Muscarinic M4; Structure-Activity Relationship; Vas Deferens

A series of 2-carbonyl analogues of the muscarinic antagonist diphenidol bearing 1-substituents of different lipophilic, electronic, and steric properties was synthesized and their affinity for the M2 and M3 muscarinic receptor subtypes was evaluated by functional tests. Two derivatives (2g and 2d) showed an M2-selective profile which was confirmed by functional tests on the M1 and M4 receptors. A possible relationship between M2 selectivity and lipophilicity of the 1-substituent was suggested by structure-activity analysis. This work showed that appropriate structural modification of diphenidol can lead to M2-selective muscarinic antagonists of possible interest in the field of Alzheimer's disease.

Topics: Animals; Dose-Response Relationship, Drug; Guinea Pigs; In Vitro Techniques; Magnetic Resonance Spectroscopy; Male; Muscarinic Antagonists; Muscle Contraction; Piperidines; Rabbits; Receptors, Muscarinic

Cochlear blood flow (CoBF) and endolymphatic sac (ES) blood flow (ESBF) were measured in different groups of guinea-pigs by laser-Doppler flowmetry after the intravenous administration of various drugs through the jugular vein for 60 sec. These drugs included 50% glycerol, 70% isosorbide, 20% mannitol, 7% sodium bicarbonate and 1% diphenidol. For CoBF measurements, a probe was positioned on the basal turn of the right cochlea via a ventral approach. For ESBF measurements, it was placed on the right ES through the posterior cranial fossa via a dorsal approach. The average initial measured value of ESBF (8.31 +/- 2.97 ml/min/100 g) was significantly greater (p < 0.0001) than that of CoBF (4.33 +/- 1.15 ml/min/100 g). Following administration of most drugs except for diphenidol, both CoBF and ESBF increased immediately after administration; however, following diphenidol administration both CoBF and ESBF decreased. The magnitude of the CoBF response tended to be greater than that of the ESBF response (p = 0.006-0.112). It seems likely that this reflects anatomical differences in the vascular supplies, i.e. CoBF from the vertebrobasilar artery and ESBF from the external carotid artery. In addition, the presence of micropores or fenestrations in the ES vasculature may contribute to the differences between CoBF and ESBF.

Topics: Animals; Blood Flow Velocity; Cochlea; Endolymphatic Sac; Glycerol; Guinea Pigs; Histamine H1 Antagonists; Injections, Intravenous; Isosorbide; Laser-Doppler Flowmetry; Mannitol; Piperidines; Regional Blood Flow; Sodium Bicarbonate

Diphenidol (Cephadol, Vontrol), an antiemetic agent used in the treatment of vomiting and vertigo, has been reported to cause various adverse effects including drowsiness, hypotension, confusion, hallucination, restlessness, and other antimuscarinic effects. Serious toxic effects might be anticipated after intentional or accidental ingestion.. Retrospective analysis of all case records of the PCC-Taiwan defining diphenidol overdose during 1985-1996.. The data of 21 patients with diphenidol overdose were analyzed; 17 were < 3 years old and unintentionally poisoned, in contrast to the suicide attempts by four adults. The average amount of ingestion was 222.5 mg with a range of 25-800 mg. Most patients manifested only transient CNS, cardiovascular, or oculo-facial effects, but four children suffered from severe toxicity after an ingestion of 11.7-80 mg/kg diphenidol. Commonly reported toxicity in diphenidol overdose included facial flush (10), tachycardia, restlessness (6), seizures (4), dyspnea, drowsiness, mydriasis, coma, and fever (3). With supportive therapy, a good recovery was the rule except for one fatality of a 2 1/2-year-old boy who ingested 15 mg/kg diphenidol and presented with recurrent seizures, hypotension, respiratory failure, and coma.. Although not previously reported, accidental diphenidol overdose may result in serious anticholinergic toxicity in children. Treatment is supportive and the therapeutic role of physostigmine in diphenidol poisoning is still unclear.

Topics: Adult; Aged; Antiemetics; Child, Preschool; Dose-Response Relationship, Drug; Drug Overdose; Female; Humans; Infant; Male; Middle Aged; Piperidines; Poison Control Centers; Poisoning; Retrospective Studies; Severity of Illness Index; Treatment Outcome

1. We studied the effect of temperature on the binding to rat heart M2 muscarinic receptors of antagonists related to the carbon/silicon pairs pridinol/sila-pridinol and diphenidol/sila-diphenidol (including three germanium compounds) and six structurally related pairs of enantiomers [(R)- and (S)-procyclidine, (R)- and (S)-trihexyphenidyl, (R)- and (S)-tricyclamol, (R)- and (S)-trihexyphenidyl methiodide, (R)- and (S)-hexahydro-diphenidol and (R)- and (S)-hexbutinol]. Binding affinities were determined in competition experiments using [3H]-N-methyl-scopolamine chloride as radioligand. The reference drugs were scopolamine and N-methyl-scopolamine bromide. 2. The affinity of the antagonists either increased or decreased with temperature. van't Hoff plots were linear in the 278-310 degrees K temperature range. Binding of all antagonists was entropy driven. Enthalpy changes varied from large negative values (down to -29 kJ mol-1) to large positive values (up to +30 kJ mol-1). 3. (R)-configurated drugs had a 10 to 100 fold greater affinity for M2 receptors than the corresponding (S)-enantiomers. Enthalpy and entropy changes of the respective enantiomers were different but no consistent pattern was observed. 4. When silanols (R3SiOH) were compared to carbinols (R3COH), the affinity increase caused by C/Si exchange varied between 3 and 10 fold for achiral drugs but was negligible in the case of chiral drugs. Silanols induced more favourable enthalpy and less favourable entropy changes than the corresponding carbinols when binding. Organogermanium compounds (R4Ge) when compared to their silicon counterparts (R4Si) showed no significant difference in affinity as well as in enthalpy and entropy changes. 5. Exchange of a cyclohexyl by a phenyl moiety was associated with an increase or a decrease in drug affinity (depending on the absolute configuration in the case of chiral drugs) and generally also with a more favourable enthalpy change and a less favourable entropy change of drug binding. 6. Replacement of a pyrrolidino by a piperidino group and increasing the length of the alkylene chain bridging the amino group and the central carbon or silicon atom were associated with either an increase or a decrease of entropy and enthalpy changes of drug binding. However, there was no clear correlation between these structural variations and the thermodynamic effects. 7. Taken together, these results suggest that hydrogen bond-forming OH groups and, to a lesser extent, pola

Topics: Animals; Heart; Histamine H1 Antagonists; In Vitro Techniques; Male; N-Methylscopolamine; Parasympatholytics; Piperidines; Rats; Rats, Inbred WKY; Receptors, Muscarinic; Scopolamine Derivatives; Stereoisomerism; Thermodynamics

A 36-year-old woman with positional headache was found to have primary low cerebrospinal fluid (CSF) pressure syndrome and galactorrhea. The CSF pressure at lumbar puncture was not measurable. Magnetic resonance imaging demonstrated that the ventricle and cerebral sulcus were narrowed and the pituitary stalk was oppressed by the brain. Hyperresponsiveness of prolactin was noted after stimulation with thyrotropin-releasing hormone. These abnormalities disappeared with normalization of CSF pressure with the treatment. Galactorrhea was apparently due to oppression of the pituitary stalk by downward movement of the brain.

Topics: Adult; Cerebrospinal Fluid Pressure; Female; Galactorrhea; Headache; Humans; Hypothalamo-Hypophyseal System; Infusions, Intravenous; Magnetic Resonance Imaging; Piperidines; Posture; Syndrome

The effects of anti-vertigo drugs on medial vestibular nucleus (MVN) neurons were examined to assess the site and mode of action using cats anesthetized with alpha-chloralose. Single neuron activity in the MVN was extracellularly recorded using a silver wire microelectrode attached along a seven-barreled micropipette, each of which was filled with diphenhydramine, diphenidol, betahistine, glutamate or NaCl. Type I of the MVN neurons were identified according to the responses obtained when the animal placed on a turn-table was rotated sinusoidally. The effects of the drugs were examined on type I neurons which received impulses primarily from the labyrinth and sent them to the oculomotor nuclei. The microiontophoretic application of diphenhydramine, diphenidol and betahistine inhibited rotation-induced firing of type I MVN neurons. Diphenhydramine and diphenidol were more potent than betahistine. These results suggest that these drugs directly act on MVN neurons to reduce the responsiveness to rotatory stimulation.

Topics: Animals; Betahistine; Cats; Diphenhydramine; Glutamates; Glutamic Acid; Iontophoresis; Male; Neurons; Piperidines; Rotation; Sodium Chloride; Vertigo; Vestibular Nuclei

(R)-Hexahydro-difenidol has a higher affinity for M1 receptors in NB-OK 1 cells, pancreas M3 and striatum M4 receptors (pKi 7.9 to 8.3) than for cardiac M2 receptors (pKi 7.0). (S)-Hexahydro-difenidol, by contrast, is nonselective (pKi 5.8 to 6.1). Our goal in the present study was to evaluate the importance of the hydrophobic phenyl, and cyclohexyl rings of hexahydro-difenidol for the stereoselectivity and receptor selectivity of hexahydro-difenidol binding to the four muscarinic receptors. Our results indicated that replacement of the phenyl ring of hexahydro-difenidol by a cyclohexyl group (----dicyclidol) and of the cyclohexyl ring by a phenyl moiety (----difenidol) induced a large (4- to 80-fold) decrease in binding affinity for all muscarinic receptors. Difenidol had a significant preference for M1, M3, and M4 over M2 receptors; dicyclidol, by contrast, had a greater affinity for M1 and M4 than for M2 and M3 receptors. The binding free energy decrease due to replacement of the phenyl and the cyclohexyl groups of (R)-hexahydro-difenidol by, respectively, a cyclohexyl and a phenyl moiety was almost additive in the case of M4 (striatum) binding sites. In the case of the cardiac M2, pancreatic M3, or NB-OK 1 M1 receptors the respective binding free energies were not completely additive. These results suggest that the four (R)-hexahydro-difenidol "binding moieties" (phenyl, cyclohexyl, hydroxy, and protonated amino group) cannot simultaneously form optimal interactions with the M1, M2, and M3 muscarinic receptors.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Binding, Competitive; Corpus Striatum; Humans; Male; Myocardium; Neuroblastoma; Pancreas; Piperidines; Rats; Rats, Inbred Strains; Receptors, Muscarinic; Stereoisomerism

To clarify the antivertiginous effect of afloqualone, an antispastic drug, we examined its action on the vestibular nervous system in cats. The results suggest that afloqualone inhibits vestibular nystagmus probably due to both inhibition of selective polysynaptic transmission and enhancement of the effects of GABA and glycine in the lateral vestibular nucleus (LVN), and its GABA-enhancing effect is thought to be attributable to the increased sensitivity of GABA receptors of the LVN neuron site.

Topics: Acetylcholine; Animals; Cats; Dose-Response Relationship, Drug; Female; gamma-Aminobutyric Acid; Histamine H1 Antagonists; Iontophoresis; Male; Muscle Relaxants, Central; Nystagmus, Physiologic; Piperidines; Propiophenones; Quinazolines; Reflex, Monosynaptic; Synaptic Transmission; Vestibular Nuclei

The present study was designed to further characterize the presynaptic muscarinic M1-receptor responsible for the inhibition of neurogenic contractions in the isolated rabbit vas deferens. Electrically induced twitch contractions of this preparation were inhibited by the M1-agonist, McN-A-343, and by some of its analogs: 4-chloro-phenyl derivative greater than McN-A-343 greater than trans-olefinic analog greater than cis-olefinic analog. The same rank order of potency was observed for these agonists to raise the blood pressure of pithed rats by stimulation of M1-receptors in sympathetic ganglia. A highly significant correlation was found between the antimuscarinic potencies of atropine, pirenzepine and a series of 9 antagonists structurally related to the ganglionic M1 beta-receptor selective compounds, hexocyclium and hexahydro-difenidol, to antagonize the McN-A-343-induced inhibition of twitch contractions in rabbit vas deferens or the muscarine-induced depolarization in rat isolated superior cervical ganglia. It is suggested that the presynaptic muscarinic receptor that mediates inhibition of neurogenic contractions in rabbit vas deferens is of the ganglionic M1 beta-type.

Topics: (4-(m-Chlorophenylcarbamoyloxy)-2-butynyl)trimethylammonium Chloride; Animals; Atropine; Binding Sites; Blood Pressure; Electric Stimulation; Ganglia, Sympathetic; Male; Muscle Contraction; Piperazines; Piperidines; Pirenzepine; Rabbits; Rats; Rats, Inbred Strains; Receptors, Muscarinic; Receptors, Neurotransmitter; Vas Deferens

Topics: Adolescent; Adult; Audiometry; Caloric Tests; Diet, Sodium-Restricted; Diuretics; Female; Humans; Male; Meniere Disease; Middle Aged; Piperidines; Vasodilator Agents

The capacity of diphenidol to influence ouabain-induced cardiotoxicity was studied in anaesthetized cats with and without spinal cord transection. 2 Diphenidol pretreatment increased the lethal dose of ouabain in both intact cats and cats in which the spinal cords had been transected. Diphenidol pretreatment increased the myocardial content of ouabain associated with death in the intact animals, but failed to influence the lethal ventricular concentration in cats with transected spinal cords. 3 The failure of diphenidol to influence tissue thresholds for toxicity in the spinal cat and the equivalence of tissue ouabain requirements for death in spinal cats and diphenidol-treated intact animals, suggest a neural mechanism for the protective effect in intact animals. 4 Ouabain administration prolonged atrio-ventricular conduction time in all animals and diphenidol attenuated this effect. Thus, the influence of both drugs on antrioventricular conduction may not be entirely mediated by central neurones.

Topics: Animals; Blood Pressure; Cats; Cordotomy; Female; Heart; Heart Conduction System; Heart Rate; Male; Ouabain; Piperidines