Biomedical subjects

S A Watson

Publications and source records attributed to S A Watson.

At least 19 recordsLinked to original sources

PubMed2001

Hypergastrinemia promotes adenoma progression in the APC(Min-/+) mouse model of familial adenomatous polyposis.

Serum hypergastrinemia promotes the growth of colorectal adenocarcinoma. Some colorectal adenomas express cholecystokinin B/gastrin receptor mRNA, and thus hypergastrinemia may increase progression through the adenoma-carcinoma sequence. This was investigated in the multiple intestinal neoplasia APC(Min-/+) mouse. Serum gastrin levels in APC(Min-/+) mice were elevated 5-6-fold by oral administration of omeprazole (75 mg/kg). Terminal tumor burden was monitored by onset of anemia. A labeling index was generated by immunohistochemical detection of bromodeoxyuridine incorporation. Serum gastrin was neutralized by antigastrin antibodies raised in situ by use of a gastrin immunogen, Gastrimmune. Hypergastrinemia resulted in reduced survival of the APC(Min-/+) mice from a median survival of 13 weeks in the controls to 10 weeks following omeprazole treatment (P < 0.00001, log-rank test). The labeling indices of adenomas from the small and large intestines of omeprazole-treated mice were increased 35 and 29%, respectively (P < 0.05 and P < 0.025, respectively). Gastrimmune immunization reversed both the survival effect and the increased proliferation resulting from serum hypergastrinemia. Hypergastrinemia may promote the progression of existing premalignant colonic lesions by increasing proliferation. Clinical investigations should determine whether this occurs in the human scenario, considering the widespread use of proton pump inhibitors.

Adenoma↗

PubMed2000

Antiserum raised against an epitope of the cholecystokinin B/gastrin receptor inhibits hepatic invasion of a human colon tumor.

Serum gastrin is known to be elevated in patients with liver-metastasizing colon cancer; thus, cholecystokinin (CCK) B/gastrin receptors may also be up-regulated. A liver-invasive model of colon cancer was established with the human colonic cell line C170HM2, which expresses the CCKB/gastrin receptor at both the gene and protein level. An antiserum has been derived that is directed against the NH2-terminal 17 amino acids of the human CCKB/gastrin receptor coupled to diphtheria toxoid. The peptide was denoted gastrin receptor protein (GRP) 1. The therapeutic effect of GRP1 antiserum was evaluated on the liver invasion of C170HM2 tumors. Biodistribution studies revealed that GRP1 antiserum localized preferentially within the liver tumors when compared with normal liver tissue (1.5-fold increase after 24 h; P < 0.05). Antiserum against GRP1 inhibited both tumor take rate and final liver tumor weight when compared with treatment with control serum in mice with an increasing tumor burden. Liver tumor weights were reduced from 0.37 to 0.10 gram (P = 0.0155), 1.25 grams to 0.76 gram (P = 0.003) and 1.89 grams to 0.76 gram (P = 0.0068, all Mann-Whitney nonparametric U test). Necrosis and apoptosis were increased in the GRP1 antiserum-treated tumors when compared with control serum-treated tumors. As shown by Western blotting, CCKB/gastrin receptor expression of C170HM2 xenografts after treatment with GRP1 antiserum shifted to a predominantly lower molecular weight form (Mr 45,000) that is known to be an internalized form of the receptor. In conclusion, targeting of the CCKB/gastrin receptor may yield a valuable therapeutic modality for the treatment of advanced colon cancer.

Amino Acid Sequence↗

PubMed2000

Transforming growth factor-alpha-mediated growth pathways in human gastro-intestinal cell lines in relation to the gastrin autocrine pathway.

Epidermal growth factor (EGF) and transforming growth factor-alpha (TGF-alpha) increase transcription of the gastrin gene, and the gastrin peptide may be phosphorylated by EGF-stimulated tyrosine kinase. Our aims were to compare EGF/TGF-alpha interactions in 2 human gastro-intestinal cell lines: MGLVA1, with a strong gastrin autocrine pathway, and C170HM2, with a weak pathway. Both cell lines expressed the TGF-alpha gene. MGLVA1 expressed TGF-alpha protein as determined by immuno-cytochemistry, which was absent in C170HM2. Both cell lines expressed the same level of EGF receptors, as assessed by flow cytometry; however, MGLVA1 did not have enhanced in vitro proliferation in response to EGF or TGF-alpha, unlike C170HM2. The basal growth of MGLVA1 was inhibited by anti-sera against TGF-alpha, the EGF receptor and G17. C170HM2 was not inhibited by any of the anti-sera. Neutralisation of TGF-alpha resulted in undetectable cell-associated progastrin levels in MGLVA1 (untreated had 391.7 fmol/5 x 10(6) cells). The progastrin level of C170HM2 remained unaffected. Tyrosine kinase activity, as assessed by phosphopeptide concentration, of unstimulated MGLVA1 was 2.6 times higher than that of C170HM2 in the cell membrane fraction (0.097 compared to 0.037 microg/mg protein, p < 0.001) and 4.8 times higher in the cytosolic fraction (0.269 compared to 0.056 microg/mg protein, p < 0.05). Following treatment with EGF, the phosphopeptide concentration increased in both the membrane and cytosolic fractions of both cell lines. Tyrphostin B42, which inhibits autophosphorylation of the EGF receptor, inhibited the basal growth of MGLVA1 (IC(50) 1.3 microM) and C170HM2 (9.5 microM, p < 0.05 from MGLVA1). Herbimycin, which inhibits pp60(c-src) kinase, reduced the basal growth of MGLVA1 (0.67 microM) but not C170HM2. Immunofluorescence studies confirmed the presence of tyrosine-phosphorylated proteins and pp60(c-src) within the cytoplasm of unstimulated MGLVA1 cells. There was no specific immunofluorescence for either parameter in C170HM2 cells until after treatment with EGF.

Blotting, Southern↗

PubMed2000

Review article: gastrin and colorectal cancer.

The polypeptide hormone gastrin was identified nearly a hundred years ago and its role in the regulation of acid secretion is well established. Gastrin also acts as a growth factor and is trophic for the normal gastric oxyntic mucosa. This growth promoting action has led to the extensive investigation of its role in carcinogenesis, in particular colorectal neoplasia. The relationship between gastrin and colorectal adenocarcinoma has been subject to controversy, however the findings from several recent studies have resulted in a clearer understanding of the mechanism of action of gastrin in this is common cancer. The majority of colorectal cancers produce their own gastrin, which may act in an autocrine manner. The tumour cells also express gastrin/CCKB receptors (and/or a combination of isoforms) which mediate the proliferative action. This locally produced gastrin gives rise to a small increase in systemic gastrin levels. Autocrine gastrin may also have a role in tumour development, as expression occurs early in the adenoma-carcinoma sequence. In addition, several studies using animal models have shown that systemic hypergastrinaemia promotes the proliferation of both normal and neoplastic colonic epithelium. Hyperproliferative colonic epithelium in the presence of hypergastrinaemia has been recorded in humans and a well-designed epidemiological study has demonstrated an increased incidence of colorectal cancer. Gastrin is a potential therapeutic target in the treatment of colorectal cancer and several approaches have been assessed. Receptor antagonists and antisecretory agents have been demonstrated to be ineffectual. Novel methods of inhibition, including the use of anti-gastrin antibodies, are currently being evaluated.

Amino Acid Sequence↗

PubMed2000

Increased type-IV collagenase (MMP-2 and MMP-9) activity following preoperative radiotherapy in rectal cancer.

The aim of this study was to investigate the effect of preoperative high-dose radiotherapy (25 Gy in 5 fractions over 5 days) on the type-IV collagenase protein profile, in patients with resectable rectal cancer, by gelatin zymography. Biopsy samples of tumour and distant normal mucosa from 12 patients with resectable rectal cancer were obtained pre- and post-radiotherapy. Expression of type-IV collagenases (both pro- and active forms) was studied using gelatin zymography. Enzyme levels were normalized for total protein content of each sample. Rectal cancer specimens expressed both pro (72 kDa) and active (62 kDa) forms of MMP-2 but only the pro form of MMP-9 (92 kDa). Normal mucosa showed expression of the pro forms of MMP-2 and MMP-9 while no active form of either enzyme was detected in any of the samples. A significant three- to fourfold increase (P < 0.01) of active matrix metalloproteinases (MMP)-2 (62 kDa) was seen in malignant rectal mucosa after radiotherapy. The effect of radiotherapy also led to a twofold increase (P = 0.047) of pro MMP-2 (72 kDa) and a two- to threefold increase (P = 0.03) of the precursor form of MMP-9 (92 kDa). In contrast, in normal mucosa expression of the precursor form of MMP-9 (92 kDa) did not change after radiation, and no significant effect on the levels of pro MMP-2 (72 kDa) was observed. Preoperative high-dose radiotherapy leads to an increase in activity of type-IV collagenases in patients with resectable rectal cancer. Type-IV collagenase inhibition may be a useful therapeutic adjunct to radiotherapy in rectal cancer.

Adenocarcinoma↗

PubMed2000

Gastrin and gastrin receptor activation: an early event in the adenoma-carcinoma sequence.

BACKGROUND AND AIMS: Gastrin and the cholecystokinin type B/gastrin receptor (CCKBR) have been shown to be expressed in colorectal adenocarcinoma. Both exogenous and autocrine gastrin have been demonstrated to stimulate growth of colorectal cancer but it is not known if gastrin affects the growth of colonic polyps. The purpose of this study was to determine if gastrin and CCKBR are expressed in human colonic polyps and to determine at which stage of progression this occurs. METHODS: A range of human colonic polyps was assessed for gastrin and CCKBR gene and protein expression. RESULTS: Normal colonic mucosa did not express gastrin or CCKBR. Gastrin and CCKBR reverse transcription-polymerase chain reaction products were detected and verified by specific hybridisation with an oligo probe on Southern blots. Gastrin and CCKBR were expressed in 78% and 81% of polyps, respectively. Both genes were coexpressed in 97% of cases. Immunohistochemistry identified progastrin in 91%, glycine extended gastrin 17 in 80%, and amidated gastrin 17 in only 47% of polyps. CCKBR was present in 96% of polyps. Expression of gastrin and CCKBR was seen in all histological types and sizes of polyps. CONCLUSIONS: This study is the first to show widespread expression of both gastrin and its receptor in colorectal polyps. Their activation occurs early in the adenoma-carcinoma sequence. Gastrin may promote progression through the adenoma-carcinoma sequence.

Adenoma↗

PubMed2000

Phase I/II study of G17-DT, an anti-gastrin immunogen, in advanced colorectal cancer.

Gastrin is a growth factor for colorectal cancer, and therefore, anti-gastrin hormone therapy has a potential role in treatment of this disease. The gastrin immunogen gastrin-17-diphtheria toxoid (G17-DT; Gastrimmune) produces anti-G17 antibodies that have been shown to be effective in the treatment of colorectal carcinoma in preclinical models. Fifty patients with advanced colorectal cancer were treated with G17-DT in a multicenter, sequential group, open label Phase I/II study. Primary injections with two booster doses were given by i.m. injection. The main aim of the study was to assess the safety and efficacy of the production of antigastrin antibodies. Locally developed and standard WHO toxicity measurements with RIA and Scatchard analysis for antibody assessment were used. One center measured tumor response radiologically. Eighty % of patients produced a measurable antibody response. Antibodies of high affinity (median Kd, 0.295 nM; interquartile range, 0.16-0.41 nM) were detected between 4 and 12 weeks after primary injection. The antigen binding capacity was high at 2.8 x 10(-9) M (interquartile range, 5.1 x 10(-10) to 7.25 x 10(-9) M). The treatment was well tolerated with no systemic side effects seen. Myalgia at the injection site was seen in 46% of patients with severe pain caused by the formation of a sterile abscess seen in 14% of patients. The abscesses were all drained under ultrasound guidance, and the patients recovered fully within 6 weeks. No radiological responses were seen, but two patients had stable disease. G17-DT immunization produces anti-G17 antibodies in patients with advanced colorectal cancer. The antibodies were of an affinity high enough to compete with the cholecystokinin B/gastrin receptor for G17 binding with adequate capacity to neutralize postprandial gastrin surges. Additional dose-ranging studies have been performed in patients with gastric cancer using 100- and 200-microg doses of G17-DT formulated without adjuvant and the emulsifier aluminum monostearate. In addition, the effect of immunizing at different time intervals has been determined.

Adult↗

PubMed1999

Demonstration of new sites of expression of the CCK-B/gastrin receptor in pancreatic acinar AR42J cells using immunoelectron microscopy.

The CCK-B/gastrin receptor has been characterised in both normal and tumour tissues. Endocytosis of the CCK-B/gastrin receptor has recently been demonstrated and this has similarly been described for other peptide receptors. In addition, ligand and ligand-receptor translocation to the nucleus has been demonstrated for other peptides. The aim of this study was to identify the sites of expression of the CCK-B/gastrin receptor in the known CCK-B/gastrin receptor bearing pancreatic acinar AR42J cells. The specificity of the CCK-B/gastrin receptor antibody (alpha-CCKBR-Ser antibody) was demonstrated by inhibition ELISA studies, radioligand inhibition studies and immunofluorescence binding studies on AR42J cells. Western blotting and immunogold electron microscopy techniques were used to identify the receptor in AR42J cell preparations. The affinity purified alpha-CCKBR-Ser antibody was shown to be specific for the CCK-B/gastrin receptor. The receptor was expressed on the cell membrane, in the cytoplasm and within the nucleus. Isoforms of the receptor protein identified in extra-nuclear and nuclear extracts ranged in molecular weight from 58 to 66 kDa. We conclude that the CCK-B/gastrin receptor is not only expressed on the cell membrane, but also in the cytoplasm and nucleus of AR42J pancreatic acinar cells.

Animals↗

PubMed1999

A comparison of an anti-gastrin antibody and cytotoxic drugs in the therapy of human gastric ascites in SCID mice.

The therapeutic effect of antibodies raised by the immunogen Gastrimmune was compared with both a CCKB/gastrin receptor antagonist, CI-988, and 5-Fluorouracil/leucovorin in a gastric cancer model. The human gastric ascites cell line, MGLVA1asc, produced and secreted progastrin and glycine-extended gastrin as determined by radioimmunoassay and immunocytochemistry. Cells were also stained with an antiserum directed against the human CCKB/gastrin receptor. MGLVAI asc cells were injected i.p. into SCID mice. Antibodies raised by Gastrimmune immunization of rabbits (affinity for G17 of 0.15 nM and GlyG17 of 0.47 nM) were passively infused i.p. and significantly enhanced survival by up to 5 days (p=0.0024 from vehicle controls). The enhancement in survival was not significantly different from that achieved by treatment with 5-Fluorouracil and leucovorin. A CCKB/gastrin receptor antagonist, CI-988, did not affect survival with cells injected at 7.5 x 10(5) cells/mouse but significantly increased the survival of mice injected with a lower cell innoculum of 5 x 10(5) cells/mouse from 30 to 35 days (p=0.0186). At this lower innoculum antibodies raised by Gastrimmune induced complete survival in 2 animals with the remaining dead by day 36 (p=0.0022). Thus, both endocrine and autocrine pathways mediated by precursor and mature gastrin molecules may be jointly operational in the gastric cancer scenario and may be important targets for therapeutic agents.

Animals↗

PubMed1999

A novel, orally administered nucleoside analogue, OGT 719, inhibits the liver invasive growth of a human colorectal tumor, C170HM2.

OGT 719 is a novel p.o. bioavailable nucleoside analogue in which galactose is incorporated onto the fluoropyrimidine moiety of the cytotoxic agent 5-fluorouracil (5-FU). OGT 719 has been designed to reduce the systemic toxicity normally associated with 5-FU while retaining activity against disease localized in the liver, in which it may be preferentially localized through the asialoglycoprotein receptor (ASGP-R). We report studies confirming the activity of OGT 719 in inhibiting growth of metastatic human colorectal tumors in the liver of nude mice. The human colorectal cancer cell line C170HM2 readily forms liver metastases in vivo. Oral administration of 1500 mg/kg/day OGT 719 inhibited liver tumor burden by 95% compared with vehicle control, without any observable signs of toxicity. When the tumor burden was increased and the same OGT 719 treatment was compared with a standard clinical dose regimen of 25 mg/kg/day 5-FU/leucovorin given i.v., both treatments were equally efficacious, although 5-FU/leucovorin treatment started 7 days earlier. In contrast to 5-FU, OGT 719 is p.o. bioavailable and has a plasma half-life between 1.5 and 3 h. Several colorectal cancer cell lines express the asialoglycoprotein receptor, although no significant levels can be detected in C170HM2 cells, consistent with the observation that OGT 719 is approximately 3 log orders of magnitude less potent in vitro than 5-FU. Flux through thymidylate synthase, as measured by 3H release from [3H]dUrd, was inhibited by OGT 719 at 4 h. The notable difference in the potency of OGT 719 efficacy on C170HM2 cells in vitro and in vivo supports our model of liver-specific activation of OGT 719. As our data suggest, OGT 719 may significantly inhibit growth of metastatic colorectal tumors in the liver in vivo. This hypothesis is presently being explored in clinical trials for primary hepatocellular carcinoma and colorectal liver metastases.

Administration, Oral↗

PubMed1999

Antibodies raised by gastrimmune inhibit the spontaneous metastasis of a human colorectal tumour, AP5LV.

Both precursor forms of gastrin and mature amidated gastrin peptides can enhance proliferation of colorectal tumours and may regulate growth in an autocrine manner. The purpose of this study was to evaluate the effect of neutralization of precursor and amidated gastrin on primary and secondary in vivo growth of a human colorectal tumour. The human colorectal cell line, AP5LV, when injected into the muscle layer of the abdominal wall of severe combined immunodeficient (SCID) mice, grows as a well-vascularized primary tumour and metastasis to the lung. AP5LV expressed the precursor gastrin forms; progastrin and glycine-extended gastrin and gastrin/CCKB receptors, as assessed by immunocytochemistry. Gastrimmune is a gastrin immunogen in which the amino terminus of the gastrin-17 molecule is linked to diphtheria toxoid and induces antibodies which neutralise the amidated and glycine-extended forms of gastrin-17. Rabbit antiserum, raised against Gastrimmune, was administered intravenously into SCID mice bearing AP5LV tumours. Control animals were treated with antiserum raised against diphtheria toxoid only. Antibodies raised against Gastrimmune significantly limited the growth of primary AP5LV tumours, as assessed by median cross-sectional area (controls = 244 mm2; antibody-treated = 179 mm2; P = 0.033). In addition Gastrimmune-induced antiserum limited the growth of lung metastasis as assessed by nodule number (controls = 3.5; antibody-treated = 1.0; P = 0.0001) and nodule cross-sectional as assessed by image analysis (controls = 11.9 mm2; antibody-treated = 3.75 mm2; P = 0.0064). In conclusion in vivo neutralization of gastrin forms, which may potentially be fueling growth by an autocrine pathway, inhibited both primary growth and, to a greater degree, lung metastasis of a human colorectal tumour cell line. Immunization against tumour-associated gastrin forms may provide an effective therapy for advanced colorectal cancer.

Animals↗

PubMed1999

Anti-gonadotrophin releasing hormone antibodies inhibit the growth of MCF7 human breast cancer xenografts.

The human breast cancer cell line (MCF7) was established as xenografts in intact female nude mice. Xenografts did not require oestrogen supplementation for growth, although oestrogen supplementation caused more rapid tumour growth. GnRH Pharmaccine is an immunogen composed of gonadotrophin releasing hormone (GnRH) linked to diphtheria toxoid. Anti-GnRH antibodies purified from the serum of rabbits immunized with GnRH Pharmaccine, were used to passively immunize nude mice. In mice treated with anti-GnRH antibodies, xenograft growth was significantly inhibited relative to controls (median times of 71 and 29 days respectively taken for tumours to attain a predetermined cross-sectional area of 200 mm2, P < 0.001). The inhibition of tumour growth achieved by anti-GnRH antibodies was not significantly different from that produced by the anti-oestrogen, tamoxifen (59 days). Ovarian/uterine weights were reduced by 61% (P < 0.001) in anti-GnRH antibody-treated animals compared with controls. Histologically there was underdevelopment and atrophy of the reproductive organs. Serum levels of both oestrogen and luteinizing hormone were reduced by treatment with anti-GnRH antibodies (to 24.9% and 53% respectively of levels in controls, both P = 0.04). It is postulated that one of the mechanisms by which anti-GnRH antibody treatment inhibits tumour growth is indirectly, by reducing serum oestrogen levels.

Animals↗

PubMed1999

Inhibition of tumour growth by marimastat in a human xenograft model of gastric cancer: relationship with levels of circulating CEA.

Inhibition of matrix metalloproteinases (MMPs) is an attractive approach to adjuvant therapy in the treatment of cancer. Marimastat is the first orally administered, synthetic MMP inhibitor to be evaluated, in this capacity, in the clinic. Measurement of the rate of change of circulating tumour antigens was used for evaluating biological activity and defining optimum dosage in the early clinical trials of marimastat. Although tumour antigen levels have been used in the clinical management of cancer for many years, they have not been validated as markers of disease progression. In order to investigate the relationship between the effects of marimastat on tumour growth and circulating tumour antigen levels, mice bearing the human gastric tumour, MGLVA1, were treated with marimastat. The MMP inhibitor exerted a significant therapeutic effect, reducing tumour growth rate by 48% (P = 0.0005), and increasing median survival from 19 to 30 days (P = 0.0001). In addition, carcinoembryonic antigen (CEA) levels were measured in serum samples from animals sacrificed at regular intervals, and correlated with excised tumour weight. It was shown that the natural log of the CEA concentration was linearly related to the natural log of the tumour weight and that treatment was not a significant factor in this relationship (P = 0.7). In conclusion, circulating CEA levels were not directly affected by marimastat, but did reflect tumour size. These results support the use of cancer antigens as markers of biological activity in early phase trials of non-cytotoxic anticancer agents.

Animals↗

PubMed1999

The changing biological warfare threat. Anti-crop and anti-animal agents.

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Animal Diseases↗

PubMed1999

A comparison of the therapeutic effectiveness of gastrin neutralisation in two human gastric cancer models: relation to endocrine and autocrine/paracrine gastrin mediated growth.

BACKGROUND: Gastrin is a growth factor for established tumours. AIMS: To investigate the therapeutic effect of antibodies, raised against the Gastrimmune immunogen, which neutralise the glycine extended and carboxy amidated forms of gastrin 17 in two human gastric cancer models. METHODS: MGLVA1 cells (which have a gastrin autocrine/paracrine phenotype) and ST16 cells (which have an endocrine phenotype) were injected into the peritoneal cavity of SCID mice. Peritoneal tumours, ascites, and cachexia formation occurred, with the monitored endpoint being morbidity. RESULTS: In MGLVA1 cells, intravenous administration of antibodies raised against Gastrimmune increased the 50% median survived by 25% at three different initial cell seeding concentrations (1 x 10(6)-5 x 10(5) per mouse). In ST16 cells, the effect of Gastrimmune induced antibodies on time to morbidity was greatest at the lowest cell seeding concentration (5 x 10(5) cells/mouse) with the 50% median survival increased by 74% and overall survival achieved in 38% of the mice. CONCLUSIONS: Gastrimmune may have potential therapeutic benefit on gastrin sensitive gastric tumours and may interact with both endocrine and autocrine mediated growth pathways.

Animals↗

PubMed1999

A comparison of the efficacy of long-acting beta 2-agonists: eformoterol via Turbohaler and salmeterol via pressurized metered dose inhaler or Accuhaler, in mild to moderate asthmatics. Force Research Group.

Four hundred and sixty nine patients were randomized to receive either 12 micrograms bd of eformoterol (Oxis, Astra Pharmaceuticals Ltd., Kings Langley, U.K.) delivered via Turbohaler or 50 micrograms bd salmeterol (Serevent, Glaxo-Wellcome Ltd., Uxbridge, U.K.) via either the Accuhaler (Glaxo-Wellcome Ltd.) or pressurized metered dose inhaler (pMDI, Glaxo-Wellcome Ltd.) for 8 weeks. This was followed by a 4-week cross-over period when patients who had received salmeterol in the previous 8 weeks were given eformoterol and patients who had received eformoterol were given either salmeterol via the Accuhaler or pMDI to assess patient device and treatment preference. For the primary efficacy variable, the increase in peak expiratory flow (PEF) rate from run-in to 8 weeks, similar significant improvements were seen in all three treatment groups. Eformoterol Turbohaler (FT) achieved a greater increase in morning PEF than salmeterol Accuhaler (SA) from randomisation to 4 weeks; the increase shown in the eformoterol Turbohaler group was 28.9 1 min-1 compared to 19.91 min-1 for the salmeterol Accuhaler group. The addition of eformoterol Turbohaler 12 micrograms bd, to patients' existing asthma therapy was found to have a significantly more beneficial effect on the severity of patients' daytime asthma symptoms than had salmeterol Accuhaler 50 micrograms bd (P = 0.014). Eformoterol Turbohaler reduced the severity of daytime asthma symptoms by 42% after only 4 weeks of treatment. The patients in the eformoterol Turbohaler treated group experienced a higher percentage of days when they were symptom-free and did not use their short-acting bronchodilator to relieve symptoms (32.8, 24.1 and 28.0% in the FT, SA and SM groups, respectively). At 8 weeks there were no significant differences in any of these variables between the three groups. Patients in all the treatment groups gained an additional 1-1.5 nights undisturbed by asthma per week. The changes in sleep disturbance were not significantly different between the three treatment groups. In addition to the therapeutic benefits provided by eformoterol Turbohaler the device (Turbohaler) was the significant preference of patients given both Turbohaler and pMDI (P = 0.0168) and was also considered to be significantly more convenient to carry around than the Accuhaler (P < 0.0001). No other differences were found between the three devices. The results of this study demonstrate that the addition of a long-acting beta 2-agonist is an effective tool for achieving the goals of asthma treatment. Eformoterol via the Turbohaler is at least as effective as salmeterol via either the Accuhaler or the pMDI in achieving these goals.

Adrenergic beta-Agonists↗

PubMed1999

A comparison of the efficacy of long-acting beta 2-agonists: eformoterol via Turbohaler and salmeterol via pressurized metered dose inhaler or Accuhaler, in mild to moderate asthmatics. Force Research Group.

Four hundred and sixty nine patients were randomized to receive either 12 micrograms bd of eformoterol (Oxis, Astra Pharmaceuticals Ltd., Kings Langley, U.K.) delivered via Turbohaler or 50 micrograms bd salmeterol (Serevent, Glaxo-Wellcome Ltd., Uxbridge, U.K.) via either the Accuhaler (Glaxo-Wellcome Ltd.) or pressurized metered dose inhaler (pMDI, Glaxo-Wellcome Ltd.) for 8 weeks. This was followed by a 4-week cross-over period when patients who had received salmeterol in the previous 8 weeks were given eformoterol and patients who had received eformoterol were given either salmeterol via the Accuhaler or pMDI to assess patient device and treatment preference. For the primary efficacy variable, the increase in peak expiratory flow (PEF) rate from run-in to 8 weeks, similar significant improvements were seen in all three treatment groups. Eformoterol Turbohaler (FT) achieved a greater increase in morning PEF than salmeterol Accuhaler (SA) from randomisation to 4 weeks; the increase shown in the eformoterol Turbohaler group was 28.9 l min-1 compared to 19.9 l min-1 for the salmeterol Accuhaler group. The addition of eformoterol Turbohaler 12 micrograms bd, to patients' existing asthma therapy was found to have a significantly more beneficial effect on the severity of patients' daytime asthma symptoms than had salmeterol Accuhaler 50 micrograms bd (P = 0.014). Eformoterol Turbohaler reduced the severity of daytime asthma symptoms by 42% after only 4 weeks of treatment. The patients in the eformoterol Turbohaler treated group experienced a higher percentage of days when they were symptom-free and did not use their short-acting bronchodilator to relieve symptoms (32.8, 24.1 and 28.0% in the FT, SA and SM groups, respectively). At 8 weeks there were no significant differences in any of these variables between the three groups. Patients in all the treatment groups gained an additional 1-1.5 nights undisturbed by asthma per week. The changes in sleep disturbance were not significantly different between the three treatment groups. In addition to the therapeutic benefits provided by eformoterol Turbohaler the device (Turbohaler) was the significant preference of patients given both Turbohaler and pMDI (P = 0.0168) and was also considered to be significantly more convenient to carry around than the Accuhaler (P < 0.0001). No other differences were found between the three devices. The results of this study demonstrate that the addition of a long-acting B2-agonist is an effective tool for achieving the goals of asthma treatment. Eformoterol via the Turbohaler is at least as effective as salmeterol via either the Accuhaler or the pMDI in achieving these goals.

Administration, Inhalation↗

PubMed1998

Expression of CCKB/gastrin receptor isoforms in gastro-intestinal tumour cells.

Anti-serum raised against the human cholecystokinin B (CCKB)/gastrin receptor was used in Western blotting to differentiate the cellular locations of receptor isoforms expressed by human gastro-intestinal (GI) tumour cell lines. Using anti-serum directed against the amino-terminal extracellular tail of the CCKB/gastrin receptor, 8/9 cell lines were shown to express immunoreactive proteins of either m.w. 70 or 40 kDa, or both. Both isoforms were found to be associated with intracellular, non-nuclear membranes, whereas only the 70 kDa protein was expressed in the plasma membrane. Receptor expression was related to gastrin production and secretion. Both progastrin and glycine-extended gastrin-17 were produced and secreted by the tumour cell lines; however, carboxy amidated gastrin was not detected by radioimmunoassay. A CCKB/gastrin receptor transfectant NIH3T3 cell line did not produce detectable gastrin and showed exclusive expression of the 70 kDa receptor on the plasma membrane. One cell line had <50 pg/ml cell-associated progastrin and no detectable receptor form. Cell lines expressing 50-150 pg/ml had both 40 and 70 kDa receptor forms. Those expressing >150 pg/ml progastrin had only the 40 kDa isoform, which was shown to be exclusively expressed on intracellular, non-nuclear membranes, in one of the cell lines. Of the 4 cell lines exclusively expressing the lower m.w. receptor, 3 had gastrin present within the cell, which was not secreted. Thus, if cell-associated gastrin induces a proliferative effect, it may be by an intracrine pathway. Our study has identified the presence of CCKB/gastrin receptor isoforms in different cellular locations and may help toward understanding the complex autocrine and intracrine pathways mediated by gastrin peptides.

3T3 Cells↗