RESUMEN
Biological products such as protein-based biopharmaceuticals are playing an important role in the healthcare and pharmaceutical industry. The interaction between biological products and packaging materials has become the focus of many studies since it can reduce the effectiveness of biological products. These interactions are heavily influenced by the surface properties and physicochemical nature of the therapeutic agents and the packaging materials. Therefore, it is critical to understand the interactions between packaging materials and biological products in order to design biocompatible packaging materials and develop approaches to minimize adverse interactions. We describe the interactions that occur when using several common packaging materials, including glass and polymer. We discuss the interaction between these materials and biological products such as blood, blood derivatives, recombinant proteins, monoclonal antibodies, and gene therapeutics. We also summarize approaches for overcoming these interactions. Understanding the interactions between biological materials and packaging materials is critical for the development of novel packaging materials that improve the safety of pharmaceutical products.
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Productos Biológicos/química , Embalaje de Productos , Industria Farmacéutica , Vidrio/química , Polímeros/químicaRESUMEN
The link between the nitrogen and one-carbon cycles forms the metabolic basis for energy and biomass synthesis in autotrophic nitrifying organisms, which in turn are crucial players in engineered nitrogen removal processes. To understand how autotrophic nitrifying organisms respond to inorganic carbon (IC) conditions that could be encountered in engineered partially nitrifying systems, we investigated the response of one of the most extensively studied model ammonia oxidizing bacteria, Nitrosomonas europaea (ATCC19718), to three IC availability conditions: excess gaseous and excess ionic IC supply (40× stoichiometric requirement), excess gaseous IC supply (4× stoichiometric requirement in gaseous form only), and limiting IC supply (0.25× stoichiometric requirement). We found that, when switching from excess gaseous and excess ionic IC supply to excess gaseous IC supply, N. europaea chemostat cultures demonstrated an acclimation period that was characterized by transient decreases in the ammonia removal efficiency and transient peaks in the specific oxygen uptake rate. Limiting IC supply led to permanent reactor failures (characterized by biomass washout and failure of ammonia removal) that were preceded by similar decreases in the ammonia removal efficiency and peaks in the specific oxygen uptake rate. Notably, both excess gaseous IC supply and limiting IC supply elicited a previously undocumented increase in nitric and nitrous oxide emissions. Further, gene expression patterns suggested that excess gaseous IC supply and limiting IC supply led to consistent up-regulation of ammonia respiration genes and carbon assimilation genes. Under these conditions, interrogation of the N. europaea proteome revealed increased levels of carbon fixation and transport proteins and decreased levels of ammonia oxidation proteins (active in energy synthesis pathways). Together, the results indicated that N. europaea mobilized enhanced IC scavenging pathways for biosynthesis and turned down respiratory pathways for energy synthesis, when challenged with excess gaseous IC supply and limiting IC supply.
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Carbono/metabolismo , Nitrosomonas europaea/metabolismo , Amoníaco/metabolismo , Nitrógeno/metabolismo , Óxido Nitroso/metabolismoRESUMEN
The objective of the present study was to investigate the effects of processing variables and formulation factors on the characteristics of hot-melt extrudates containing a copolymer (Kollidon® VA 64). Nifedipine was used as a model drug in all of the extrudates. Differential scanning calorimetry (DSC) was utilized on the physical mixtures and melts of varying drug-polymer concentrations to study their miscibility. The drug-polymer binary mixtures were studied for powder flow, drug release, and physical and chemical stabilities. The effects of moisture absorption on the content uniformity of the extrudates were also studied. Processing the materials at lower barrel temperatures (115-135°C) and higher screw speeds (50-100 rpm) exhibited higher post-processing drug content (~99-100%). DSC and X-ray diffraction studies confirmed that melt extrusion of drug-polymer mixtures led to the formation of solid dispersions. Interestingly, the extrusion process also enhanced the powder flow characteristics, which occurred irrespective of the drug load (up to 40% w/w). Moreover, the content uniformity of the extrudates, unlike the physical mixtures, was not sensitive to the amount of moisture absorbed. The extrusion conditions did not influence drug release from the extrudates; however, release was greatly affected by the drug loading. Additionally, the drug release from the physical mixture of nifedipine-Kollidon® VA 64 was significantly different when compared to the corresponding extrudates (f2 = 36.70). The extrudates exhibited both physical and chemical stabilities throughout the period of study. Overall, hot-melt extrusion technology in combination with Kollidon® VA 64 produced extrudates capable of higher drug loading, with enhanced flow characteristics, and excellent stability.
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Pirrolidinas/química , Compuestos de Vinilo/química , Química Farmacéutica/métodos , Portadores de Fármacos/química , Estabilidad de Medicamentos , Calor , Polímeros/química , Solubilidad , Tecnología Farmacéutica/métodosRESUMEN
Millets, small-seeded grasses, are gaining interest for their nutrition and health benefits. This abstract provides a comprehensive overview of millets' pharmacological activities, highlighting their rich bioactive compounds. These compounds, including phenolic compounds, flavonoids, and dietary fibers, contribute to antioxidant effects, safeguarding against chronic diseases. Millets also possess anti-inflammatory properties, potentially alleviating conditions, like arthritis and asthma. They show anti-carcinogenic potential, possibly preventing various cancers' development through mechanisms, like apoptosis induction and inhibiting tumor growth. Moreover, millets offer hypolipidemic and hypoglycemic effects, beneficial for managing conditions, such as dyslipidemia and diabetes. Their high dietary fiber and resistant starch content regulate blood lipids and glucose, reducing the cardiovascular risk. Additionally, millets act as antimicrobials, inhibiting pathogens and serving as natural alternatives to synthetic antimicrobials. They exhibit immunomodulatory effects, enhancing immune function and response. Overall, millets' pharmacological properties, including antioxidant, antiinflammatory, anti-carcinogenic, hypolipidemic, hypoglycemic, antimicrobial, and immunomodulatory traits, position them as functional foods with varied health benefits. Further research can integrate millets into preventive and therapeutic approaches for diverse diseases.
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Suplementos Dietéticos , Humanos , Alimentos Funcionales , Antioxidantes/farmacología , Antioxidantes/uso terapéutico , Animales , Antiinflamatorios/farmacología , Antiinflamatorios/uso terapéutico , Fibras de la Dieta/uso terapéutico , Hipoglucemiantes/uso terapéutico , Hipoglucemiantes/farmacologíaRESUMEN
Despite its remarkable barrier function, the skin remains an attractive site for systemic drug delivery given its easy accessibility, large surface area and the possibility to bypass the gastrointestinal tract and the liver and so modify drug absorption kinetics. The pioneering work of Scheuplein, Higuchi and others in the 1960s helped to explain the processes involved in passive percutaneous absorption and led to the development of mathematical models to describe transdermal drug delivery. The intervening years have seen these theories turned to practice and a significant number of transdermal systems are now available including some that employ active drug delivery. This review briefly discusses the evolution of transdermal therapeutic systems over the years and the potential of newer transdermal technologies to deliver hydrophilic drugs and macromolecules through the skin.
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Sistemas de Liberación de Medicamentos/tendencias , Modelos Teóricos , Absorción Cutánea , Administración Cutánea , Diseño de Fármacos , Humanos , Interacciones Hidrofóbicas e Hidrofílicas , Sustancias Macromoleculares/administración & dosificación , Sustancias Macromoleculares/química , Sustancias Macromoleculares/farmacocinética , Preparaciones Farmacéuticas/administración & dosificación , Preparaciones Farmacéuticas/química , Preparaciones Farmacéuticas/metabolismo , Piel/metabolismo , Tecnología Farmacéutica/tendenciasRESUMEN
Although intermediate filaments are one of three major cytoskeletal systems of vertebrate cells, they remain the least understood with respect to their structure and function. This is due in part to the fact that they are encoded by a large gene family which is developmentally regulated in a cell and tissue type specific fashion. This article is in honor of Ueli Aebi. It highlights the studies on IF that have been carried out by our laboratory for more than 40 years. Many of our advances in understanding IF are based on conversations with Ueli which have taken place during adventurous and sometimes dangerous hiking and biking trips throughout the world.
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Filamentos Intermedios/metabolismo , Filamentos Intermedios/ultraestructura , Animales , Movimiento Celular , Citoesqueleto/metabolismo , Citoesqueleto/ultraestructura , Queratinas/metabolismo , Queratinas/ultraestructura , Fosforilación , Vimentina/metabolismo , Vimentina/ultraestructuraRESUMEN
Transglutaminases (TGs) are known to exhibit remarkable specificities not only for the Q (or Gln) sites but also for the K (or Lys) sites of proteins with which they react. To gain further insight into K-site specificity, we examined the reactions of dansyl-epsilon-aminocaproyl-GlnGlnIleVal with three chemically and structurally well-characterized proteins (bovine pancreatic ribonuclease A, bovine pancreatic trypsin inhibitor, and chicken egg white lysozyme), as catalyzed by TG2, a biologically important post-translational enzyme. The substrates represent a total of 20 potential surface sites for acylation by the fluorescent Gln probe, yet only two of the lysine side chains reacted with TG2. While the K1 site of ribonuclease and the K15 site of the trypsin inhibitor could be readily acylated by the enzyme, none of the lysines in lysozyme were modified. The findings lead us to suggest that the selection of lysine residues by TG2 is not encoded in the primary amino acid sequence surrounding the target side chain but depends primarily on its being positioned in an accessible segment of the protein structure.
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Lisina/metabolismo , Procesamiento Proteico-Postraduccional , Transglutaminasas/metabolismo , Acilación , Animales , Sitios de Unión , Bovinos , Modelos Moleculares , Conformación Proteica , Especificidad por SustratoRESUMEN
The effectiveness of four different electron donors, specifically methanol, ethanol, glycerol, and sulfide (added as Na(2)S), were evaluated in post-denitrifying bench-scale moving bed biofilm reactors (MBBRs). With the requirement for more wastewater treatment plants to reach effluent total nitrogen levels approaching 3 mg/L, alternative electron donors could promote more rapid MBBR startup/acclimation times and increased cold weather denitrification rates compared to methanol, which has been most commonly used for post-denitrification processes due to low cost and effectiveness. While the application of alternative substrates in suspended growth processes has been studied extensively, fixed film post denitrification processes have been designed to use primarily low yield substrates like methanol. Bench-scale MBBRs were operated continuously at 12 degrees Celsius, and performance was monitored by weekly sampling and insitu batch profile testing. Ethanol and glycerol, though visually exhibited much higher biofilm carrier biomass content, performed better than methanol in terms of removal rate (0.9 and 1.0 versus 0.6 g N/m(2)/day, respectively.) Maximum denitrification rate measurements from profile testing suggested that ethanol and glycerol (2.2 and 1.9 g N/m(2)/day, respectively) exhibited rates that were four times that of methanol (0.49 g N/m(2)/day.) Sulfide also performed much better than either of the other three electron donors with maximum rates at 3.6 g N/m(2)/day and with yield (COD/NO(3)-N) that was similar to or slightly less than that of methanol.
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Bacterias/metabolismo , Biopelículas/crecimiento & desarrollo , Transporte de Electrón , Biodegradación Ambiental , Reactores Biológicos , Carbono/metabolismo , Electrones , Nitritos/metabolismo , Factores de Tiempo , Eliminación de Residuos Líquidos/métodos , Contaminantes Químicos del Agua , Purificación del Agua/métodosRESUMEN
BACKGROUND AND PURPOSE: Ephedrine and amphetamine can cause substantial increases in systemic arterial pressure. However, the role of endogenous noradrenaline release in mediating the pressor response to ephedrine is controversial. Studies using pharmacologic agents to decrease the synthesis, storage, and release of catecholamines have supported both a direct and an indirect mechanism of action for ephedrine. The purpose of the present study was to determine if endogenous noradrenaline release is required for cardiovascular responses to ephedrine and amphetamine using a genetic mouse model. EXPERIMENTAL APPROACH: Increases in systemic arterial pressure and heart rate in response to ephedrine and amphetamine were investigated and compared in dopamine beta-hydroxylase knockout (Dbh -/-) mice that cannot synthesize noradrenaline. Dbh +/- littermates have normal noradrenaline and adrenaline tissue levels, and served as controls in all experiments. KEY RESULTS: In Dbh -/- mice the increases in systemic arterial pressure and heart rate in response to i.v. injections of ephedrine were not impaired whereas responses to amphetamine were markedly reduced, when compared with responses in Dbh +/- mice. The pressor response to tyramine was abolished whereas pressor responses to noradrenaline, phenylephrine, dopamine, and angiotensin II were similar in Dbh -/- and Dbh +/- mice. CONCLUSIONS AND IMPLICATIONS: The present results in Dbh -/- mice provide support for the hypothesis that pressor responses to ephedrine are directly mediated whereas responses to amphetamine are dependent on the release of noradrenaline and suggest that Dbh +/- and Dbh -/- mice are useful for the study of direct and indirect mechanisms.
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Dopamina beta-Hidroxilasa/metabolismo , Efedrina/farmacología , Animales , Western Blotting , Catecolaminas/metabolismo , Cromatografía Líquida de Alta Presión , Dopamina beta-Hidroxilasa/genética , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Fentolamina/farmacología , Propranolol/farmacología , Tiramina/farmacologíaAsunto(s)
Baños , Dismenorrea/terapia , Adolescente , Adulto , Terapias Complementarias , Femenino , Calor , Humanos , Dimensión del Dolor , Proyectos Piloto , Resultado del Tratamiento , Adulto JovenRESUMEN
Holarrhena antidysenterica (L.) Wall. ex A. DC. is a medicinal plant abundantly found in India. Its uses are mentioned in the classical Ayurvedic literature and by many folklore claims. The plant is also of extreme economic importance. Its seeds are mainly used as an antidiabetic remedy. All pharmacological and toxicological aspects of this plant are discussed in this review.
RESUMEN
The main objective of this novel study was to develop chlorpheniramine maleate orally disintegrating films (ODF) using hot-melt extrusion technology and evaluate the characteristics of the formulation using in vitro and in vivo methods. Modified starch with glycerol was used as a polymer matrix for melt extrusion. Sweetening and saliva-simulating agents were incorporated to improve palatability and lower the disintegration time of film formulations. A standard screw configuration was applied, and the last zone of the barrel was opened to discharge water vapors, which helped to manufacture non-sticky, clear, and uniform films. The film formulations demonstrated rapid disintegration times (6-11s) and more than 95% dissolution in 5min. In addition, the films had characteristic mechanical properties that were helpful in handling and storage. An animal model was employed to determine the taste masking of melt-extruded films. The lead film formulation was subjected to a human panel for evaluation of extent of taste masking and disintegration.
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Antialérgicos/administración & dosificación , Clorfeniramina/administración & dosificación , Portadores de Fármacos/administración & dosificación , Calor , Tecnología Farmacéutica/métodos , Administración Oral , Adolescente , Adulto , Animales , Antialérgicos/síntesis química , Antialérgicos/metabolismo , Clorfeniramina/síntesis química , Clorfeniramina/metabolismo , Portadores de Fármacos/síntesis química , Portadores de Fármacos/metabolismo , Evaluación Preclínica de Medicamentos/métodos , Femenino , Humanos , Masculino , Ratas , Ratas Sprague-Dawley , Solubilidad , Percepción del Gusto/efectos de los fármacos , Percepción del Gusto/fisiología , Difracción de Rayos X/métodos , Adulto JovenRESUMEN
Land application of wastewater biosolids is both economical and beneficial to resource recycling. However, this environmentally friendly practice can be at risk due to odor complaints. Volatile organic sulfur compounds (VOSCs) including methanethiol, dimethyl sulfide, and dimethyl disulfide, have been identified as major contributors to biosolids odor. In this study, methanogens were shown to play a key role in removing VOSCs and reducing odors, and methane production was related to reduced VOSC production. Factors influencing the growth of methanogens such as the shear during dewatering and storage temperature showed a strong impact on net odor production. Examination of the microbial communities of both bacteria and archaea indicated a simplified archaeal community in biosolids, which is susceptible to environmental perturbations. Therefore, one possible odor control strategy is the preservation and enhancement of the methanogenic population during biosolids storage.
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Bacterias Anaerobias/metabolismo , Euryarchaeota/metabolismo , Odorantes , Aguas del Alcantarillado/microbiología , Compuestos de Sulfhidrilo/metabolismo , Contaminantes Atmosféricos/metabolismo , Bacterias Anaerobias/genética , ADN de Archaea/análisis , ADN Bacteriano/análisis , Euryarchaeota/genética , Metano/metabolismo , Volatilización , Eliminación de Residuos LíquidosRESUMEN
The objective of this study was to develop caffeine citrate orally disintegrating tablet (ODT) formulations utilizing hot-melt extrusion technology and evaluate the ability of the formulation composition to mask the unpleasant bitter taste of the drug using in vitro and in vivo methods. Ethylcellulose, along with a suitable plasticizer, was used as a polymeric carrier. Pore forming agents were incorporated into the extruded matrix to enhance drug release. A modified screw configuration was applied to improve the extrusion processability and to preserve the crystallinity of the API. The milled extrudates were subjected to dissolution testing in an artificial salivary fluid and investigations using e-tongue, to assess the extent of masking of bitter taste of the API. There was an insignificant amount of drug released from the formulation in the salivary medium while over 80% of drug released within 30 min in 0.1N HCl. ODTs were also developed with the extrudate mixed with mannitol and crospovidone. The quality properties such as friability and disintegration time of the ODTs met the USP specifications. The lead extrudate formulations and the ODTs prepared using this formulation were subjected to human gustatory evaluation. The formulations were found to mask the unpleasant taste of caffeine citrate significantly.
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Cafeína/efectos adversos , Citratos/efectos adversos , Gusto/efectos de los fármacos , Cafeína/química , Celulosa/análogos & derivados , Química Farmacéutica , Citratos/química , Portadores de Fármacos , Composición de Medicamentos , Humanos , Plastificantes , Solubilidad , Comprimidos , Percepción del GustoRESUMEN
Oral administration of 5 g of lysine to healthy male volunteers produced a marked and progressive rise in plasma trimethyllysine (TML) from 3 to 24 h after the lysine load. Urinary TML did not register a similar rise. Plasma and urinary carnitine also increased after the lysine load. A similar rise in TML or carnitine was not seen after a 5 g tryptophan load. This suggests that the effect is specific for lysine and is not a nonspecific consequence of amino acid load.
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Lisina/análogos & derivados , Lisina/farmacología , Administración Oral , Adulto , Carnitina/sangre , Carnitina/orina , Humanos , Lisina/sangre , Lisina/orina , Masculino , Factores de Tiempo , Triptófano/farmacologíaRESUMEN
We examined the effects of the divalent cation calcium (Ca2+) and the monovalent cations potassium (K+) and sodium (Na+) and different modalities that affect the fluxes of these cations on immunoreactive secretin (IRS) secretion from canine duodenal mucosa in vitro. In the absence of extracellular Ca2+, the basal IRS secretion was inhibited by 29%. Increased uptake of Ca2+ by passive diffusion and facilitated uptake of Ca2+ by ionophore A23187 had no effect on basal IRS secretion. However, Ca2+ channel blocking agents, LaCl3 and verapamil, inhibited basal IRS secretion by 18 and 33% respectively. High concentrations of extracellular K+ caused a dose-dependent but delayed stimulation of IRS secretion. K+-stimulated IRS secretion was not neurally mediated. Similarly, 9-aminoacridine, which blocks K+ exchange, mimicked the effects of K+. Valinomycin (10(-6) M) inhibited both K+-stimulated and 9-aminoacridine-stimulated IRS secretion. In the absence of extracellular Na+, there was a delayed inhibition of both basal and K+-stimulated IRS secretion. These results suggest that changes in cationic environment are associated with alterations in the secretion of IRS. High extracellular K+ concentration is conducive, and the absence of extracellular Na+ and Ca2+ is inhibitory to IRS secretion.
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Calcio/farmacología , Potasio/farmacología , Secretina/metabolismo , Sodio/farmacología , Aminacrina/farmacología , Animales , Perros , Duodeno/metabolismo , Femenino , Técnicas In Vitro , Mucosa Intestinal/metabolismo , Valinomicina/farmacologíaRESUMEN
We studied the effect of troglitazone on the plasma concentrations of homocysteine (tHcy), the erythrocyte and hepatic concentrations of S-adenosylmethionine (SAM) and S-adenosylhomocysteine (SAH), and the hepatic activities of cystathionine-beta-synthase (C beta S) and methylenetetrahydrofolate reductase (MTHFR) in lean and fatty Zucker rats (a model of insulin resistance). Four groups of female Zucker rats were studied. Troglitazone (200 mg/kg) was administered by gavage daily for 3 weeks to lean and fatty Zucker rats. The other 2 groups served as controls. The blood parameters were determined at days 0, 10, and 21. The hepatic SAM and SAH concentrations and MTHFR and C beta S were measured in the 3-week liver samples. Plasma homocysteine fell significantly in all troglitazone-treated animals from a mean +/- SD of 7.6 +/- 1.5 micromol/L to 4.5 +/- 1.1 micromol/L (P <.02) but not in control animals (5.7 +/-1.8 micromol/L to 5.9 +/- 1.8 micromol/L). The decreases induced by troglitazone in homocysteine were seen in both the lean and the fatty Zucker rats. This was accompanied by significant rises in the hepatic concentrations of SAH and SAM + SAH. In addition, a significant decline in the hepatic SAM/SAH ratio was observed. The mean +/- SD hepatic C beta S (expressed as nmol of cystathionine formed at 37 degrees C) in the troglitazone-treated rats was 1,226 +/- 47 nmol/h/mg protein, which was significantly higher than that in the control group (964 +/- 64 nmol/h/mg protein; P =.03). We conclude that troglitazone lowers plasma homocysteine in insulin-resistant animals. The homocysteine-lowering effects of troglitazone may be mediated in part by a shift in the concentrations of tHcy and its related metabolites from the blood to the liver as well as by an upregulation of hepatic C beta S activity. These data support the hypothesis that insulin may regulate homocysteine metabolism through regulation of hepatic C beta S activity, although activity of other hepatic enzymes not studied here may also contribute to these observations.
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Cromanos/farmacología , Eritrocitos/metabolismo , Homocisteína/sangre , Hígado/metabolismo , S-Adenosilhomocisteína/metabolismo , S-Adenosilmetionina/metabolismo , Tiazoles/farmacología , Tiazolidinedionas , Animales , Cistationina betasintasa/metabolismo , Eritrocitos/efectos de los fármacos , Femenino , Hipoglucemiantes/farmacología , Insulina/sangre , Resistencia a la Insulina/fisiología , Hígado/efectos de los fármacos , Metilenotetrahidrofolato Reductasa (NADPH2) , Obesidad/metabolismo , Oxidorreductasas actuantes sobre Donantes de Grupo CH-NH/metabolismo , Ratas , Ratas Zucker , Delgadez/metabolismo , TroglitazonaRESUMEN
We examined the potential role of protein kinase C in signal transduction induced by gastrin's stimulation of rat colonic epithelium. Protein synthesis ([35S]methionine incorporation into protein) and enzyme activity (decrease in the cytosolic activity) were measured following epithelial stimulation with gastrin. Gastrin (10 nM) increased [35S]methionine incorporation into protein to 265% above maintenance level. The effect of gastrin was comparable to the stimulation induced by phorbol 12-myristate, 13-acetate (PMA), a strong activator of protein kinase C. The increase in protein synthesis induced by gastrin was totally abolished by 1-(5-isoquinolinyl)-2-methylpiperazine, an inhibitor of protein kinase C activity. Gastrin also decreased the cytosolic activity of the enzyme, an index of its activation and subsequent translocation to other cellular compartments. Therefore, we conclude that gastrin may be acting through a protein kinase C mechanism.
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Colon/metabolismo , Gastrinas/farmacología , Isoquinolinas/farmacología , Piperazinas/farmacología , Biosíntesis de Proteínas , Proteína Quinasa C/metabolismo , Acetato de Tetradecanoilforbol/farmacología , 1-(5-Isoquinolinesulfonil)-2-Metilpiperazina , Análisis de Varianza , Animales , Colon/efectos de los fármacos , Colon/enzimología , Epitelio/efectos de los fármacos , Epitelio/enzimología , Epitelio/metabolismo , Técnicas In Vitro , Cinética , Masculino , Metionina/metabolismo , Proteína Quinasa C/antagonistas & inhibidores , Ratas , Ratas EndogámicasRESUMEN
We have compared the effects of the secretin family of peptides and their synthetic fragments on gastric emptying (GE) and small intestinal transit (SIT) using an unanesthetized rat model which simultaneously measures the GE and SIT of both solids and liquids. The meal consisting of 5% polyethylene glycol w/v, 5% Indian ink v/v and 20 non-digestible plastic beads was given intragastrically 10 minutes after the intraperitoneal injection of 0.5 ml of saline or peptides (2 and 5 micrograms/kg). Plasma secretin and the immunospecificity of secretin fragments were determined. In control rats, the t1/2 for the GE of both solids and liquids were 56 +/- 3.8 and 19 +/- 2.3 minutes, respectively. Liquids emptied faster than the solids and liquids travelled ahead of the solids in the intestine. Secretin (5 micrograms/kg) inhibited GE of both solids and liquids by 33-37%. Secretin delayed the SIT of the meal by approximately 35%. Fragments of secretin and of VIP had no effect on GE and SIT of both solids and liquids. The whole molecule of secretin was required to inhibit GE and to delay SIT of solids and liquids. Glucagon, PHI and growth hormone releasing factor (GHRF1-44) inhibited GE and SIT of both solids and liquids. For all peptides tested, the inhibition of SIT was proportional to the inhibition of GE suggesting that the prolongation of SIT was secondary to delayed GE. These observations indicate that the peptides of the secretin family inhibit GE and prolong SIT. Thus, the structural requirement required for the secretin family of peptides to effect their motor actions on the stomach is similar to that required for pancreatic enzyme secretion.
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Vaciamiento Gástrico/efectos de los fármacos , Hormonas Gastrointestinales/farmacología , Tránsito Gastrointestinal/efectos de los fármacos , Intestino Delgado/fisiología , Secretina/farmacología , Animales , Glucagón/farmacología , Hormona Liberadora de Gonadotropina/farmacología , Intestino Delgado/efectos de los fármacos , Masculino , Fragmentos de Péptidos/farmacología , Ratas , Ratas Endogámicas , Secretina/sangre , Factores de Tiempo , Péptido Intestinal Vasoactivo/farmacologíaRESUMEN
We examined the effects of cholinergic, peptidergic and GABAergic agents on secretin secretion from canine duodenal mucosal explants incubated in organ culture media. Carbachol (10(-12) to 10(-4) M), atropine (10(-6) to 10(-4) M), hexamethonium (10(-6) to 10(-4) M), and somatostatin did not alter basal secretion of secretin. Somatostatin (10(-7) to 10(-8) M) inhibited secretin secretion stimulated by pH 4.5. Met, Leu and their D-ala2-analogs inhibited both basal and pH 4.5-stimulated secretin. Naloxone reversed the inhibition caused by met-enkephalin at pH 7.4. GABA (10(-9) to 10(-6) M) stimulated both basal and pH 4.5-stimulated secretin secretion. GABA-stimulated secretin secretion was neuronal in nature, bicuculline sensitive and was mediated via post ganglionic cholinergic neurons. GABA-stimulated secretin secretion was inhibited by both somatostatin and metenkephalin, suggesting that GABA-stimulated secretin secretion may be under the inhibitory control of peptidergic agents as well.