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PubMed2001

Abrupt rate accelerations or premature beats cause life-threatening arrhythmias in mice with long-QT3 syndrome.

Deletion of amino-acid residues 1505-1507 (KPQ) in the cardiac SCN5A Na(+) channel causes autosomal dominant prolongation of the electrocardiographic QT interval (long-QT syndrome type 3 or LQT3). Excessive prolongation of the action potential at low heart rates predisposes individuals with LQT3 to fatal arrhythmias, typically at rest or during sleep. Here we report that mice heterozygous for a knock-in KPQ-deletion (SCN5A(Delta/+)) show the essential LQT3 features and spontaneously develop life-threatening polymorphous ventricular arrhythmias. Unexpectedly, sudden accelerations in heart rate or premature beats caused lengthening of the action potential with early afterdepolarization and triggered arrhythmias in Scn5a(Delta/+) mice. Adrenergic agonists normalized the response to rate acceleration in vitro and suppressed arrhythmias upon premature stimulation in vivo. These results show the possible risk of sudden heart-rate accelerations. The Scn5a(Delta/+) mouse with its predisposition for pacing-induced arrhythmia might be useful for the development of new treatments for the LQT3 syndrome.

Adrenergic beta-Agonists↗

PubMed1997

Lenograstim administration to HLA-identical donor-recipient pairs to accelerate marrow recovery post-transplant.

In an attempt to accelerate marrow recovery after HLA-identical sibling bone marrow transplantation, the donors of 12 patients with haematological malignancy were given recombinant human granulocyte colony-stimulating factor (rHuG-CSF; lenograstim; Granocyte) 5 micrograms/kg/day for seven doses prior to marrow harvest. All 12 recipients also received lenograstim 5 micrograms/kg/day from the day of transplant until their neutrophil count was 1.0 x 10(9)/1. In addition to lenograstim post-transplant and lenograstim-stimulated donor bone marrow the first six recipients also received donor peripheral blood stem cells that had been enriched for CD34+ stem/progenitor cells and T cell depleted on an immune absorption column (cohort 1). The second six patients (cohort 2) received lenograstim post-transplant and lenograstim-stimulated donor marrow only. All 12 patients showed a marked elevation of their circulating white blood cell count (predominantly neutrophils) on day 1 post-transplant. Compared to carefully matched historical control patients the rate of neutrophil engraftment was significantly accelerated in both patient cohorts and platelet engraftment was accelerated in cohort 2.

Adjuvants, Immunologic↗

PubMed1998

Bax-alpha promotes apoptosis induced by cancer chemotherapy and accelerates the activation of caspase 3-like cysteine proteases in p53 double mutant B lymphoma Namalwa cells.

Stable transfected human p53 (mt/mt) B lymphoma Namalwa variant lines showing differential expression of the Bax-alpha protein were derived under hygromycin selection. Overexpression of Bax-alpha in these variant cells accelerates cell death induced by short or continuous treatments with various concentrations of camptothecin, etoposide, vinblastine and shows no accelerating cell death activity in cis-platinum and paclitaxel-treated cells. Activation of apoptosis and oligonucleosome-sized DNA fragmentation was observed in the variant lines with more pronounced effect in cells containing high level of Bax-alpha protein. These results suggest that increased cell death mediated by anticancer drugs correlates with Bax-alpha level of expression and that Bax-alpha sensitizes Namalwa cells treated at low drug concentrations. The extent of DNA synthesis inhibition following DNA topoisomerase inhibitor treatments was similar in control and all transfected Namalwa cells suggesting that Bax-alpha acts downstream of DNA topoisomerase-mediated DNA strand breaks. To define further the relation between Bax-alpha expression and apoptosis activation, kinetics of caspase activation was measured in drug-treated cells. Caspase activities were measured using specific fluorogenic peptide derivatives DABCYL-YVADAPV-EDANS and Ac-DEVD-AMC, substrates of the caspase 1-like and caspase 3-like families, respectively. In control and Bax-alpha transfected Namalwa cells no increase in caspase 1-like activity was detected following camptothecin and etoposide treatments. In contrast, a significant difference in Ac-DEVD-AMC hydrolysis activity was observed in Bax-alpha transfected Namalwa cells compared to that of control Namalwa cells after camptothecin and etoposide treatment. Increased caspase 3-like activity correlated also with poly(ADPribosyl) polymerase cleavage. Taken together, these results suggest that Bax-alpha sensitize B lymphoma cells to series of anticancer drugs and accelerates the activation of apoptotic protease cascade.

Antineoplastic Agents↗

PubMed2006

Cardiolipin deficiency releases cytochrome c from the inner mitochondrial membrane and accelerates stimuli-elicited apoptosis.

Cardiolipin (CL) is a mitochondria-specific phospholipid synthesized by CL synthase (CLS). We describe here a human gene for CLS and its analysis via RNAi knockdown on apoptotic progression. Although mitochondrial membrane potential is unchanged in cells containing only 25% of the normal amount of CL, free cytochrome c (cyt. c) is detected in the intermembrane space and the mitochondria exhibit signs of reorganized cristae. However, the release of cyt. c from the mitochondria still requires apoptotic stimulation. Increased sensitivity to apoptotic signals and accelerated rates of apoptosis are observed in CL-deficient cells, followed by elevated levels of secondary necrosis. Apoptosis is thought to progress via binding of truncated Bid (tBid) to mitochondrial CL, followed by CL oxidation which results in cyt. c release. The exaggerated and accelerated apoptosis observed in CL-deficient cells is matched by an accelerated reduction in membrane potential and increased cyt. c release, but not by decreased tBid binding. This study suggests that the CL/cyt. c relationship is important in apoptotic progression and that regulating CL oxidation or/and deacylation could represent a possible therapeutic target.

Animals↗

PubMed2006

Genetic susceptibility to polyI:C-induced IFNalpha/beta-dependent accelerated disease in lupus-prone mice.

Systemic lupus erythematosus (SLE) is an autoimmune disease of unknown etiology. Associations between viral infections and the onset of SLE have been suggested, and recent studies have provided evidence that type I interferons (IFNalpha/beta) might play a role in the SLE disease process. Viruses and interferons have also been implicated in mouse models of SLE. We generated a model of accelerated proteinuria, in which lupus-prone mice were injected repeatedly with polyinosinic:polycytidylic acid (polyI:C), mimicking exposure to virus-derived double stranded RNA (dsRNA), leading to the production of IFNalpha/beta. PolyI:C-treated (B6.Nba2 x NZW)F1 and (B6 x NZW)F1 hybrid mice developed significantly increased levels of anti-dsDNA autoantibodies, characteristic of lupus. Most significantly, polyI:C-treated (B6.Nba2 x NZW)F1 mice, but not (B6 x NZW)F1 or parental strains, developed lupus-like nephritis in an accelerated fashion, which was dependent on IFNalpha/beta and associated with elevated deposition of total IgG, IgG2a and complement factor C3 in the glomerular capillary walls. These data suggest that reagents, which increase the levels of endogenous IFNalpha/beta (directly or indirectly), can accelerate the course of lupus-like nephritis, the development of which is dependent on the presence of both NZW- and Nba2-encoded genes.

Animals↗

PubMed2006

Local RANKL gene transfer to the periodontal tissue accelerates orthodontic tooth movement.

It has been reported that not only selective alveolar-bone resorption, but also receptor activator of nuclear factor kappa B ligand (RANKL) expression is induced on the compressed side of an orthodontically moving tooth. Numerous reports have described the pharmacological acceleration of tooth movement (TM) through the activation of osteoclasts. However, because of rapid flush out by blood circulation, daily systemic administration or daily local injection is needed. Previously, we discovered that every-3-days OPG gene transfer to the periodontal-tissue inhibited RANKL-mediated osteoclastogenesis and diminished experimental TM. Therefore, we hypothesized that local RANKL gene transfer into the periodontal tissue would accelerate TM. The upper first molars of 6-week-old male Wistar rats were moved palatally using fixed orthodontic wires. The inactivated hemagglutinating-virus of Japan (HVJ) envelope vector containing the mouse RANKL expression plasmid was injected periodically into the palatal periodontal tissue of the upper first molars during TM. Local RANKL gene transfer significantly enhanced RANKL expression and osteoclastogenesis in periodontal tissue without any systemic effects. The TM rate was significantly increased in the RANKL gene transfer side. In conclusion, we demonstrated that transfer of the RANKL gene to the periodontal-tissue activated osteoclastogenesis and accelerated the amount of experimental TM. Local RANKL gene transfer might be a useful tool not only for shortening orthodontic treatment, but also for moving ankylosed teeth where teeth, fuse to the surrounding bone.

Animals↗

PubMed2006

The accelerating effect of histamine on the cutaneous wound-healing process through the action of basic fibroblast growth factor.

This study revealed that the absence of histamine in histidine decarboxylase gene-knockout (HDC(-/-)) mice resulted in delayed cutaneous wound healing and that exogenously administered histamine compensated this process. With the overproduction of histamine in HDC gene-transgenic mice, the healing was accelerated compared to the HDC(+/+) mice. These results indicate that histamine positively accelerated the cutaneous wound healing. Macrophage recruitment and angiogenesis at the wound edge were specifically impaired in HDC(-/-) mice, and histamine-treated wounds in HDC(-/-) mice demonstrated increased macrophage recruitment and angiogenesis. The amount of basic fibroblast growth factor (bFGF) in protein level at the wound edge was higher in HDC(+/+) mice, especially on the 3rd and 5th day of wound healing compared to those in HDC(-/-) mice. Topically administered SU5402, a specific antagonist to fibroblast growth factor receptor-1 tyrosine kinase, to the wound surface suppressed the wound healing in HDC(+/+) mice but not in HDC(-/-) mice. Moreover, SU5402 reduced macrophage recruitment and angiogenesis in HDC(+/+) mice. From these observations, it was concluded that the accelerated wound-healing activity of histamine was mediated by the activity of bFGF, which leads to angiogenesis, and macrophage recruitment in the wound-healing process.

Angiogenesis Inhibitors↗

PubMed1997

Bak can accelerate chemotherapy-induced cell death independently of its heterodimerization with Bcl-XL and Bcl-2.

Bak has been shown to both promote apoptosis and to inhibit cell death while two other members of the Bcl-2 family of proteins, Bcl-XL and Bcl-2 delay apoptosis induced by various stimuli including chemotherapeutic agents. We generated clones with stable expression of Bak wild-type (wt) and Bak with its BH3 (delta78-86) domain deleted (deltaBH3) in FL5.12 cells or FL5.12 cells expressing either Bcl-XL or Bcl-2 to determine if Bak could accelerate apoptosis and antagonize the death repressor activity of Bcl-XL and Bcl-2 during chemotherapy-induced apoptosis. We found that Bak accelerated cell death in FL5.12 cells treated with etoposide, fluorouracil or taxol. In FL5.12 cells expressing Bcl-XL and Bak wt or Bak deltaBH3, both Bak wt or Bak deltaBH3 were able to antagonize the protective effect of Bcl-XL when treated with etoposide or fluorouracil. Bak wt or Bak deltaBH3 were also able to abrogate the protective effect of Bcl-2 in cells expressing Bcl-2 and Bak wt or Bak deltaBH3 when challenged by etoposide or fluorouracil. Immunoprecipitation studies revealed that deletion of BH3 disrupted heterodimerization between Bak and Bcl-XL and that both Bak wt and Bak deltaBH3 failed to interact with Bcl-2. These results demonstrate that Bak does not require its BH3 domain to promote apoptosis in stably transfected cells. Furthermore, Bak can accelerate chemotherapy-induced cell death independently of its heterodimerization with Bcl-XL and Bcl-2.

Antineoplastic Agents↗

PubMed1998

Transgenic N-myc mouse model for indolent B cell lymphoma: tumor characterization and analysis of genetic alterations in spontaneous and retrovirally accelerated tumors.

Little is known about stepwise deregulation of specific genes leading to lymphoid malignancy. Aberrant myc gene expression in transgenic mice is correlated with B cell lymphomagenesis. We generated a unique transgenic mouse model in which deregulated murine E mu-N-myc transgene expression leads to development of indolent B cell lymphoma. Tumor cells were monoclonal, morphologically mature and surface immunoglobulin expressing B cells. Tumors arose in a disease course and exhibited a cytoarchitectural appearance reminiscent of human follicular lymphoma. Yet tumor cells were staged as preB since they failed to rearrange the immunoglobulin light chain genes. Retroviral insertion mutagenesis analyses of adult transgenic mice infected as newborns with murine leukemia virus revealed decreased disease latency, increased lymphoma incidence and a histologically more mature tumor type. Proviral insertion sites were not equivalent when accelerated E mu-N-myc indolent lymphomas were compared to accelerated c-myc preB cell lymphomas. The bcl-2 gene was not disrupted in either spontaneous or provirally accelerated E mu-N-myc lymphomas. These findings suggest that tumor progression in N-myc-associated indolent B cell lymphoma can proceed along diverse pathways involving distinctly different combinations of deregulated and/or intact genes than those pathways described in highly aggressive forms of myc-related murine preB cell disease.

Animals↗

PubMed2006

Sustained trophism of the mammary gland is sufficient to accelerate and synchronize development of ErbB2/Neu-induced tumors.

Epidemiological studies indicate that parity enhances HER2/ErbB2/Neu-induced breast tumorigenesis. Furthermore, recent studies using multiparous, ErbB2/Neu-overexpressing mouse mammary tumor virus (MMTV-Neu) mice have shown that parity induces a population of cells that are targeted for ErbB2/Neu-induced transformation. Although parity accelerates mammary tumorigenesis, the pattern of tumor development in multiparous MMTV-Neu mice remains stochastic, suggesting that additional events are required for ErbB2/Neu to cause mammary tumors. Whether such events are genetic in nature or reflective of the dynamic hormonal control of the gland that occurs with pregnancy remains unclear. We postulated that young age at pregnancy initiation or chronic trophic maintenance of mammary epithelial cells might provide a cellular environment that significantly increases susceptibility to ErbB2/Neu-induced tumorigenesis. MMTV-Neu mice that were maintained pregnant or lactating beginning at 3 weeks of age demonstrated accelerated tumorigenesis, but this process was still stochastic, indicating that early pregnancy does not provide the requisite events of tumorigenesis. However, bitransgenic mice that were generated by breeding MMTV-Neu mice with a luteinizing hormone-overexpressing mouse model of ovarian hyperstimulation developed multifocal mammary tumors in an accelerated, synchronous manner compared to virgin MMTV-Neu animals. This synchrony of tumor development in the bitransgenic mice suggests that trophic maintenance of the mammary gland provides the additional events required for tumor formation and maintains the population of cells that are targeted by ErbB2/Neu for transformation. Both the synchrony of tumor appearance and the ability to characterize a window of commitment by ovariectomy/palpation studies permitted microarray analysis to evaluate changes in gene expression over a defined timeline that spans the progression from normal to preneoplastic mammary tissue. These approaches led to identification of several candidate genes whose expression changes in the mammary gland with commitment to ErbB2/Neu-induced tumorigenesis, suggesting that they may either be regulated by ErbB2/Neu and/or contribute to tumor formation.

Animals↗

PubMed1986

The acceleration of the inhibition of platelet prothrombinase complex by heparin.

The influence of heparin on the inhibition of factor Xa has been studied under conditions where factor Xa is bound to collagen-thrombin-stimulated platelets to form the prothrombinase complex. Unfractionated heparin was found to cause a concentration-dependent acceleration of the inhibition of the platelet prothrombinase complex up to a maximum rate constant of 4.1 X 10(7) M-1 X min-1 at heparin concentrations of 0.2 microM and above. This is equivalent to a 4800-fold acceleration over the rate constant for the inhibition in the absence of heparin, and is 6.8-fold lower than the rate constant for the inhibition of uncomplexed factor Xa in the presence of saturating concentrations of heparin which was determined as 2.8 X 10(8) M-1 X min-1. The effects of three Mr fractions of heparin were also studied. These were a gel-filtered heparin of Mr 15000, a gel-filtered heparin of Mr 6000 and a heparin oligosaccharide (primarily 8-10 monosaccharide units) prepared by nitrous acid depolymerization, each with high affinity for antithrombin III. These fractions all accelerated the rate of the antithrombin III inhibition of the platelet prothrombinase complex, with maximum rate constants of 6.8 X 10(7), 1.4 X 10(7) and 9.8 X 10(6) M-1 X min-1, respectively. On comparison with the effect of these heparin fractions on the rate of inhibition of uncomplexed factor Xa a progressively increasing disparity between the rate of inhibition of uncomplexed and complexed factor Xa was observed, rising from 1.7-fold with the oligosaccharide to 6.8-fold with the unfractionated heparin. A possible mechanism for this differential activity between uncomplexed and complexed factor Xa with the various heparin fractions is discussed in terms of an involvement of heparin binding to factor Xa.

Antithrombin III↗

PubMed1987

Glycosaminoglycans on fibroblasts accelerate thrombin inhibition by protease nexin-1.

Protease nexin-1 (PN-1) is a proteinase inhibitor that is secreted by human fibroblasts in culture. PN-1 inhibits certain regulatory serine proteinases by forming a covalent complex with the catalytic-site serine residue; the complex then binds to the cell surface and is internalized and degraded. The fibroblast surface was recently shown to accelerate the rate of complex-formation between PN-1 and thrombin. The present paper demonstrates that the accelerative activity is primarily due to cell-surface heparan sulphate, with a much smaller contribution from chondroitin sulphate. This conclusion is supported by the effects of purified glycosaminoglycans on the second-order rate constant for the inhibition of thrombin by PN-1. Also, treatment of 35SO4(2-)-labelled cells with heparitin sulphate lyase or chondroitin sulphate ABC lyase demonstrated two discrete pools of 35S-labelled glycosaminoglycans; subsequent treatment of plasma membranes with these glycosidases showed that heparitin sulphate lyase treatment abolished about 80% of the accelerative activity and chondroitin sulphate ABC lyase removed the remaining 20%. These results show that two components are responsible for the acceleration of PN-1-thrombin complex-formation by human fibroblasts. Although dermatan sulphate is also present on fibroblasts, it did not accelerate the inhibition of thrombin by PN-1.

Amyloid beta-Protein Precursor↗

PubMed1982

The contribution of the accelerating phase of inspiratory flow to resistive load detection in man.

1. By the use of Signal Detection Theory techniques resistive load detection sensitivity was estimated in ten normal subjects during loading of the whole of inspiration and compared with loading restricted to the initial, accelerating phase of inspiratory air flow. 2. Detection sensitivity during the accelerating-flow phase of inspiration was not significantly different from that in the control conditions. 3. These results suggest that the information for detection is generated in the accelerating phase of inspiratory air flow. 4. We propose that the stimulus for resistive load detection is the ratio of the rate of change of pressure to the rate of change of flow.

Adult↗

PubMed2002

Negative electric potential induces alteration of ion gradient and lamellar body secretion in the epidermis, and accelerates skin barrier recovery after barrier disruption.

Previous reports suggested that ion gradients of ions such as calcium and magnesium in the epidermis play a crucial part in skin barrier homeostasis. We hypothesized that external electric potential affects the ionic gradient and skin barrier homeostasis. We demonstrated here that application of a negative electric potential (0.50 V) on hairless mice skin accelerated the barrier recovery approximately 60.7% of the original level within 1 h compared with control (37.5%) after barrier disruption by acetone treatment. Even after the application of a negative potential, the skin showed accelerated repair for 6 h. On the contrary, the skin that was applied a positive potential for 1 h showed a significant delay in barrier recovery (25.3%) than the control. Ultrastructural studies by electron microscopy suggested that the extent of lamellar body exocytosis into the stratum corneum/stratum granulosum interface increased under a negative potential. Magnesium and calcium ion concentrations in the upper epidermis were relatively higher in the negative portion than in the portion where the positive potential was applied. Topical application of these ions on mice skin also accelerated the barrier recovery. These results suggest that the external electric potential affects the ionic gradients in the epidermis and also influences the skin barrier homeostasis.

Acetone↗

PubMed2001

Enhanced inactivation and acceleration of activation of the sodium channel associated with epilepsy in man.

Generalized epilepsy with febrile seizures-plus (GEFS+) is a benign Mendelian syndrome characterized by childhood-onset febrile and afebrile seizures. Three point mutations within two voltage-gated sodium channel genes have been identified so far: in GEFS+ type 1 a mutation in the beta1-subunit gene SCN1B, and in GEFS+ type 2 two mutations within the neuronal alpha-subunit gene SCN1A. Functional expression of the SCN1B and one of the SCN1A mutations revealed defects in fast channel inactivation which are in line with previous findings on myotonia causing mutations in SCN4A, the skeletal muscle sodium channel alpha-subunit gene, all showing an impaired fast inactivation. We now studied the second GEFS+ mutation (T875M in SCN1A), using the highly homologous SCN4A gene (mutation T685M). Unexpectedly, the experiments revealed a pronounced enhancement of both fast and slow inactivation and a defect of channel activation for T685M compared to wild-type channels. Steady-state fast and slow inactivation curves were shifted in the hyperpolarizing direction, entry into slow inactivation was threefold accelerated, recovery from slow inactivation was slowed by threefold and the time course of activation was slightly but significantly accelerated. In contrast to other disease-causing mutations in SCN1A, SCN1B and SCN4A, the only mechanism that could explain hyperexcitability of the cell membrane would be the acceleration of activation. Because the enhancement of slow inactivation was the most obvious alteration in gating found for T685M, this might be the disease-causing mechanism for that mutation. In this case, the occurrence of epileptic seizures could be explained by a decrease of excitability of inhibitory neurons.

Animals↗

PubMed2001

Neuroinflammation-induced acceleration of amyloid deposition in the APPV717F transgenic mouse.

It has been postulated that neuroinflammation plays a critical role in the pathogenesis of Alzheimer's disease (AD). To directly test whether an inflammatory stimulus can accelerate amyloid deposition in vivo, we chronically administered the bacterial endotoxin, lipopolysaccharide (LPS), intracerebroventricularly (i.c.v.) to 2-month-old APPV717F+/+ transgenic (TG) mice, which overexpress a mutant human amyloid precursor protein (APP 717V-F) with or without apolipoprotein E (apoE) for 2 weeks. Two weeks following central LPS administration a striking global reactive astrocytosis with increased GFAP immunoreactivity was found throughout the brains of all LPS-treated wild-type and transgenic mice including the contralateral brain hemisphere. Localized microglial activation was also evident from lectin immunostaining adjacent to the cannula track of LPS-treated mice. Quantification of thioflavine-S-positive Abeta deposits revealed a marked acceleration of amyloid deposition in LPS-treated APPV717F+/+-apoE+/+ mice compared to nontreated or vehicle-treated APPV717F+/+-apoE+/+ mice (P = 0.005). By contrast, no amyloid deposits were detected by thioflavine-S staining in LPS or vehicle-treated apoE-deficient APPV717F TG mice. Our data suggest that neuroinflammation can accelerate amyloid deposition in the APPV717F+/+ mouse model of AD and that this process requires the expression of apoE.

Amyloid↗

PubMed2000

Motilides accelerate regional gastrointestinal transit in the dog.

BACKGROUND: Motilides have prokinetic effects on the upper gut during fasting, increasing the strength of antral contractions and stimulating gastroduodenal phase 3 sequences. Effects on the distal gut, and postprandially, are less well documented. AIM: To evaluate dose-response effects of motilin and erythromycin on gastric emptying, small bowel and colonic transit in the dog using a validated scintigraphic technique. METHODS: For gastric emptying and small bowel transit, 99mTc labelled beads were added to a meal of dog chow (450 kcal). Regional colonic transit was measured by 111In labelled beads placed in a capsule which dissolved and released radiation into the proximal colon. Scintiscans were taken at regular intervals and indices of whole-gut transit were calculated. Drugs were given by slow intravenous administration. RESULTS: In the doses used, motilin accelerated regional colonic transit but did not hasten gastric emptying or small bowel transit. Single or repeated doses of motilin had similar effects on colonic transit. Erythromycin accelerated gastric emptying, small bowel transit and regional colonic transit. CONCLUSIONS: Motilin receptors are apparently present in the canine small bowel and colon. Postprandially, motilides accelerate transit in the distal gut.

Animals↗

PubMed2001

Tegaserod, a 5-HT4 receptor partial agonist, accelerates gastric emptying and gastrointestinal transit in healthy male subjects.

BACKGROUND: Serotonin and its type-4 (5-hydroxytryptamine4) receptor play a major role in the physiology of the gastrointestinal tract. The effect of intravenous and/or oral tegaserod, a 5-hydroxytryptamine4 receptor partial agonist, on gastric emptying, small bowel transit and colonic transit has not been studied in detail in humans. AIM: To assess the pharmacodynamic effects of repeated oral and intravenous administration of tegaserod on gastric emptying and small intestine and colonic transit. METHODS: A randomized, placebo-controlled, double-blind, three-way, crossover study of 6 mg oral and 0.6 mg intravenous tegaserod in 12 healthy male subjects was performed. Each treatment arm of the study involved 3 days of twice-daily administration and 1 day of daily administration of the study drugs. RESULTS: In comparison with placebo, oral and intravenous tegaserod significantly increased the gastric emptying rate (P < 0.01), accelerated colonic filling (P < 0.01) and shortened colonic transit at 48 h (P < 0.05). Tegaserod shortened the small intestine transit time by 30% after oral and by 37% after intravenous administration. CONCLUSIONS: In healthy subjects, tegaserod markedly accelerated gastric emptying and small intestinal transit, and induced a small but significant acceleration of colonic transit. Tegaserod can act as a promotile agent throughout the gastrointestinal tract.

Administration, Oral↗