RESUMO
Irritable bowel syndrome (IBS) is a common gastrointestinal (GI) disorder characterized by abdominal pain or discomfort. Mebeverine is an antispasmodic that has been widely used in clinical practice to relieve the symptoms of IBS. However, its systemic use usually leads to side effects. Therefore, the current paper aimed to synthesize more effective medicines for IBS treatment. We used ring opening of isatoic anhydride for the synthesis in reaction with 2-phenylethylamine. In silico simulation predicted spasmolytic activity for 2-amino-N-phenethylbenzamides. The newly synthesized compounds demonstrated a relaxation effect similar to mebeverine but did not affect the serotonin or Ca2+-dependent signaling pathway of contractile activity (CA) in contrast. Having in mind the anti-inflammatory potential of antispasmodics, the synthesized molecules were tested in vitro and ex vivo for their anti-inflammatory effects. Four of the newly synthesized compounds demonstrated very good activity by preventing albumin denaturation compared to anti-inflammatory drugs/agents well-established in medicinal practice. The newly synthesized compounds also inhibited the expression of interleukin-1ß and stimulated the expression of neuronal nitric oxide synthase (nNOS), and, consequently, nitric oxide (NO) synthesis by neurons of the myenteric plexus. This characterizes the newly synthesized compounds as biologically active relaxants, offering a cleaner and more precise application in pharmacological practice, thereby enhancing their potential therapeutic value.
Assuntos
Síndrome do Intestino Irritável , Fenetilaminas , Síndrome do Intestino Irritável/tratamento farmacológico , Animais , Fenetilaminas/farmacologia , Fenetilaminas/química , Humanos , Interleucina-1beta/metabolismo , Óxido Nítrico/metabolismo , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/química , Ratos , Parassimpatolíticos/farmacologia , Parassimpatolíticos/química , Óxido Nítrico Sintase Tipo I/metabolismoRESUMO
The study was performed to assess and rationalize the traditional utilization of the fruit part of Grewia tenax (G. tenax). The phytoconstituents present in the methanolic extract were analyzed using Gas-Chromatography-Mass Spectroscopy (GC-MS), while the anti-diarrheal activity was investigated in the Swiss albino mice against castor oil-provoked diarrhea in vivo. The antispasmodic effect and the possible pharmacodynamics of the observed antispasmodic effect were determined in an isolated rat ileum using the organ bath setup as an ex vivo model. GC-MS findings indicate that G. tenax is rich in alcohol (6,6-dideutero-nonen-1-ol-3) as the main constituent (20.98%), while 3-Deoxy-d-mannoic lactone (15.36%) was detected as the second major constituents whereas methyl furfural, pyranone, carboxylic acid, vitamin E, fatty acid ester, hydrocarbon, steroids, sesquiterpenes, phytosterols, and ketones were verified as added constituents in the methanolic extract. In mice, the orally administered G. tenax inhibited the diarrheal episodes significantly (p < 0.05) at 200 mg/kg (40% protection), and this protection was escalated to 80% with the next higher dose of 400 mg/kg. Loperamide (10 mg/kg), a positive control drug, imparted 100% protection, whereas no protection was shown by saline. In isolated rat ileum, G. tenax completely inhibited the carbamylcholine (CCh; 1 µM) and KCl (high K+; 80 mM)-evoked spasms in a concentrations-mediated manner (0.03 to 3 mg/mL) by expressing equal potencies (p > 0.05) against both types of evoked spasms, similar to papaverine, having dual inhibitory actions at phosphodiesterase enzyme (PDE) and Ca2+ channels (CCB). Similar to papaverine, the inhibitory effect of G. tenax on PDE was further confirmed indirectly when G. tenax (0.1 and 0.3 mg/mL) preincubated ileal tissues shifted the isoprenaline-relaxation curve towards the left. Whereas, pre-incubating the tissue with 0.3 and 1 mg/mL of G. tenax established the CCB-like effect by non-specific inhibition of CaCl2−mediated concentration-response curves towards the right with suppression of the maximum peaks, similar to verapamil, a standard CCB. Thus, the present investigation revealed the phytochemical constituents and explored the detailed pharmacodynamic basis for the curative use of G. tenax in diarrhea and hyperactive gut motility disorders.
Assuntos
Grewia , Parassimpatolíticos , Ratos , Camundongos , Animais , Parassimpatolíticos/química , Antidiarreicos/química , Papaverina/farmacologia , Jejuno , Frutas , Cromatografia Gasosa-Espectrometria de Massas , Extratos Vegetais/farmacologia , Extratos Vegetais/uso terapêutico , Diarreia/tratamento farmacológico , Diester Fosfórico Hidrolases/farmacologia , EspasmoRESUMO
This present study evaluated and rationalized the medicinal use of the fruit part of Acacia nilotica methanolic extract. The phytochemicals were detected using gas chromatography−mass spectrometry (GC−MS) while the in vivo antidiarrheal test was done using Swiss albino mice. To determine the details of the mechanism(s) involved in the antispasmodic effect, isolated rat ileum was chosen using different ex vivo assays by maintaining a physiological environment. GC−MS results showed that A. nilotica contained pyrogallol as the major polyphenol present (64.04%) in addition to polysaccharides, polyphenol, amino acid, steroids, fatty acid esters, and triterpenoids. In the antidiarrheal experiment, A. nilotica inhibited diarrheal episodes in mice significantly (p < 0.05) by 40% protection of mice at 200 mg/kg, while 80% protection was observed at 400 mg/kg by the orally administered extract. The highest antidiarrheal effect was observed with loperamide (p < 0.01), used as a control drug. In the ex vivo experiments, A. nilotica inhibited completely in increasing concentrations (0.3 to 10 mg/mL) the carbachol (CCh; 1 µM) and high K+ (80 mM)-evoked spasms in ileum tissues at equal potencies (p > 0.05), similar to papaverine, a dual inhibitor of the phosphodiesterase enzyme (PDE) and Ca++ channels. The dual inhibitory-like effects of A. nilotica on PDE and Ca++ were further validated when A. nilotica extract (1 and 3 mg/mL)-pre-incubated ileum tissues potentiated and shifted isoprenaline relaxation curves towards lower doses (leftward), similar to papaverine, thus confirming the PDE inhibitory-like mechanism whereas its CCB-like effect of the extract was confirmed at 3 and 5 mg/mL by non-specific inhibition of CaCl2-mediated concentration response curves towards the right with suppression of the maximum peaks, similar to verapamil, used as standard CCB. Thus, this study characterized the chemical composition and provides mechanistic support for medicinal use of A. nilotica in diarrheal and hyperactive gut motility disorders.
Assuntos
Acacia , Antidiarreicos , Animais , Antidiarreicos/química , Diarreia/tratamento farmacológico , Cromatografia Gasosa-Espectrometria de Massas , Fármacos Gastrointestinais/farmacologia , Jejuno , Metanol/farmacologia , Camundongos , Papaverina/farmacologia , Parassimpatolíticos/química , Diester Fosfórico Hidrolases/farmacologia , Extratos Vegetais/farmacologia , Extratos Vegetais/uso terapêutico , Polifenóis/farmacologia , RatosRESUMO
Fenchone is a bicyclic monoterpene found in a variety of aromatic plants, including Foeniculum vulgare and Peumus boldus, and is used in the management of airways disorders. This study aimed to explore the bronchodilator effect of fenchone using guinea pig tracheal muscles as an ex vivo model and in silico studies. A concentration-mediated tracheal relaxant effect of fenchone was evaluated using isolated guinea pig trachea mounted in an organ bath provided with physiological conditions. Sustained contractions were achieved using low K+ (25 mM), high K+ (80 mM), and carbamylcholine (CCh; 1 µM), and fenchone inhibitory concentration-response curves (CRCs) were obtained against these contractions. Fenchone selectively inhibited with higher potency contractions evoked by low K+ compared to high K+ with resultant EC50 values of 0.62 mg/mL (0.58-0.72; n = 5) and 6.44 mg/mL (5.86-7.32; n = 5), respectively. Verapamil (VRP) inhibited both low and high K+ contractions at similar concentrations. Pre-incubation of the tracheal tissues with K+ channel blockers such as glibenclamide (Gb), 4-aminopyridine (4-AP), and tetraethylammonium (TEA) significantly shifted the inhibitory CRCs of fenchone to the right towards higher doses. Fenchone also inhibited CCh-mediated contractions at comparable potency to its effect against high K+ [6.28 mg/mL (5.88-6.42, n = 4); CCh] and [6.44 mg/mL (5.86-7.32; n = 5); high K+]. A similar pattern was obtained with papaverine (PPV), a phosphodiesterase (PDE), and Ca2+ inhibitor which inhibited both CCh and high K+ at similar concentrations [10.46 µM (9.82-11.22, n = 4); CCh] and [10.28 µM (9.18-11.36; n = 5); high K+]. However, verapamil, a standard Ca2+ channel blocker, showed selectively higher potency against high K+ compared to CCh-mediated contractions with respective EC50 values of 0.84 mg/mL (0.82-0.96; n = 5) 14.46 mg/mL (12.24-16.38, n = 4). The PDE-inhibitory action of fenchone was further confirmed when its pre-incubation at 3 and 5 mg/mL potentiated and shifted the isoprenaline inhibitory CRCs towards the left, similar to papaverine, whereas the Ca2+ inhibitory-like action of fenchone pretreated tracheal tissues were authenticated by the rightward shift of Ca2+ CRCs with suppression of maximum response, similar to verapamil, a standard Ca2+ channel blocker. Fenchone showed a spasmolytic effect in isolated trachea mediated predominantly by K+ channel activation followed by dual inhibition of PDE and Ca2+ channels. Further in silico molecular docking studies provided the insight for binding of fenchone with Ca2+ channel (-5.3 kcal/mol) and K+ channel (-5.7), which also endorsed the idea of dual inhibition.
Assuntos
Canfanos/química , Canfanos/farmacologia , Norbornanos/química , Norbornanos/farmacologia , Parassimpatolíticos/química , Parassimpatolíticos/farmacologia , Traqueia/efeitos dos fármacos , Animais , Bloqueadores dos Canais de Cálcio/química , Bloqueadores dos Canais de Cálcio/farmacologia , Fenômenos Químicos , Relação Dose-Resposta a Droga , Cobaias , Técnicas In Vitro , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Estrutura Molecular , Inibidores de Fosfodiesterase/química , Inibidores de Fosfodiesterase/farmacologia , Canais de Potássio/agonistas , Canais de Potássio/química , Relação Estrutura-AtividadeRESUMO
Parmotremaperlatum is traditionally used in different areas of Pakistan to treat gastrointestinal, respiratory, and vascular diseases. This study evaluates the underlying mechanisms for traditional uses of P. perlatum in diarrhea, asthma, and hypertension. In vitro pharmacological studies were conducted using isolated jejunum, trachea, and aortic preparations, while the cytotoxic study was conducted in mice. Crude extract of P. perlatum(Pp.Cr), comprising appreciable quantities of alkaloids and flavonoids, relaxed spontaneously contracting jejunum preparation, K+ (80 mM)-induced, and carbachol (1 µM)-induced jejunum contractions in a concentration-dependent manner similar to dicyclomine and dantrolene. Pp.Cr showed a rightward parallel shift of concentration-response curves (CRCs) of Cch after a non-parallel shift similarto dicyclomine and shifted CRCs of Ca+2 to rightward much likeverapamil and dantrolene, demonstrating the coexistence of antimuscarinic and Ca+2 antagonistic mechanism. Furthermore, Pp.Cr, dicyclomine, and dantrolene relaxed K+ (80 mM)-induced and Cch (1 µM)-induced tracheal contractions and shifted rightward CRCs of Cch similar to dicyclomine, signifying the dual blockade. Additionally, Pp.Cr also relaxed the K+ (80 mM)-induced and phenylephrine (1 µM)-induced aortic contraction, similarly to verapamil and dantrolene, suggesting Ca+2 channel antagonism. Here, we explored for the first time thespasmolytic and bronchodilator effects of Pp.Crand whether they maybe due to the dual blockade of Ca+2 channels and muscarinic receptors, while the vasodilator effect might be owing to Ca+2 antagonism. Our results provide the pharmacological evidence that P. perlatum could be a new potential therapeutic option to treat gastrointestinal, respiratory, and vascular diseases. Hence, there is a need for further research to explore bioactive constituent of P. perlatum as well as further investigation by suitable experimental models are required to further confirm the importance and usefulness of P. perlatum in diarrhea, asthma, and hypertension treatment.
Assuntos
Produtos Biológicos/farmacologia , Broncodilatadores/farmacologia , Bloqueadores dos Canais de Cálcio/farmacologia , Antagonistas Muscarínicos/farmacologia , Parassimpatolíticos/farmacologia , Parmeliaceae/química , Vasodilatadores/farmacologia , Animais , Produtos Biológicos/química , Broncodilatadores/química , Bloqueadores dos Canais de Cálcio/química , Cromatografia Líquida de Alta Pressão , Relação Dose-Resposta a Droga , Camundongos , Estrutura Molecular , Antagonistas Muscarínicos/química , Parassimpatolíticos/química , Análise Espectral , Testes de Toxicidade Aguda , Vasodilatadores/químicaRESUMO
Antispasmodic agents are used for modulating gastrointestinal motility. Several compounds isolated from terrestrial plants have antispasmodic properties. This study aimed to explore the inhibitory effect of the pyrrolidine derivative, asperidine B, isolated from the soil-derived fungus Aspergillus sclerotiorum PSU-RSPG178, on spasmodic activity. Isolated rat ileum was set up in an organ bath. The contractile responses of asperidine B (0.3 to 30 µM) on potassium chloride and acetylcholine-induced contractions were recorded. To investigate its antispasmodic mechanism, CaCl2, acetylcholine, Nω-nitro-l-arginine methyl ester (l-NAME), nifedipine, methylene blue and tetraethylammonium chloride (TEA) were tested in the absence or in the presence of asperidine B. Cumulative concentrations of asperidine B reduced the ileal contraction by ~37%. The calcium chloride and acetylcholine-induced ileal contraction was suppressed by asperidine B. The effects of asperidine B combined with nifedipine, atropine or TEA were similar to those treated with nifedipine, atropine or TEA, respectively. In contrast, in the presence of l-NAME and methylene blue, the antispasmodic effect of asperidine B was unaltered. These results suggest that the antispasmodic property of asperidine B is probably due to the blockage of the L-type Ca2+ channel and is associated with K+ channels and muscarinic receptor, possibly by affecting non-selective cation channels and/or releasing intracellular calcium.
Assuntos
Canais de Cálcio Tipo L/metabolismo , Músculo Liso/efeitos dos fármacos , Parassimpatolíticos/farmacologia , Pirrolidinas/farmacologia , Acetilcolina/metabolismo , Acetilcolina/farmacologia , Animais , Cálcio/metabolismo , Bloqueadores dos Canais de Cálcio/farmacologia , GMP Cíclico/metabolismo , Íleo/efeitos dos fármacos , Íleo/metabolismo , Masculino , Azul de Metileno/farmacologia , Contração Muscular/efeitos dos fármacos , Músculo Liso/metabolismo , NG-Nitroarginina Metil Éster/farmacologia , Parassimpatolíticos/química , Cloreto de Potássio/farmacologia , Pirrolidinas/química , Ratos Wistar , Tetraetilamônio/farmacologiaRESUMO
The aim of the present study was to evaluate the possible gut inhibitory role of the phosphodiesterase (PDE) inhibitor roflumilast. Increasing doses of roflumilast were tested against castor oil-induced diarrhea in mice, whereas the pharmacodynamics of the same effect was determined in isolated rabbit jejunum tissues. For in silico analysis, the identified PDE protein was docked with roflumilast and papaverine using the Autodock vina program from the PyRx virtual screening tool. Roflumilast protected against diarrhea significantly at 0.5 and 1.5 mg/kg doses, with 40% and 80% protection. Ex vivo findings from jejunum tissues show that roflumilast possesses an antispasmodic effect by inhibiting spontaneous contractions in a concentration-dependent manner. Roflumilast reversed carbachol (CCh, 1 µM)-mediated and potassium (K+, 80 mM)-mediated contractile responses with comparable efficacies but different potencies. The observed potency against K+ was significantly higher in comparison to CCh, similar to verapamil. Experiments were extended to further confirm the inhibitory effect on Ca++ channels. Interestingly, roflumilast deflected Ca++ concentration-response curves (CRCs) to the right with suppression of the maximum peak at both tested doses (0.001-0.003 mg/mL), similar to verapamil. The PDE-inhibitory effect was authenticated when pre-incubation of jejunum tissues with roflumilast (0.03-0.1 mg/mL) produced a leftward deflection of isoprenaline-mediated inhibitory CRCs and increased the tissue level of cAMP, similar to papaverine. This idea was further strengthened by molecular docking studies, where roflumilast exhibited a better binding affinity (-9.4 kcal/mol) with the PDE protein than the standard papaverine (-8.3 kcal/mol). In conclusion, inhibition of Ca++ channels and the PDE-4 enzyme explains the pharmacodynamics of the gut inhibitory effect of roflumilast.
Assuntos
Aminopiridinas/farmacologia , Antidiarreicos/farmacologia , Benzamidas/farmacologia , Bloqueadores dos Canais de Cálcio/farmacologia , Nucleotídeo Cíclico Fosfodiesterase do Tipo 4/metabolismo , Diarreia/prevenção & controle , Parassimpatolíticos/farmacologia , Inibidores da Fosfodiesterase 4/farmacologia , Aminopiridinas/química , Aminopiridinas/farmacocinética , Animais , Antidiarreicos/química , Antidiarreicos/farmacocinética , Benzamidas/química , Benzamidas/farmacocinética , Sítios de Ligação , Bloqueadores dos Canais de Cálcio/química , Bloqueadores dos Canais de Cálcio/farmacocinética , Carbacol/farmacologia , Óleo de Rícino/administração & dosagem , AMP Cíclico/metabolismo , Nucleotídeo Cíclico Fosfodiesterase do Tipo 4/química , Ciclopropanos/química , Ciclopropanos/farmacocinética , Ciclopropanos/farmacologia , Diarreia/induzido quimicamente , Diarreia/metabolismo , Diarreia/fisiopatologia , Isoproterenol/farmacologia , Jejuno/efeitos dos fármacos , Jejuno/metabolismo , Camundongos , Simulação de Acoplamento Molecular , Papaverina/farmacologia , Parassimpatolíticos/química , Parassimpatolíticos/farmacocinética , Inibidores da Fosfodiesterase 4/química , Inibidores da Fosfodiesterase 4/farmacocinética , Ligação Proteica , Domínios e Motivos de Interação entre Proteínas , Estrutura Secundária de Proteína , Coelhos , Verapamil/farmacologiaRESUMO
5-Oxo-hexahydroquinoline (5-oxo-HHQ) represents a biologically attractive fused heterocyclic core. Various synthetic analogs of 5-oxo-HHQ have been synthesized and assessed for different biological activities. Some derivatives have exhibited myorelaxant, analgesic, anticancer, antibacterial, antifungal, antitubercular, antimalarial, antioxidant, anti-inflammatory, multidrug resistance reversal, anti-Alzheimer, neuroprotective, antidiabetic, antidyslipidemic and antiosteoporotic activities. This review provides a comprehensive report regarding the preparation and pharmacological characterization of 5-oxo-HHQ derivatives that have been reported so far. This information will be beneficial for medicinal chemists in the field of drug discovery to design and develop new and potent therapeutical agents bearing the 5-oxo-HHQ nucleus.
Assuntos
Quinolinas/química , Quinolinas/farmacologia , Animais , Anti-Infecciosos/química , Anti-Infecciosos/farmacologia , Anti-Inflamatórios/química , Anti-Inflamatórios/farmacologia , Antineoplásicos/química , Antineoplásicos/farmacologia , Humanos , Hipoglicemiantes/química , Hipoglicemiantes/farmacologia , Hipolipemiantes/química , Hipolipemiantes/farmacologia , Parassimpatolíticos/química , Parassimpatolíticos/farmacologiaRESUMO
Bladder relaxation through drug administration is an interesting topic in medicinal and combinatorial chemistry. In fact, compounds targeting catecholamine receptors [dopamine receptors and beta-adrenergic receptors (ßAR) expressed in the bladder] are among the compounds commonly employed for this purpose. In particular, recent investigations have tended to focus on the ß3-adrenoceptor (ß3AR) as a target in the treatment of urinary incontinence and other disorders. However, organoboron compounds have been suggested as potent and efficient agents on these drug targets. In this work, through a docking study, we identified the parameters that induce a theoretical improvement in the affinity and activity of the organoboron compounds on the catecholamine receptors expressed in the bladder. Then, the identified potential drug, a boron-containing dopa-derivative named DPBX-L-Dopa, was synthesized and characterized. This compound induces a relaxation on the smooth muscle of the rat bladder, behaving as a weak relaxant compared to isoproterenol but with similar efficacy to BRL377, a selective ß3AR agonist. However, unexpectedly, this effect was not blocked by propranolol or haloperidol at the concentrations at which they are able to block the catecholamine receptors in bladder tissue. In view of these results, the effect of DPBX-L-Dopa compound on the alpha 1 adrenergic receptors (α1AR) of aorta of the rats was also explored; however, no response of the tissue to this compound was obtained. The possible mechanisms of the action of this compound were explored and are discussed further.
Assuntos
Boro , Di-Hidroxifenilalanina , Parassimpatolíticos , Animais , Aorta/efeitos dos fármacos , Aorta/fisiologia , Boro/química , Boro/farmacologia , Di-Hidroxifenilalanina/química , Di-Hidroxifenilalanina/farmacologia , Desenho de Fármacos , Técnicas In Vitro , Masculino , Modelos Moleculares , Músculo Liso/efeitos dos fármacos , Músculo Liso/fisiologia , Parassimpatolíticos/química , Parassimpatolíticos/farmacologia , Ratos Wistar , Receptores de Catecolaminas , Bexiga Urinária/efeitos dos fármacos , Bexiga Urinária/fisiologiaRESUMO
BACKGROUND: Fruit, bark and leaves of Zanthoxylum armatum DC are popular remedies for gastrointestinal, cardiovascular and respiratory disorders in the subcontinent traditional practices. The aim of the study was to individually probe the profile of methanol extracts from three different parts of Zanthoxylum armatum. METHODS: The ex-vivo muscle relaxant effects of extracts were assessed in the isolated intestine, trachea and thoracic aortic rings and were compared with the positive controls and CRC were constructed. The anti-diarrheal effect of extracts was evaluated in mice by inducing diarrhea with castor oil. The extracts were also studied for acute toxicity and butyrylcholine esterase inhibition. RESULTS: The extracts from fruit, bark and leaves of Z. armatum showed inhibitory effect against the butyrylcholine esterase enzyme with percent inhibition of 50.75 ± 1.23, 82.57 ± 1.33, and 37.52 ± 1.11respectively, compared to standard serine (IC50: 0.04 ± 0.001 µmol/L). The fruit and bark extracts provided 75, and 52% diarrheal protection, compared to verapamil (96%). In isolated rabbit jejunum strips, increasing addition of the extracts inhibited the spontaneous and high K+ precontractions with EC50 values of 0.71 and 3 mg/mL for fruit, EC50 values of 0.61 and 0.5 mg/mL for bark, EC50 0.81 and 3.1 mg/mL for leaves, like verapamil. The extracts induced a concentration-dependent relaxation of the carbachol (1 µM) and high K+ (80 mM) precontractions with EC50 values of 2.4 and 0.9 mg/mL for fruit, EC50 values of 1.2 and 3 for leaves. The bark extract was equipotent against both contractions with EC50 3.1 and 0.7 mg/mL, respectively. In the aortic rings, the fruit extract completely relaxed the phenylephrine (1 µM)-induced contractions with (EC50 value = 0.8 mg/ml) and a partial inhibition of high K+ induced contractions. The leaves extract completely relaxed the aortic contractions with (EC50 values = 1.0 and 8.5 mg/ml). The extracts caused no acute toxicity up to 3 g/kg dose. CONCLUSIONS: The experiments revealed that the extracts of aerial parts of Z. armatum have antidiarrheal properties in vivo and showed spasmolytic effect in intestinal and tracheal preparations with possible mechanism involving the blockage of Ca++ channels. These experiments provide enough justification for use of this plant in ethnomedicine in diarrhea, gut and bronchial spasms.
Assuntos
Inibidores Enzimáticos/farmacologia , Esterases/antagonistas & inibidores , Músculo Liso Vascular/efeitos dos fármacos , Parassimpatolíticos/química , Extratos Vegetais/farmacologia , Zanthoxylum/química , Animais , Antidiarreicos/química , Antidiarreicos/farmacologia , Aorta Torácica/efeitos dos fármacos , Inibidores Enzimáticos/química , Esterases/química , Frutas/química , Jejuno/efeitos dos fármacos , Masculino , Camundongos , Parassimpatolíticos/farmacologia , Casca de Planta/química , Extratos Vegetais/química , Folhas de Planta/química , Coelhos , Traqueia/efeitos dos fármacosRESUMO
BACKGROUND: Ficus palmata (Fig), are distributed in different parts of the world, and are used in traditional medicine to treat various ailments including inflammation, tumor, epilepsy, jaundice, influenza and bacillary dysentery. The present study aimed to evaluate the antidiarrheal, antisecretary, antispasmodic, antiulcer and anti motility properties of Ficus palmata. METHODS: In-vivo, in-vitro and in-silico techniques were used to investigate various gastrointestinal effects of Ficus palmata. Antidiarrheal, antisecretary, antispasmodic, antiulcer, anti motility and molecular docking were performed using castor oil induced diarrhea and fluid accumulation, isolated tissue preparations, ethanol-HCl induced ulcer assay, charcoal meal transit time and Auto Doc Vina. RESULTS: Ficus palmata crude extract (Fp.Cr) exhibited protection against castor oil-induced diarrhea in mice and dose-dependently inhibited intestinal fluid secretions. Fp.Cr caused relaxation of spontaneous and K+ (80 Mm)-induced contractions in isolated rabbit jejunum preparations. It showed protective effect against gastric ulcers induced by ethanol-hydrochloric acid in rats. Fp.Cr reduced distance travelled by charcoal meal in the gastrointestinal transit model in mice. The plant constituents: psoralenoside and bergapten showed high binding affinities (E-value ≥ - 6.5 Kcal/mol) against histaminergic H1, calmodulin and voltage gated L-type calcium channels, while showed moderate affinities (E-value ≥7 Kcal/mol) against dopaminergic D2, adrenergic α1, muscranic M3, mu-opioid, whereas revealed lower affinities (E-value ≥9.5 Kcal/mol) vs. muscranic M1, histaminergic H2 and H+/K+ ATPase pump. Germanicol acetate and psoralene exhibited weak affinities against aforementioned targets. CONCLUSION: This study reveals that Ficus palmata possesses anti-diarrheal, anti-secretory, anti-spasmodic, anti-motility and anti-ulcer activities. The various constituents reveal different binding affinities against target proteins, which mediate the gastrointestinal functions.
Assuntos
Diarreia , Ficus , Fármacos Gastrointestinais , Parassimpatolíticos , Extratos Vegetais , Animais , Óleo de Rícino/efeitos adversos , Diarreia/induzido quimicamente , Diarreia/metabolismo , Feminino , Fármacos Gastrointestinais/química , Fármacos Gastrointestinais/metabolismo , Fármacos Gastrointestinais/farmacologia , Trânsito Gastrointestinal/efeitos dos fármacos , Jejuno/química , Jejuno/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Simulação de Acoplamento Molecular , Parassimpatolíticos/química , Parassimpatolíticos/metabolismo , Parassimpatolíticos/farmacologia , Extratos Vegetais/química , Extratos Vegetais/metabolismo , Extratos Vegetais/farmacologia , Coelhos , Ratos Sprague-Dawley , Receptores de Superfície Celular/química , Receptores de Superfície Celular/metabolismoRESUMO
Black mulberry is a widely acknowledged ancient traditional medicine. Its extract and constituents have been reported to exert various bioactivities including antimicrobial, hypotensive, analgesic etc. effects. While black mulberry preparations are also used as antispasmodic agents in folk medicine, no related studies are available on its isolated constituents. Through an extensive chromatographic purification, seven phenolic compounds were isolated from the methanol extract of Morus nigra root bark, including morusin (1), kuwanon U (2), kuwanon E (3), moracin P (4), moracin O (5), albanol A (6), and albanol B (7). A complete NMR signal assignment of moracin P and O was achieved, and related literature errors confusing the identity of moracin derivatives are hereby clarified. Compounds 2, 5 and 7 were identified as strong antispasmodic agents on isolated rat ileum and tracheal smooth muscles, while compound 3, a methoxy derivative of 2, was inactive. Moracin O (5) inhibited the ileal and tracheal smooth muscle contractions with Emax values of 85% and 302 mg, respectively. Those actions were superior as compared with papaverine. Our findings demonstrate that prenylated arylbenzofurans, geranylated flavonoids and Diels-Alder adducts from Morus nigra are valuable antispasmodic agents. Compounds 2, 5 and 7 are suggested as marker compounds for quality control of antispasmodic mulberry preparations. Moracin O (5) is a new lead compound for related drug development initiatives.
Assuntos
Morus/química , Parassimpatolíticos/química , Fenóis/química , Casca de Planta/química , Extratos Vegetais/química , Raízes de Plantas/química , Benzofuranos/metabolismo , Avaliação Pré-Clínica de Medicamentos , Flavanonas/metabolismo , Metanol/química , Parassimpatolíticos/farmacologia , Prenilação , Resorcinóis/metabolismo , Solventes/química , Relação Estrutura-AtividadeRESUMO
The antispasmodic effect of drugs is used for the symptomatic treatment of cramping and discomfort affecting smooth muscles from the gastrointestinal, billiary or genitourinary tract in a variety of clinical situations.The existing synthetic antispasmodic drugs may cause a series of unpleasant side effects, and therefore the discovery of new molecules of natural origin is an important goal for the pharmaceutical industry. This review describes a series of recent studies investigating the antispasmodic effect of essential oils from 39 plant species belonging to 12 families. The pharmacological models used in the studies together with the mechanistic discussions and the chemical composition of the essential oils are also detailed. The data clearly demonstrate the antispasmodic effect of the essential oils from the aromatic plant species studied. Further research is needed in order to ascertain the therapeutic importance of these findings.
Assuntos
Óleos Voláteis/química , Óleos Voláteis/farmacologia , Parassimpatolíticos/química , Parassimpatolíticos/farmacologia , Animais , Bloqueadores dos Canais de Cálcio/química , Bloqueadores dos Canais de Cálcio/farmacologia , Canais de Cálcio/metabolismo , Estudos Clínicos como Assunto , AMP Cíclico/metabolismo , Avaliação Pré-Clínica de Medicamentos , Humanos , Estrutura Molecular , Contração Muscular/efeitos dos fármacos , Músculo Liso/efeitos dos fármacos , Músculo Liso/metabolismo , Óleos Voláteis/análise , Óleos Voláteis/uso terapêutico , Parassimpatolíticos/uso terapêutico , Compostos Fitoquímicos/química , Compostos Fitoquímicos/farmacologia , Extratos Vegetais/análise , Extratos Vegetais/química , Extratos Vegetais/farmacologia , Relação Estrutura-Atividade , Resultado do TratamentoRESUMO
Present review discuss the reported work on structures, origins and the potent biologically active natural products isolated from Genus Buddleja, which is known for having many important pharmacologically active substances. The Genus Buddleja have more than 100 species, many of them are distributed in Mediterranean and Asian regions. A very small number of common species of the Genus in majority of fruiting plants have been investigated for their biological potential. So for, isolation of about 153 or more new/novel chemical substances have been reported. Purposes of the review is to discuss the structurally established and pharmacologically significant natural substances from wide variety of different species of this genus. Traditionally, species of the genus are reported to be used for healing, treatment of liver diseases, bronchial complaints, preventing several other diseases by exhibiting diuretic properties, sedative functions, analgesic potential, antirheumatic actions, antimicrobial activities, anti hyperglycemic functions and antioxidant properties. In this review we will describe recently established medicinal chemistry aspects and complete list of phytoconstituents as well as their sources and reference.
Assuntos
Anti-Infecciosos/farmacologia , Antioxidantes/farmacologia , Buddleja/química , Parassimpatolíticos/farmacologia , Plantas Medicinais/química , Analgésicos/farmacologia , Animais , Anti-Infecciosos/química , Antioxidantes/química , Buddleja/metabolismo , Diuréticos/farmacologia , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Flavonoides/química , Flavonoides/isolamento & purificação , Humanos , Hipnóticos e Sedativos/farmacologia , Parassimpatolíticos/química , Plantas Medicinais/metabolismo , Esteroides/química , Esteroides/isolamento & purificação , Terpenos/química , Terpenos/isolamento & purificaçãoRESUMO
Haematoxylum campechianum is a medicinal plant employed as an astringent to purify the blood and to treat stomach problems such as diarrhea and dysentery. A bio-guided chemical fractionation of the methanolic extract obtained from this plant allowed for the isolation of five compounds: two chalcones known as sappanchalcone (1); 3-deoxysappanchalcone (2); three homoisoflavonoids known as hematoxylol A (3); 4-O-methylhematoxylol (4); and, hematoxin (5). The spasmolytic activity was determined in an in vitro model (electrically induced contractions of guinea pig ileum), and allowed to demonstrate that the methanolic extract (EC50 = 62.11 ± 3.23) fractions HcF7 (EC50 = 61.75 ± 3.55) and HcF9 (EC50 = 125.5 ± 10.65) and compounds 1 (EC50 = 16.06 ± 2.15) and 2 (EC50 = 25.37 ± 3.47) of Haematoxylum campechianum present significant relaxing activity as compared to papaverine (EC50 = 20.08 ± 2.0) as a positive control.
Assuntos
Cassia/química , Chalconas/química , Chalconas/farmacologia , Isoflavonas/química , Isoflavonas/farmacologia , Parassimpatolíticos/química , Parassimpatolíticos/farmacologia , Extratos Vegetais/química , Extratos Vegetais/farmacologia , Animais , Espectroscopia de Ressonância Magnética Nuclear de Carbono-13 , Chalconas/isolamento & purificação , Cobaias , Estrutura Molecular , Extratos Vegetais/isolamento & purificação , Espectroscopia de Prótons por Ressonância MagnéticaRESUMO
Licorice derived from the roots and rhizomes of Glycyrrhiza uralensis Fisch. (Fabaceae), is one of the most widely-used traditional herbal medicines in China. It has been reported to possess significant analgesic activity for treating spastic pain. The aim of this study is to investigate the spasmolytic molecular mechanism of licorice on oxytocin-induced uterine contractions and predict the relevant bioactive constituents in the aqueous extract. The aqueous extraction from licorice inhibited the amplitude and frequency of uterine contraction in a concentration-dependent manner. A morphological examination showed that myometrial smooth muscle cells of oxytocin-stimulated group were oval-shaped and arranged irregularly, while those with a single centrally located nucleus of control and licorice-treated groups were fusiform and arranged orderly. The percentage of phosphorylation of HSP27 at Ser-15 residue increased up to 50.33% at 60 min after oxytocin stimulation. Furthermore, this increase was significantly suppressed by licorice treatment at the concentration of 0.2 and 0.4 mg/mL. Colocalization between HSP27 and α-SMA was observed in the myometrial tissues, especially along the actin bundles in the oxytocin-stimulated group. On the contrary, the colocalization was no longer shown after treatment with licorice. Additionally, employing ChemGPS-NP provided support for a preliminary assignment of liquiritigenin and isoliquiritigenin as protein kinase C (PKC) inhibitors in addition to liquiritigenin, isoliquiritigenin, liquiritin and isoliquiritin as MAPK-activated protein kinase 2 (MK2) inhibitors. These assigned compounds were docked with corresponding crystal structures of respective proteins with negative and low binding energy, which indicated a high affinity and tight binding capacity for the active site of the kinases. These results suggest that licorice exerts its spasmolytic effect through inhibiting the phosphorylation of HSP27 to alter the interaction between HSP27 and actin. Furthermore, our results provide support for the prediction that potential bioactive constituents from aqueous licorice extract inhibit the relevant up-stream kinases that phosphorylate HSP27.
Assuntos
Glycyrrhiza uralensis/química , Proteínas de Choque Térmico HSP27/metabolismo , Oxicodona/efeitos adversos , Parassimpatolíticos/química , Extratos Vegetais/química , Contração Uterina/efeitos dos fármacos , Animais , Relação Dose-Resposta a Droga , Feminino , Regulação da Expressão Gênica/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos ICR , Simulação de Acoplamento Molecular , Parassimpatolíticos/administração & dosagem , Parassimpatolíticos/farmacologia , Fosforilação/efeitos dos fármacos , Extratos Vegetais/administração & dosagem , Extratos Vegetais/farmacologia , Útero/efeitos dos fármacos , Útero/metabolismo , Útero/fisiologiaRESUMO
In this study, we formulated and evaluated the effects of tablet dimensions and drug load on the characteristics of atropine sulfate (AS) fast-disintegrating sublingual tablets (FDSTs). We aim to develop AS FDSTs as an alternative non-invasive and portable dosage form for the emergency treatment of organophosphate (OP) toxicity. AS autoinjector, AtroPen®, is the only self-administered dosage form available as an antidote for-out-of-hospital emergency use, but it is associated with several limitations and drawbacks. Seven FDST formulations of two tablet sizes, 150 mg (A) and 50 mg (B), and of several AS loads, 0 mg (A1, B1), 2 mg (A2, B2), 4 mg (B3), and 8 mg (B4a, B4b), were formulated and manufactured by direct compression. AS FDST characteristics were evaluated using USP and non-USP tests. Results were statistically compared at p < 0.05. All FDSTs passed the USP content uniformity and friability tests, disintegrated and released AS in ≤30 and 60 s. B1 and B2 were significantly harder than A1 and A2. Water uptake of A1 was significantly the highest. However, B1 and B2 had shorter disintegration and wetting times and higher amounts of AS dissolved than did A1 and A2 (p < 0.05). Increasing AS negatively affected FDST tensile strength (p < 0.05 for B4a) and water uptake (p < 0.05 for B3, B4a and B4b), however, without affecting AS dissolution. Formulation of AS up to 16% into smaller FDSTs was successful. Smaller FDSTs were harder and disintegrated more quickly. These AS FDSTS have the potential for further in vivo testing to evaluate their OP antidote potential.
Assuntos
Atropina , Intoxicação por Organofosfatos/tratamento farmacológico , Administração Sublingual , Atropina/química , Atropina/farmacocinética , Composição de Medicamentos/métodos , Dureza , Humanos , Parassimpatolíticos/química , Parassimpatolíticos/farmacocinética , Solubilidade , Comprimidos , MolhabilidadeRESUMO
Caulis Sinomenii (CS) is a valuable traditional medicine in China. Its extract can act as an anti-inflammatory agent and a vascular smooth muscle relaxant. However, the underlying mechanisms remain unknown. In this study, we developed a simple dual-target method based on ultra-performance liquid chromatography/quadrupole time-of-flight mass spectrometry combined with a dual-target bioactive screening assay for anti-inflammatory and antispasmodic activities to characterize the chemical structure of various bioactive compounds of CS rapidly. Seven potential NF-κB inhibitors were identified, including laudanosoline-1-O-xylopyranose, 6-O-methyl-laudanosoline-1-O-glucopyranoside, menisperine, sinomenine, laurifoline, magnoflorine and norsinoacutin. Furthermore, IL-6 and IL-8 assays confirmed the anti-inflammatory effects of these potential NF-κB inhibitors, in which laudanosoline-1-O-d-xylopyranose and menisperine were revealed as novel NF-κB inhibitors. Among the seven identified alkaloids, three potential ß2 -adrenergic receptor agonists, including sinomenine, magnoflorine and laurifoline, were characterized using a luciferase reporter system to measure for the activity of ß2 -adrenergic receptor agonists. Finally, sinomenine, magnoflorine and laurifoline were identified not only as potential NF-κB inhibitors but also as potential ß2 -adrenegic receptor agonists, which is the first time this has been reported. Molecular dynamic simulation and docking results suggest that the three dual-bioactive constituents could not only inhibit Pseudomonas aeruginosa PAK strain-induced inflammatory responses via a negative regulation of the Braf protein that participates in MAPK signaling pathway but also activate the ß2 -adrenegic receptor. These results suggest that CS extract has dual signaling activities with potential clinical application as a novel drug for asthma.
Assuntos
Agonistas de Receptores Adrenérgicos beta 2/química , Anti-Inflamatórios/química , Medicamentos de Ervas Chinesas/química , NF-kappa B/antagonistas & inibidores , Parassimpatolíticos/química , Sinomenium/química , Agonistas de Receptores Adrenérgicos beta 2/farmacologia , Animais , Antibacterianos/química , Antibacterianos/farmacologia , Anti-Inflamatórios/farmacologia , Cromatografia Líquida de Alta Pressão , Medicamentos de Ervas Chinesas/farmacologia , Cobaias , Células HEK293 , Humanos , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Masculino , Espectrometria de Massas , Camundongos Endogâmicos ICR , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Fármacos Neuromusculares/química , Fármacos Neuromusculares/farmacologia , Parassimpatolíticos/farmacologia , Infecções por Pseudomonas/tratamento farmacológico , Pseudomonas aeruginosa/efeitos dos fármacosRESUMO
The Chrysactinia mexicana A. Gray (C. mexicana) plant is used in folk medicine to treat fever and rheumatism; it is used as a diuretic, antispasmodic; and it is used for its aphrodisiac properties. This study investigates the effects of the essential oil of C. mexicana (EOCM) on the contractility of rabbit ileum and the mechanisms of action involved. Muscle contractility studies in vitro in an organ bath to evaluate the response to EOCM were performed in the rabbit ileum. EOCM (1-100 µg·mL(-1)) reduced the amplitude and area under the curve of spontaneous contractions of the ileum. The contractions induced by carbachol 1 µM, potassium chloride (KCl) 60 mM or Bay K8644 1 µM were reduced by EOCM (30 µg·mL(-1)). Apamin 1 µM and charybdotoxin 0.01 µM decreased the inhibition induced by EOCM. The d-cAMP 1 µM decreased the inhibition induced by EOCM. l-NNA 10 µM, Rp-8-Br-PET-cGMPS 1 µM, d,l-propargylglycine 2 mM, or aminooxyacetic acid hemihydrochloride 2 mM did not modify the EOCM effect. In conclusion, EOCM induces an antispasmodic effect and could be used in the treatment of intestinal spasms or diarrhea processes. This effect would be mediated by Ca(2+), Ca(2+)-activated K⺠channels and cAMP.
Assuntos
Íleo/efeitos dos fármacos , Contração Muscular/efeitos dos fármacos , Óleos Voláteis/administração & dosagem , Parassimpatolíticos/administração & dosagem , Óleos de Plantas/administração & dosagem , Animais , Apamina/administração & dosagem , Asteraceae/química , Cálcio/metabolismo , Humanos , Íleo/patologia , Músculo Liso/efeitos dos fármacos , Óleos Voláteis/química , Parassimpatolíticos/química , Óleos de Plantas/química , Cloreto de Potássio/química , CoelhosRESUMO
CONTEXT: Plants of the genus Heracleum L. (Apiaceae) have a long history of being used in traditional medicines for the treatment of alimentary tract disorders, and these biological effects have been ascribed to the presence of furanocoumarins (including bergapten). OBJECTIVES: This study aimed to develop an efficient, preparative, counter-current chromatographic separation of bergapten in order to characterize its spasmolytic activity in isolated rat jejunum strips. MATERIALS AND METHODS: Successful separation of the dichloromethane extract of the fruits of Heracleum leskovii Grossh. was achieved by high-performance countercurrent chromatography (HPCCC) using a two-phase solvent system composed of n-heptane/EtOAc/MeOH/H2O (6:5:6:5, v/v/v/v). The pharmacological assessment of bergapten (0.0001-50 µM) on jejunum smooth muscle strips isolated from rats was conducted under isotonic conditions, following up to three hours of incubation. RESULTS: The separation method was scaled up six-fold from analytical to semi-preparative conditions, affording bergapten of >99% purity in less than 30 min. This permitted bergapten to be available in quantity for spasmolytic tests on isolated jejunum strips from rats. Bergapten caused myorelaxation of the intestine preparations in the concentration range of 0.0001-1 µM. At higher doses, bergapten caused either relaxation or contraction of the smooth muscle. DISCUSSION AND CONCLUSION: Bergapten was successfully isolated by rapid HPCCC and its spasmolytic activity was confirmed, thereby providing a preliminary evidence base for the traditional medicine application. The data suggest that bergapten causes no irreversible changes to intestinal tissue.