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1.
Rev Med Inst Mex Seguro Soc ; 53(3): 260-2, 2015.
Artigo em Espanhol | MEDLINE | ID: mdl-25984627

RESUMO

On January 15, 2015, Carl Djerassi, an extraordinary personality, died at the age of 91 years. He was born in Vienna, Austria, on October 29, 1923. His parents were physicians and probably he wanted to be also a physician, but sooner than later he chose to be a chemist. In 1939 he arrived to live to New York with his mother. In 1945 he became American citizen. Part of his work is the first commercial antihistamine, pyribenzamine, and the first successful combined oral contraceptive pill. With this editorial we make a tribute to this steroid pioneer.


Assuntos
Descoberta de Drogas/história , Áustria , Anticoncepcionais Orais Hormonais/história , Antagonistas dos Receptores Histamínicos H1/história , História do Século XX , Tripelenamina/história , Estados Unidos
2.
Acta Pol Pharm ; 71(5): 709-19, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-25362799

RESUMO

The study was aimed at developing a HPLC method to identify and quantify domiphen bromide, tripelennamine hydrochloride and clioquinol in Viosept ointment. The tested substances were successfully separated using Inertsil ODS-3 (250 x 4.6 mm, 5 µm) as a stationary phase and a gradient elution. Detection at 310 nm wavelength was applied for tripelennamine hydrochloride and clioquinol, and at 215 nm wavelength for domiphen bromide. Methods of extraction of the tested substances were developed: domiphen bromide and clioquinol were extracted with acetone from heated solutions, and tripelennamine hydrochloride was extracted in a hexane-water system. Validation procedure confirmed the method to be sufficiently selective, precise and accurate. Correlation coefficients of calibration curves pointed out that they were linear within the examined concentration range.


Assuntos
Cromatografia Líquida de Alta Pressão/normas , Clioquinol/análise , Fármacos Dermatológicos/análise , Compostos de Amônio Quaternário/análise , Tripelenamina/análise , Calibragem , Combinação de Medicamentos , Modelos Lineares , Pomadas , Padrões de Referência , Reprodutibilidade dos Testes , Espectrofotometria Ultravioleta
3.
PLoS One ; 7(8): e42853, 2012.
Artigo em Inglês | MEDLINE | ID: mdl-22905177

RESUMO

Meiosis is a highly regulated developmental process that occurs in all eukaryotes that engage in sexual reproduction. Previous epidemiological work shows that male and female infertility is rising and environmental factors, including pollutants such as organic solvents, are thought to play a role in this phenomenon. To better understand how organic compounds interfere with meiotic development, the model organism Saccharomyces cerevisiae was exposed to 446 bioactive molecules while undergoing meiotic development, and sporulation efficiency was quantified employing two different high-throughput assays. 12 chemicals were identified that strongly inhibited spore formation but did not interfere with vegetative growth. Many of these chemicals are known to bind to monoamine-receptors in higher eukaryotes and are cationic amphiphilic drugs. A detailed analysis of one of these drugs, tripelennamine, revealed that it induces sporulation-specific cytotoxicity and a strong inhibition of meiotic M phase. The drug, however, only mildly interfered with pre-meiotic DNA synthesis and the early meiotic transcriptional program. Chemical-genomic screening identified genes involved in autophagy as hypersensitive to tripelennamine. In addition, we found that growing and sporulating yeast cells heterozygous for the aminophospholipid translocase, NEO1, are haploinsufficient in the presence of the drug.


Assuntos
Cátions/química , Saccharomyces cerevisiae/metabolismo , Esporos Fúngicos/fisiologia , Tensoativos/farmacologia , Antifúngicos/farmacologia , Autofagia , DNA/biossíntese , Desenho de Fármacos , Deleção de Genes , Regulação Fúngica da Expressão Gênica , Genômica , Proteínas de Fluorescência Verde/metabolismo , Humanos , Meiose , Metabolômica/métodos , Modelos Genéticos , Mutação , Análise de Sequência com Séries de Oligonucleotídeos , Esporos Fúngicos/metabolismo , Fatores de Tempo , Transcrição Genética , Tripelenamina/farmacologia
4.
J Phys Chem B ; 116(12): 3808-15, 2012 Mar 29.
Artigo em Inglês | MEDLINE | ID: mdl-22372713

RESUMO

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.


Assuntos
Antagonistas dos Receptores Histamínicos H1/química , Receptores Histamínicos H1/química , Albumina Sérica/química , Espectrofotometria Ultravioleta , Análise Espectral Raman , Sítios de Ligação , Bromofeniramina/química , Antagonistas dos Receptores Histamínicos H1/metabolismo , Humanos , Ligação de Hidrogênio , Concentração de Íons de Hidrogênio , Pirilamina/química , Receptores Histamínicos H1/metabolismo , Albumina Sérica/metabolismo , Tripelenamina/química , Triptofano/química
5.
Ann Neurol ; 65(2): 184-93, 2009 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-19259966

RESUMO

OBJECTIVE: To develop and validate a model of cutaneous allodynia triggered by dural inflammation for pain associated with headaches. To explore neural mechanisms underlying cephalic and extracephalic allodynia. METHODS: Inflammatory mediators (IM) were applied to the dura of unanesthetized rats via previously implanted cannulas, and sensory thresholds of the face and hind-paws were characterized. RESULTS: IM elicited robust facial and hind-paw allodynia, which peaked within 3 hours. These effects were reminiscent of cutaneous allodynia seen in patients with migraine or other primary headache conditions, and were reversed by agents used clinically in the treatment of migraine, including sumatriptan, naproxen, and a calcitonin gene-related peptide antagonist. Consistent with clinical observations, the allodynia was unaffected by a neurokinin-1 antagonist. Having established facial and hind-paw allodynia as a useful animal surrogate of headache-associated allodynia, we next showed that blocking pain-facilitating processes in the rostral ventromedial medulla (RVM) interfered with its expression. Bupivacaine, destruction of putative pain-facilitating neurons, or block of cholecystokinin receptors prevented or significantly attenuated IM-induced allodynia. Electrophysiological studies confirmed activation of pain-facilitating RVM "on" cells and transient suppression of RVM "off" cells after IM. INTERPRETATION: Facial and hind-paw allodynia associated with dural stimulation is a useful surrogate of pain associated with primary headache including migraine and may be exploited mechanistically for development of novel therapeutic strategies for headache pain. The data also demonstrate the requirement for activation of descending facilitation from the RVM for the expression of cranial and extracranial cutaneous allodynia, and are consistent with a brainstem generator of allodynia associated with headache disorders.


Assuntos
Transtornos da Cefaleia/complicações , Hiperalgesia/etiologia , Bulbo/fisiopatologia , Neurônios/fisiologia , Limiar da Dor/fisiologia , Potenciais de Ação/fisiologia , Animais , Anti-Inflamatórios/uso terapêutico , Bradicinina/administração & dosagem , Dinoprostona/administração & dosagem , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Dura-Máter/patologia , Dura-Máter/fisiologia , Transtornos da Cefaleia/tratamento farmacológico , Transtornos da Cefaleia/patologia , Hiperalgesia/tratamento farmacológico , Inflamação/induzido quimicamente , Inflamação/tratamento farmacológico , Inflamação/patologia , Masculino , Bulbo/patologia , Neurônios/efeitos dos fármacos , Neurotransmissores/farmacologia , Proteínas Oncogênicas v-fos/metabolismo , Medição da Dor/métodos , Limiar da Dor/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Serotonina/administração & dosagem , Tripelenamina/administração & dosagem
7.
Int Immunopharmacol ; 5(7-8): 1299-309, 2005 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-15914334

RESUMO

Signal transducer and activator of transcription-1 (STAT1) is a latent signal transducer protein which, on phosphorylation, is translocated from the cytoplasm to the nucleus and is subsequently activated. This study was designed to determine the involvement of histamine receptors in histamine-mediated effect on STAT1 phosphorylation. It is known that the actions of histamine mediated through H1 and H2 receptors are dependent on their respective downstream pathways, Ca(2+)-PKC and cAMP-PKA. In this study, we investigated the significance of PKA in STAT1 phosphorylation. C57BL/6 mouse splenocytes were isolated and treated with histamine (10(-7)-10(-4) M) and then activated with PMA (phorbol 12 myristate 13-acetate) plus ionomycin. The phosphorylated STAT1 levels were analyzed by immunoblotting. Histamine receptor agonists amthamine and betahistine, histamine receptor antagonists pyrilamine maleate, tripelennamine, ranitidine, cimetidine and thioperamide, cAMP agonists N(6), 2'-0-dibutyryladenosine-3',5'-cyclic monophosphate sodium salt (db-cAMP) and forskolin, protein kinase A inhibitors N-(2-[p-bromocinnamylamino]ethyl)-5-isoquinoline-sulfonamide (H89) and Rp diastereomer of adenosine cyclic 3',5'-phosphorothioate (RpcAMPs) and tyrosine kinase inhibitor tyrphostin were used to identify the upstream signal transduction pathways. We observed that histamine augmented the phosphorylation of STAT1 through both H1 and H2 receptors. Furthermore, H1 and H2 receptor antagonists displayed inverse agonism. Ca(2+)-PKC-induced phosphorylation of STAT1 was completely inhibited by H89 and significantly inhibited by RpcAMPs. DbcAMP and forskolin augmented the Ca(2+)-PKC-induced STAT1 phosphorylation thus suggesting a convergent crosstalk between the two histamine receptor signaling pathways, PKA and PKC.


Assuntos
Proteínas de Ligação a DNA/metabolismo , Receptores Histamínicos H1/fisiologia , Receptores Histamínicos H2/fisiologia , Transativadores/metabolismo , Animais , Cálcio/metabolismo , AMP Cíclico/fisiologia , Proteínas Quinases Dependentes de AMP Cíclico/antagonistas & inibidores , Proteínas Quinases Dependentes de AMP Cíclico/fisiologia , Feminino , Histamina/farmacologia , Camundongos , Camundongos Endogâmicos C57BL , Fosforilação , Proteína Quinase C/fisiologia , Pirilamina/farmacologia , Fator de Transcrição STAT1 , Tripelenamina/farmacologia
8.
J Neurosci Res ; 77(5): 730-8, 2004 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-15352220

RESUMO

Ionotropic N-methyl-D-aspartate (NMDA) receptor agonists, L-aspartic acid (L-Asp) and NMDA, have been shown to inhibit histamine-stimulated acid secretion, but their effect on gastric mucosal blood flow (GMBF) is largely unknown. The aim of this study was to investigate whether L-Asp and NMDA inhibit histamine-stimulated GMBF and to examine the expression patterns of NMDA receptor subunits NR1, NR2A, and NR2B in rat stomach. Laser Doppler flowmetry was used to measure gastric blood flow in anesthetized rats. The GMBF was assessed during an intravenous infusion of histamine in the presence of tripelennamine. The effects of L-Asp and NMDA on histamine-induced gastric blood flow were examined. In addition, the distribution patterns of NR1-, NR2A-, and NR2B-contaning NMDA receptors in rat stomach were determined immunohistochemically by using specific antibodies against NR1, NR2A, and NR2B. Histamine-induced enhancement of GMBF depended on acid secretion and the activation of H(2)-receptors. Neither L-Asp nor NMDA had an effect on the spontaneous GMBF. However, L-Asp and NMDA reduced the histamine-induced increase in GMBF. DL-2-amino-5-phosphonopentanoic acid (AP-5), an NMDA receptor antagonist; and prazosin, an alpha(1)-receptor antagonist; but not propanolol, a beta(2)-receptor antagonist; or yohimbine, a alpha(2)-receptor antagonist; reversed the inhibitory effect of L-Asp and NMDA on the histamine-induced increase in GMBF. Therefore, L-Asp and NMDA inhibit histamine-induced GMBF via a mechanism involving the activation of NMDA receptors and alpha(1)- adrenoceptors. The fact that NMDA receptor subunits NR1, NR2A, and NR2B were found to be localized in the rat stomach as visualized immunohistochemically with specific antibodies against NR1, NR2A, and NR2B is consistent with this hypothesis.


Assuntos
Mucosa Gástrica/efeitos dos fármacos , Histamina/farmacologia , Receptores de N-Metil-D-Aspartato/fisiologia , Valina/análogos & derivados , Ácidos/metabolismo , Antagonistas Adrenérgicos alfa/farmacologia , Antagonistas Adrenérgicos beta/farmacologia , Animais , Ácido Aspártico/farmacologia , Cimetidina/farmacologia , Interações Medicamentosas , Mucosa Gástrica/irrigação sanguínea , Mucosa Gástrica/metabolismo , Antagonistas dos Receptores Histamínicos H1/farmacologia , Antagonistas dos Receptores H2 da Histamina/farmacologia , Imuno-Histoquímica/métodos , Fluxometria por Laser-Doppler , Masculino , N-Metilaspartato/farmacologia , Prazosina/farmacologia , Propranolol/farmacologia , Ratos , Ratos Sprague-Dawley , Receptores de N-Metil-D-Aspartato/agonistas , Receptores de N-Metil-D-Aspartato/antagonistas & inibidores , Fluxo Sanguíneo Regional/efeitos dos fármacos , Fatores de Tempo , Tripelenamina/farmacologia , Valina/farmacologia , Ioimbina/farmacologia
9.
Pharmazie ; 59(12): 948-51, 2004 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-15638084

RESUMO

The influence of mast cell activation on the secretion of prolactin has been studied in rats receiving lysophosphatidylserine, a natural occurring phospholipid with secretagogue activity in these cells. After the i.v. injection of lysophosphatidylserine (10 mg/kg) a plasma prolactin peak correlates with an increased blood histamine level. Following the secretory event, which is inhibited by the H1 anti-histamine tripelenamine, plasma prolactin level drops below the basal line. Repeated lysophosphatidylserine administrations induce mast cell desensitisation, thus reducing also the pituitary response. Under these conditions a decrease in prolactin basal level is still observed, although the pituitary stores of this hormone are preserved. Control tests in vitro with lysophosphatidylserine, show that the diacyl lysophosphatidylserine derivative amplifies the inhibitory effect of dopamine on prolactin secretion from isolated pituitaries. The data suggests that lysophosphatidylserine induces prolactin secretion through mast cell activation. After this event, the reacylation of this phospholipid into lysophosphatidylserine in the pituitary membrane may enhance the inhibitory control by dopamine.


Assuntos
Mastócitos/fisiologia , Fosfatidilserinas/farmacologia , Hipófise/fisiologia , Animais , Ácido Araquidônico/metabolismo , Dopamina/farmacologia , Histamina/sangue , Injeções Intravenosas , Masculino , Mastócitos/efeitos dos fármacos , Mastócitos/metabolismo , Fosfatidilserinas/administração & dosagem , Fosfatidilserinas/antagonistas & inibidores , Hipófise/efeitos dos fármacos , Hipófise/metabolismo , Prolactina/sangue , Ratos , Ratos Sprague-Dawley , Tripelenamina/farmacologia , p-Metoxi-N-metilfenetilamina/farmacologia
10.
Vis Neurosci ; 19(3): 307-19, 2002.
Artigo em Inglês | MEDLINE | ID: mdl-12392180

RESUMO

Using autoradiographic and biochemical techniques, we studied the sodium-dependent forward and reverse transport of the neurotransmitter histamine in an arthropod photoreceptor in order to test whether the transporter plays a central role in visual signal transfer at this synapse. In particular, we asked whether the histamine transporter might be the important factor in synaptic adaptation, the process by which the operating range of the synapse adapts to increasing depolarizations of the photoreceptor in increasing background light. Drugs known from electrophysiological observations to interfere with synaptic adaptation blocked the uptake of [3H]histamine into photoreceptors. These drugs also blocked the sodium (Na)-triggered efflux of [3H]histamine, previously loaded into photoreceptors, via the histamine transporter. Several lines of evidence showed that efflux of [3H]histamine did not occur via calcium-dependent exocytosis. First, efflux occurred when the preparation was bathed in calcium (Ca)-free/EGTA salines or in cobalt (Co)-containing salines. Even more importantly, efflux could be elicited from axons, whose membranes must contain the transporter protein since they take up [3H]histamine independently from the presynaptic terminals. Since both adaptation and the histamine transporter are blocked by the same agents, the transporter may underlie adaptation by maintaining the cleft histamine concentration in a particular range independent of light intensity. We also characterized the transporter further and found that it is partially dependent on chloride ions, and that neither [3H]norepinephrine nor [3H]dopamine are transported (at 20 microM), adding to evidence that the transporter is highly selective for histamine.


Assuntos
Proteínas de Transporte/fisiologia , Histamina/metabolismo , Células Fotorreceptoras de Invertebrados/fisiologia , Sinapses/fisiologia , Adaptação Fisiológica/fisiologia , Aminas/metabolismo , Animais , Transporte Biológico/efeitos dos fármacos , Cálcio/fisiologia , Cloretos/fisiologia , Antagonistas dos Receptores Histamínicos H1/farmacologia , Pirilamina/farmacologia , Sódio/farmacologia , Estricnina/farmacologia , Thoracica , Tripelenamina/farmacologia
11.
Pa Dent J (Harrisb) ; 69(3): 22-9, 2002.
Artigo em Inglês | MEDLINE | ID: mdl-12174527

RESUMO

This article discusses various alternative methods of treating the patient who encounters problems with local anesthetics. Those alternative methods include: acupuncture, hypnosis, sedation, general anesthesia, and antihistamines as a substitute for local anesthetics with more of a focus in using antihistamines as an effective local anesthetic agent. Although not frequently encountered in the clinical setting, allergic reactions to local anesthetics do occur. Various surveys indicate the number of deaths attributed to local anesthesia range from 1:1,500,000 to 1:4,000,000, with oral surgery offices having higher mortality rates than general dentistry offices. This occurs despite clinicians' attention to patient medical histories, aspiration of the local anesthetic syringe during injections, and minimizing the dosage of local anesthetic solutions. Generally speaking, local anesthetics can be divided into two groups: ester of benzoic and aminobenzoic derivatives (cocaine, benzocaine, procaine, tetracaine, butacaine, etc.) or amide-derivatives of xylidine and toluidine groups (lidocaine, mepivacaine, prilocaine a.k.a. Citanest, etc.). Adverse effects include allergic or toxic reactions, as well as negative effects of any vasoconstrictors contained within the local anesthetic solution. This article will concentrate on how to successfully manage patients who have previously encountered allergic reactions.


Assuntos
Anestesia Dentária/métodos , Anestésicos Locais/efeitos adversos , Difenidramina/administração & dosagem , Hipersensibilidade a Drogas/etiologia , Antagonistas dos Receptores Histamínicos H1/administração & dosagem , Analgesia por Acupuntura/métodos , Analgésicos/administração & dosagem , Anestesia Geral , Humanos , Hipnóticos e Sedativos/administração & dosagem , Injeções , Tripelenamina/administração & dosagem
12.
J Appl Physiol (1985) ; 92(4): 1515-23, 2002 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-11896018

RESUMO

It has been suggested that pulmonary injury and inflammation-induced histamine release from airway mast cells may contribute to exercise-induced arterial hypoxemia (EIAH). Because stress failure of pulmonary capillaries and EIAH are routinely observed in exercising horses, we examined whether preexercise administration of an H1-receptor antagonist may mitigate EIAH. Two sets of experiments, placebo (saline) and antihistaminic (tripelennamine HCl at 1.10 mg/kg iv, 15 min preexercise) studies, were carried out on seven healthy, exercise-trained Thoroughbred horses in random order 7 days apart. Arterial and mixed venous blood-gas and pH measurements were made at rest before and after saline or drug administration and during incremental exercise leading to maximal exertion at 14 m/s on 3.5% uphill grade for 120 s. Galloping at this workload elicited maximal heart rate and induced exercise-induced pulmonary hemorrhage in all horses in both treatments, thereby indicating that capillary stress failure-related pulmonary injury had occurred. In both treatments, EIAH, desaturation of hemoglobin, hypercapnia, and acidosis of a similar magnitude developed during maximal exertion, and statistically significant differences between the placebo and antihistaminic studies could not be demonstrated. The failure of the H1-receptor antagonist to modify EIAH significantly suggests that pulmonary injury-induced histamine release may not play a major role in bringing about EIAH in Thoroughbred horses.


Assuntos
Antagonistas dos Receptores Histamínicos H1/farmacologia , Hipóxia/tratamento farmacológico , Esforço Físico/fisiologia , Tripelenamina/farmacologia , Animais , Artérias , Temperatura Corporal , Dióxido de Carbono/sangue , Endoscopia , Feminino , Cavalos , Hipóxia/diagnóstico , Hipóxia/prevenção & controle , Injeções Intravenosas , Masculino , Mastócitos/efeitos dos fármacos , Mastócitos/fisiologia , Oxigênio/sangue , Oxiemoglobinas/metabolismo , Pressão Parcial , Veias
13.
J Vet Pharmacol Ther ; 23(3): 145-52, 2000 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-11110101

RESUMO

The pharmacokinetics of tripelennamine (T) was compared in horses (n = 6) and camels (n = 5) following intravenous (i.v.) administration of a dose of 0.5 mg/kg body weight. Furthermore, the metabolism and urinary detection time was studied in camels. The data obtained (median and range in brackets) in camels and horses, respectively, were as follows: the terminal elimination half-lives were 2.39 (1.91-6.54) and 2.08 (1.31-5.65) h, total body clearances were 0.97 (0.82-1.42) and 0.84 (0.64-1.17)L/h/kg. The volumes of distribution at steady state were 2.87 (1.59-6.67) and 1.69 (1.18-3.50) L/kg, the volumes of the central compartment of the two compartment pharmacokinetic model were 1.75 (0.68-2.27) and 1.06 (0.91-2.20) L/kg. There was no significant difference (Mann-Whitney) in any parameter between camels and horses. The extent of protein binding (mean +/- SEM) 73.6 + 8.5 and 83.4 +/- 3.6% for horses and camels, respectively, was not significantly statistically different (t-test). Three metabolites of T were identified in urine samples of camels. The first one resulted from N-depyridination of T, with a molecular ion of m/z 178, and was exclusively eliminated in conjugate form. This metabolite was not detected after 6 h of T administration. The second metabolite, resulted from pyridine ring hydroxylation, had a molecular ion of m/z 271, and was also exclusively eliminated in conjugate form. This metabolite could be detected in urine sample for up to 12 h after T administration. The third metabolite has a suspected molecular ion of m/z 285, was eliminated exclusively in conjugate form and could be detected for up to 24 h following T administration. T itself could be detected for up to 27 h after i.v. administration, with about 90% of eliminated T being in the conjugated form.


Assuntos
Antagonistas dos Receptores Histamínicos H1/metabolismo , Antagonistas dos Receptores Histamínicos H1/farmacocinética , Tripelenamina/metabolismo , Tripelenamina/farmacocinética , Animais , Área Sob a Curva , Camelus , Feminino , Cromatografia Gasosa-Espectrometria de Massas , Meia-Vida , Antagonistas dos Receptores Histamínicos H1/sangue , Antagonistas dos Receptores Histamínicos H1/urina , Cavalos , Injeções Intravenosas , Masculino , Taxa de Depuração Metabólica , Especificidade da Espécie , Distribuição Tecidual , Tripelenamina/sangue , Tripelenamina/urina
14.
Ann Allergy Asthma Immunol ; 84(5): 475-80, 2000 May.
Artigo em Inglês | MEDLINE | ID: mdl-10830999
16.
Mol Pharmacol ; 57(1): 135-43, 2000 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-10617688

RESUMO

Diphenhydramine is an H1 histamine receptor antagonist, yet it also has a clinically useful local anesthetic effect. We found that diphenhydramine inhibits the neuronal Na(+) current, and the inhibition is stronger with more positive holding potentials. The dissociation constant between diphenhydramine and the inactivated Na(+) channel is approximately 10 microM, whereas the dissociation constant between diphenhydramine and the resting channel is more than 300 microM. The local anesthetic effect of diphenhydramine thus is ascribable to inhibition of Na(+) current by selective binding of the drug to the inactivated channels. Most interestingly, many other compounds, such as the anti-inflammatory drug diclofenac, the anticonvulsant drug phenytoin, the antidepressant drug imipramine, and the anticholinergic drug benztropine, have similar effects on neuronal Na(+) current. There is no apparent common motif in the chemical structure of these compounds, except that they all contain two phenyl groups. Molecular modeling further shows that the two benzene rings in all these drugs have very similar spatial orientations (stem bond angle, approximately 110 degrees; center-center distance, approximately 5 A). In contrast, the two phenyl groups in phenylbutazone, a drug that has only a slight effect on Na(+) current, are oriented in quite a different way. These findings strongly suggest that the two phenyl groups are the key ligands interacting with the channel. Because the binding counterpart of a benzene ring usually is also a benzene ring, some aromatic side chain groups of the Na(+) channel presumably are realigned during the gating process to make the very different affinity to the aforementioned drugs between the inactivated and the resting channels.


Assuntos
Anestésicos Locais/farmacologia , Difenidramina/farmacologia , Antagonistas dos Receptores Histamínicos H1/farmacologia , Bloqueadores dos Canais de Sódio , Animais , Anti-Inflamatórios não Esteroides/farmacologia , Sítios de Ligação , Diclofenaco/farmacologia , Difenidramina/análogos & derivados , Técnicas In Vitro , Lidocaína/farmacologia , Potenciais da Membrana/efeitos dos fármacos , Modelos Moleculares , Ratos , Ratos Long-Evans , Canais de Sódio/química , Canais de Sódio/fisiologia , Relação Estrutura-Atividade , Tripelenamina/farmacologia
18.
Pharmacol Res ; 39(4): 261-7, 1999 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-10208755

RESUMO

In unanaethetised rats with a single injection of compound 48/80, a mast cell degranulator (0.75 mg kg-1, i.p.), gastric lesions occurred with increased serum serotonin and histamine levels and reduced gastric mucosal blood flow at 0.5 h after the injection and developed at 3 h. Pretreatment with either cyproheptadine (a serotonin and histamine antagonist) or methysergide (a serotonin antagonist) prevented the formation of gastric mucosal lesions with attenuation of reduced gastric mucosal blood flow at 0.5 h after compound 48/80 injection, while pretreatment with either amitriptyline (a selective inhibitor of histamine release from mast cells), tripelennamine (a histamine H1-receptor antagonist), famotidine (a histamine H2-receptor antagonist) or cimetidine (a histamine H2-receptor antagonist) had no effect. Pretreatment with either cyproheptadine, methysergide, amitriptyline or tripelennamine prevented the development of gastric mucosal lesions at 3 h after compound 48/80 injection, while pretreatment with either famotidine or cimetidine had no effect. These results indicate that in unanaesthetised rats with a single compound 48/80 treatment, acutely released endogenous serotonin causes gastric mucosal lesions, while released endogenous histamine mainly contributes to the lesion development and that gastric acid plays little role in the pathogenesis of the compound 48/80-induced acute gastric lesions.


Assuntos
Degranulação Celular/efeitos dos fármacos , Mucosa Gástrica/efeitos dos fármacos , Histamina/fisiologia , Mastócitos/efeitos dos fármacos , Serotonina/fisiologia , Úlcera Gástrica/sangue , Úlcera Gástrica/induzido quimicamente , p-Metoxi-N-metilfenetilamina/toxicidade , Inibidores da Captação Adrenérgica/uso terapêutico , Amitriptilina/uso terapêutico , Animais , Cimetidina/uso terapêutico , Ciproeptadina/uso terapêutico , Famotidina/uso terapêutico , Mucosa Gástrica/irrigação sanguínea , Histamina/sangue , Antagonistas dos Receptores Histamínicos H1/uso terapêutico , Antagonistas dos Receptores H2 da Histamina/uso terapêutico , Masculino , Metisergida/uso terapêutico , Ratos , Ratos Wistar , Serotonina/sangue , Antagonistas da Serotonina/uso terapêutico , Úlcera Gástrica/prevenção & controle , Tripelenamina/uso terapêutico
19.
Exp Clin Psychopharmacol ; 6(4): 427-32, 1998 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-9861557

RESUMO

Participants discriminated between tripelennamine and placebo in experiments differing in instructional set. In 1 experiment (SED), participants were told that 1 of the 2 drugs was more sedative-like, and during the other (STIM), 1 was more stimulant-like. During generalization tests, participants received diazepam or d-amphetamine. Percent correct was the same in both experiments. Tripelennamine increased sedative and decreased stimulant effects. Amphetamine and diazepam produced typical subjective effects. Some subjective effects differed across experiments with more sedative and less stimulant effects during SED than STIM. In SED and STIM, capsules were labeled 80% of the time as a sedative and stimulant, respectively. Thus, instructions designed to give expectations had no effect on discrimination and only a few changes in subjective effects. When asked to name the drug that they believed they received, labels reflected instructional set.


Assuntos
Estimulantes do Sistema Nervoso Central/administração & dosagem , Sinais (Psicologia) , Aprendizagem por Discriminação , Discriminação Psicológica , Hipnóticos e Sedativos/administração & dosagem , Adulto , Dextroanfetamina/administração & dosagem , Diazepam/administração & dosagem , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Placebos , Tripelenamina/administração & dosagem
20.
Respir Physiol ; 112(1): 13-22, 1998 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-9696279

RESUMO

The response to histamine of nasal afferents has been studied in guinea pigs by recording the electrical activity of the whole ethmoidal nerve (EN) or that of single units. Guinea pigs were anaesthetized with urethane and breathed through a tracheostomy. Prior to intranasal instillation of histamine (1 x 10(-4)-10(-1) M), the nasal mucosa was treated with 20 microl of saline (0.9% NaCl) or HCl (pH = 2), and in some cases, H2SO4 (pH = 2). In other experiments, following HCl instillation animals were pretreated by tripelennamine (1 x 10(-2) M) and/or cimetidine (1 x 10(-2) M) in order to determine the histamine receptor type of sensory nerve endings. Whole EN activity was not stimulated even by the highest dose (1 x 10(-1) M) of histamine when the nose was pretreated with saline, but was substantially stimulated by histamine in a dose-response fashion (1 x 10(-2) M) after pretreatment with HCI or H2SO4. Pretreatment with tripelennamine and HCl prevented the effect of histamine on the afferent EN activity; but after cimetidine and HCl pretreatment histamine still had a marked stimulant effect. In the case of single unit activities, histamine with HCl pretreatment had a long-lasting stimulatory effect (110.2 +/- 26.6 sec). It is concluded that the EN in guinea pigs include histamine-sensitive fibers whose sensitivity is mediated by H1 receptors and can respond to histamine only under abnormal conditions of the nasal mucosa.


Assuntos
Seio Etmoidal/inervação , Histamina/farmacologia , Nervo Trigêmeo/fisiologia , Potenciais de Ação , Animais , Cimetidina/farmacologia , Feminino , Cobaias , Antagonistas dos Receptores Histamínicos H1/farmacologia , Antagonistas dos Receptores H2 da Histamina/farmacologia , Masculino , Neurônios Aferentes/efeitos dos fármacos , Neurônios Aferentes/fisiologia , Receptores Histamínicos/metabolismo , Nervo Trigêmeo/efeitos dos fármacos , Tripelenamina/farmacologia
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