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PubMed1996

Human trefoil peptides: genomic structure in 21q22.3 and coordinated expression.

Trefoil peptides are small secretory proteins characterized by three intrachain disulfide bonds forming the trefoil motif or P-domain. They are abundantly expressed on mucosal surfaces, especially of the gastrointestinal tract. In pathological conditions such as ulcers, metaplasia and neoplasia, their expression is upregulated. Three human trefoil peptides have been described: the estrogen-inducible pS2 protein, the spasmolytic protein and the intestinal trefoil factor. Recently, their role in the maintenance of surface integrity and ulcer healing was discussed. We already mapped the corresponding three genes (BCEI), SML1, TFF3) to the same genomic region (21q22.3). In this paper, we show that the three genes are clustered in a tandemly orientated fashion within 50 kb on a bacterial artificial chromosome (BAC) recombinant. This cluster is located adjacent to D21S19 and the locus order is cen-D21S212-TFF3-SML1-BCEI-D21S19-tel, whereas transcription of all three genes is directed towards the centromere. The gene structure of SML1 exhibits four exons, two of which encode the two separate trefoil motifs. TFF3 and BCEI, both containing one trefoil motif, are composed of three exons each, suggesting gene duplication and exon-shuffling events during evolution. The 5'-flanking region of SML1 was compared to the corresponding region of other trefoil genes. Two motifs with identical sequence and positions are shared between SML1 and BCEI, thus presenting possible targets for stomach-specific gene regulation. Two other motifs are shared within all known human and rat trefoil genes, suggesting a coordinated regulation and/or a common locus-controlling region. Using RT-PCR, a change in the pattern of trefoil gene expression is detected in tissue samples from normal gastric mucosa, hyperplastic polyps, gastric cancer, and gastric cancer cell lines, respectively.

Amino Acid Sequence↗

PubMed1984

An atrial peptide is a potent renal vasodilator substance.

Renal intra-arterial administration of rat atrial extracts elicits a concentration dependent renal vasodilation (independent of prostaglandin or dopamine release) in anesthetized rats. The atrial extracts do not alter skeletal musculature (hindlimb) vascular resistance or systemic arterial blood pressure. The high molecular weight peptide fraction of atrial extracts obtained by gel filtration, reduces renal resistance intra-arterially only after proteolytic activation (in vitro) or following intravenous (i.e., systemic in vivo activation) administration. The low molecular weight peptide fraction of the atrial extract which is active intra-arterially as a renal vasodilator has been further purified to yield two major peptides. The 21 amino acid peptide, designated atriopeptin I, was previously demonstrated to be natriuretic and to relax intestinal but not vascular smooth muscle strips. This peptide exerted little or no intra-arterial effect on renal resistance. The 23 amino acid peptide (the phenylalanine-arginine C terminal extension of atriopeptin I), designated atriopeptin II, was natriuretic and spasmolytic (in vitro) on both intestinal and vascular strips and was a potent renal vasodilator in vivo. Thus, the renal vasodilator activity present in cardiac atrial extracts appears to derive from a proteolytic process which selectively generates the 23 amino acid peptide, atriopeptin II. Further cleavage with the loss of phenylalanine-arginine C-terminal, as occurs with atriopeptin I, markedly suppresses the renal vasodilation.

Animals↗

PubMed1986

George E. Brown memorial lecture. Role of atrial peptides in body fluid homeostasis.

Extracts of mammalian atria, but not ventricles, induce marked diuresis, natriuresis, and reduction in blood pressure when infused systemically in rats and dogs. These extracts also inhibit aldosterone biosynthesis and renal renin release. Natriuretic peptides, 21 amino acids and longer, have been isolated from atria of rodents and man, and share a nearly homologous amino acid sequence at the carboxyterminus. Natriuretic activity resides in a 17-amino acid ring formed by a disulfide bridge, and the C-terminal Phe-Arg appears necessary for full biological potency. The deoxyribonucleic acid-encoding atrial natriuretic peptides have been cloned and the gene structure elucidated. Reduction of the diuretic and natriuretic responses to an acute volume load by right atrial appendectomy first suggested a role for atrial peptides in the physiological response to plasma volume expansion. Subsequently, release of peptides with natriuretic and spasmolytic properties from isolated heart preparations in response to right atrial distension was demonstrated by bioassay and radioimmunoassay. The presence of these peptides in normal rat and human plasma in concentrations of 20-100 pM, and the findings of increased levels in response to acute and chronic plasma volume expansion, rapid atrial tachyarrhythmias, systemic hypertension, congestive heart failure, and renal insufficiency imply that they play an important role in body fluid homeostasis. The mechanisms by which atrial peptides increase renal salt and water excretion are as yet unclear. Renal vascular effects have been consistently demonstrated, and limited evidence for direct actions on tubule ion transport has also been reported recently. In vitro, these peptides cause precontracted vascular and nonvascular smooth muscle to relax, mediated by a direct action on smooth muscle cells. Specific receptors for these peptides have been characterized in crude membranes prepared from whole kidney homogenates and adrenal glomerulosa cells, in intact glomeruli and cultured glomerular mesangial cells, and in intact bovine aortic smooth muscle and endothelial cells. Natriuretic peptides stimulate cyclic guanosine monophosphate accumulation in target tissues, and augment particulate guanylate cyclase activity in membrane fractions, suggesting that cyclic guanosine monophosphate is the second messenger mediating their cellular action.

Aldosterone↗

PubMed1994

Trefoil peptides promote epithelial migration through a transforming growth factor beta-independent pathway.

The trefoil peptides, a recently recognized family of protease-resistant peptides, expressed in a regional specific pattern throughout the normal gastrointestinal tract. Although these peptides have been hypothesized to act as growth factors, their functional properties are largely unknown. Addition of recombinant trefoil peptides human spasmolytic polypeptide (HSP), rat and human intestinal trefoil factor (RITF and HITF) to subconfluent nontransformed rat intestinal epithelial cell lines (IEC-6 and IEC-17), human colon cancer-derived cell lines (HT-29 and CaCO2) or nontransformed fibroblasts (NRK and BHK) had no significant effect on proliferation. However addition of the trefoil peptides to wounded monolayers of confluent IEC-6 cells in an in vitro model of epithelial restitution resulted in a 3-6-fold increase in the rate of epithelial migration into the wound. Stimulation of restitution by the trefoil peptide HSP was enhanced in a cooperative fashion by the addition of mucin glycoproteins purified from the colon or small intestine of either rat or man, achieving up to a 15-fold enhancement in restitution. No synergistic effect was observed by the addition of nonmucin glycoproteins. In contrast to cytokine stimulation of intestinal epithelial cell restitution which is mediated through enhanced TGF beta bioactivity, trefoil peptide, and trefoil peptide-mucin glycoprotein stimulation of restitution was not associated with alteration in concentrations of bioactive TGF-beta and was not affected by the presence of immunoneutralizing anti-TGF beta antiserum. Collectively, these findings suggest that the trefoil peptides which are secreted onto the lumenal surface of the gastrointestinal tract may act in conjunction with the mucin glycoprotein products of goblet cells to promote reestablishment of mucosal integrity after injury through mechanisms distinct from those which may act at the basolateral pole of the epithelium.

Animals↗

PubMed2002

TFF2/SP-deficient mice show decreased gastric proliferation, increased acid secretion, and increased susceptibility to NSAID injury.

Trefoil factor family 2 (TFF2), also known as spasmolytic polypeptide, is a member of the trefoil family of peptides and is expressed primarily in the mucous neck cells of the gastric mucosa. To study the physiologic role of TFF2, we have generated TFF2-deficient mice through targeted gene disruption. Homozygous mutant mice were viable and fertile without obvious gastrointestinal abnormalities. However, quantitative measurements revealed a significant decrease in gastric mucosal thickness and in gastric mucosal proliferation rates. In addition, there was a twofold increase in activated parietal cells resulting in a twofold increase in basal and stimulated gastric acid output and an undetectable serum gastrin level. The TFF2-deficient mice also showed a significant increase in the degree of gastric ulceration after administration of indomethacin. Taken together, these results suggest a physiologic role for TFF2 to promote mucosal healing through the stimulation of proliferation and downregulation of gastric acid secretion.

Alleles↗

PubMed1999

The trefoil gene family are coordinately expressed immediate-early genes: EGF receptor- and MAP kinase-dependent interregulation.

The trefoil gene family of mucus cell-secreted proteins is a critical mediator of gastrointestinal mucosal restitution. Transcription of trefoil genes is induced during mucosal repair, but the regulatory mechanisms involved are unknown. Mice deficient in the intestine-specific peptide intestinal trefoil factor (ITF), in which colonic restitution is lethally impaired, showed reduced expression of the gastric trefoil genes SP and pS2, suggesting that trefoil peptides may individually regulate transcription of the entire family. In gastric cell lines, the trefoils were shown to act in a manner suggestive of immediate-early genes capable of auto- and cross-induction through cis-acting regulatory regions. Trefoil-mediated transcriptional regulation required activation of the Ras/MEK/MAP kinase signal transduction pathway. EGF receptor (EGF-R) activation was also necessary for trefoil auto- and cross-induction, and both spasmolytic polypeptide (SP) and ITF stimulation of gastric cell lines led to phosphorylation of EGF-R. Nevertheless, ITF and ITF-thioredoxin cell surface binding at 4 degrees C colocalized not with EGF-R, but with CD71, which is found in clathrin-coated pits, suggesting that integration of trefoil peptide responses may occur after internalization. As EGF-R expression is itself strongly induced after mucosal damage, the trefoil/EGF-R relationship may be pivotal in the generation and maintenance of the mucosal repair phenotype.

Animals↗

PubMedDate not supplied

A multiple-dose, double-blind comparison of intramuscularly and orally administered ketorolac tromethamine and Ketogan in patients with pain following orthopaedic surgery.

In this multiple-dose, double-blind study 100 patients with moderate, severe or very severe pain following orthopaedic surgery were randomly assigned to receive ketorolac, a non-steroidal anti-inflammatory drug with potent analgesic properties (10 mg), or the standard regimen of Ketogan (a combination product containing the narcotic analgesic, ketobemidone, plus a spasmolytic agent) by intramuscular injection every 1-6 h as needed for pain. When patients were able to tolerate an oral diet and were expected to respond to oral analgesic medication, based on overall pain sensitivity, they were switched to oral doses of the same medication every 4-6 h as needed. A maximum of four daily doses of medication was allowed for up to 10 days. The severity of pain was scored on a five-point scale and was recorded before the first intramuscular dose, at fixed time points thereafter for up to 6 h and at the end of each day. Both treatments were effective immediately after the first dose and during the subsequent multiple-dose phase. There were no statistically significant differences between ketorolac and Ketogan. The results show that 10-mg doses of ketorolac in intramuscular injections followed by 10-mg doses of oral ketorolac are as effective as Ketogan for the treatment of pain following orthopaedic surgery. Ketorolac appears to be better tolerated than Ketogan since significantly fewer patients reported adverse events (P = 0.004) when taking ketorolac.

Administration, Oral↗

PubMed1983

Study of serum levels, venous irritation and gastrointestinal side-effects with intravenous erythromycin lactobionate in patients with bronchopulmonary infection.

Sixteen patients with bronchopulmonary infection received 500 mg erythromycin lactobionate by intravenous infusion every 8 h for 2 days. The duration of infusion was either 30 (8 patients) or 60 min (8 patients). An inline filterset (0.22 micrometer) was included in the intravenous administration set in 4 patients of each infusion group. Serum erythromycin levels were obtained before and at various times for 8 h after the first and fourth doses and before and immediately after the other doses. The incidence and severity of venous irritation and gastrointestinal side-effects were assessed. Mean (S.D.) peak erythromycin levels for the 30 min infusion were 26.31 (6.89) micrograms/ml (first dose) and 26.85 (6.11) micrograms/ml (fourth dose) and for the 60 min infusions, 23.96 (7.91) micrograms/ml (first dose) and 23.65 (6.55) micrograms/ml (fourth dose). Venous irritation was experienced by 12 patients, ranging from localized discomfort to thrombophlebitis, but the severity was significantly reduced by inline filtration (P less than 0.005). Gastrointestinal side-effects were reported by 8 patients and 1 patient withdrew because of severe abdominal pain and nausea. These symptoms were usually relieved by spasmolytic agents and possibly could be explained by high concentrations reaching the gut wall either by biliary excretion or direct transport from blood and stimulating smooth muscle motility.

Aged↗

PubMed1995

Fenoverine-induced rhabdomyolysis.

Fenoverine is a spasmolytic drug that inhibits calcium channel currents. We describe the clinicopathologic findings in two patients with fenoverine-induced rhabdomyolysis, of whom one died. A transient left-bundle-branch block was observed in both patients. In one case, pre-existing hepatic dysfunction may have induced accumulation of the drug. Concurrent treatment by fibrates, as observed in the second patient, may have been a predisposing factor for fenoverine-induced rhabdomyolysis. The incidence of muscular complications of fenoverine therapy could be reduced by avoidance of prescription of the drug in patients with hepatopathy or those being treated with cholesterol-lowering agents. Physicians should be aware of life-threatening adverse effects of apparently innocuous drugs.

Aged↗

PubMedDate not supplied

Calcium-channel blockers in acute myocardial infarction.

The calcium-channel blockers are useful in treating a variety of cardiovascular disorders. Due to their antiischemic and spasmolytic properties, these agents have been studied in the prophylaxis and treatment of acute myocardial infarction. This article reviews this application with respect to reduction of mortality, infarct size, and reinfarction rate. Of the agents currently available for clinical use, nifedipine has been studied most extensively. This agent shows no beneficial effects in this setting and its use may in fact be harmful. Of the few trials that have been conducted with verapamil, none have shown decreased mortality. Verapamil may reduce infarct size although further confirmation is required. Diltiazem is the only agent that has been shown to have short- and long-term benefits in the patient with acute myocardial infarction. Proper patient selection is of utmost importance in ensuring successful therapy. In particular, those patients with non-Q-wave infarctions and/or normal left ventricular function can be expected to derive the most benefit in terms of reducing mortality and reinfarction rate associated with the acute event.

Calcium Channel Blockers↗

PubMed1990

Intramuscular diclofenac sodium versus intravenous Baralgin in the treatment of renal colic.

A comparative, randomized, double-blind study of diclofenac sodium 75 mg im versus Baralgin (a combination drug composed of dipyrone and two spasmolytics) 5 mL iv was performed on 57 patients with renal colic. Both groups were comparable as to age, sex, pain evolution time before treatment, and no treatment for renal colic in the six hours preceding trial drug administration. No significant differences were found between the two groups with respect to the evolution of pain after the first dose or in the frequency of administration of a second dose. Tolerability was good in both groups, but sweating and pain throughout the vein were observed in one patient in the Baralgin group. We concluded that diclofenac sodium constitutes an excellent alternative to pyrazolone analgesics, with the advantages of being monotherapy and having good tolerability, when used as intramuscular injection in ambulatory patients.

Adult↗

PubMedDate not supplied

Relative potency of the atropine-like effects of a new parasympatholytic drug, scopolamine-N-(cyclopropyl methyl) bromide and those of hyoscine-N-butyl bromide.

A double-blind crossover trial with a 4-point bioassay was carried out in 8 convalescent in-patients to study the relative potency of scopolamine-N-(cyclopropyl methyl) bromide (DA 3177), a new parasympatholytic drug, administered at doses of 2.5 mg and 5 mg i.v., and hyoscine-N-butyl bromide, administered at doses of 10 mg and 20 mg i.v., in producing atropine-like effects. The results showed that the effects on heart rate and near point of accommodation were slightly less with DA 3177, while its effects on salivary secretion were a little greater than those of hyoscine-N-butyl bromide. It is suggested that study of the pharmacodynamic effects of parasympatholytic drugs is a relatively simple way of predicting which doses should be effective spasmolytically.

Accommodation, Ocular↗

PubMed1983

Investigation of possible interaction between pinaverium bromide and digoxin.

A single-blind study was carried out in 25 patients, who were receiving maintenance therapy for congestive heart failure with digoxin, to investigate the effect on steady-state plasma digoxin levels of concomitant administration of the spasmolytic, pinaverium bromide (50 mg 3-times daily). Patients received pinaverium bromide for 12 days followed by placebo for a further 7 days. Assessment of the results in 21 patients showed no evidence of any statistically significant variations in plasma digoxin levels during either treatment period or in the clinical observations which might indicate drug interaction.

Adult↗

PubMed1986

Investigation of drug interactions with pinaverium bromide.

A series of studies was carried out at 6 centres to investigate possible drug interaction between the spasmolytic, pinaverium bromide, and cardiac glycosides, anticoagulants and hypoglycaemic agents given to patients as part of the long-term treatment of their condition. The results of clinical and laboratory investigations did not show any evidence of pinaverium bromide interfering with the action or activity of any of the drugs studied.

Acenocoumarol↗

PubMed1988

Electrophysiological study of intravenous pinaverium bromide in cardiology.

Pinaverium bromide is a musculotropic spasmolytic agent which acts by inhibiting transmembrane calcium movements, an effect similar to that of verapamil. Because of this, an investigation was carried out to see if it had any electrophysiological effects in patients with various cardiac disorders. In an open study, 10 patients received 2 mg pinaverium bromide intravenously. In a double-blind study, 10 patients received 4 mg pinaverium bromide intravenously and 10 patients placebo. Patients included those with either normal or pathological basal conduction, such as bundle-branch block and 1st degree atrioventricular block. Measurements were made of electrophysiological parameters before and 10 minutes after injection. The results showed that neither of the two doses of pinaverium bromide had any effect on atrial excitability, sino-atrial conduction, node and trunk atrioventricular conduction or on intraventricular conduction. No significant difference was seen in comparison with placebo. Pinaverium bromide had no anti-arrhythmic properties in these studies. Local, cardiac and general clinical tolerability was good in all patients.

Aged↗

PubMed2002

Antineoplastic activity of Solidago virgaurea on prostatic tumor cells in an SCID mouse model.

Solidago virgaurea (goldenrod) has traditionally been used as an anti-inflammatory herbal medicine for the treatment of various symptoms, including prostatic diseases. The plant has also been reported to have antibacterial, spasmolytic, and carminative properties. During the course of our screening for antineoplastic activities in various herbal plants, we found that the extract of S. virgaurea exhibits strong cytotoxic activities on various tumor cell lines. The active component mostly resides in the leaves of the plant and is soluble in water. When the extract was fractionated by a Sephadex G-100 column, the active fraction corresponded to a molecular weight of approximately 40,000. This cytotoxic activity is effective on various tumor cell lines, including human prostate (PC3), breast (MDA435), melanoma (C8161), and small cell lung carcinoma (H520). To examine the effect of the cytotoxic activity on tumor cells in vivo, we used the rat prostate cell line (AT6.1) and an SCID mouse model. AT6.1 cells were injected into the flank of SCID mice, and then the G-100 fraction of S. virgaurea was administered intraperitoneally or subcutaneously every 3 days. The size of the tumor was measured for up to 25 days. The growth of the tumor was significantly suppressed by the G-100 fraction at 5 mg/kg without any apparent side effects. Therefore, S. virgaurea is considered to be promising as an antineoplastic medicine with minimal toxicities.

Animals↗

PubMed1985

Dehydration-induced alterations in rat brain vasopressin and atrial natriuretic factor immunoreactivity.

Potent natriuretic and spasmolytic peptides present in cardiac extracts recently have been identified. These atrial natriuretic factors (ANF) exert vascular and renal actions quite contrary to those of vasopressin (AVP). The ability of ANF to inhibit AVP secretion suggested a role for the peptides in the control of AVP release. The present studies report the measurement of ANF-like immunoreactivity within brain regions associated with the hypothalamo-neurohypophyseal tract and demonstrate significant water deprivation-induced reductions in ANF content of several structures (neural lobe, organum vasculosum lamina terminalis, suprachiasmatic and supraoptic nuclei) but not in others (median eminence, paraventricular nucleus, cortex and pituitary). The data suggest the production of ANF-like peptides within the brain and, further, the involvement of central ANF in extracellular fluid volume regulation.

Animals↗

PubMed2004

Melissa officinalis L. essential oil: antitumoral and antioxidant activities.

Melissa officinalis L (lemon balm) is a traditional herbal medicine used widely as a mild sedative, spasmolytic and antibacterial agent. This paper focuses on the analysis of the chemical composition and the biological activities of M. officinalis essential oil obtained under controlled harvesting and drying conditions. An in-vitro cytotoxicity assay using MTT indicated that this oil was very effective against a series of human cancer cell lines (A549, MCF-7, Caco-2, HL-60, K562) and a mouse cell line (B16F10). This oil possessed antioxidant activity, as evidenced by reduction of 1,1-diphenyl-2-picryl-hydrazyl (DPPH). These results pointed to the potential use of M. officinalis essential oil as an antitumoral agent.

Animals↗