Biomedical subjects

J Graff

Publications and source records attributed to J Graff.

At least 19 recordsLinked to original sources

PubMed2006

Effect of intravenous infusion of glyceryl trinitrate on gastric and small intestinal motor function in healthy humans.

BACKGROUND: Glyceryl trinitrate is a donor of nitric oxide that relaxes smooth muscle cells of the gastrointestinal tract. Little is known about the effect of glyceryl trinitrate on gastric emptying and no data exist on the possible effect of glyceryl trinitrate on small intestinal transit. AIM: To examine the effect of intravenous infusion of glyceryl trinitrate on gastric and small intestinal motor function after a meal in healthy humans. METHODS: Nine healthy volunteers participated in a placebo-controlled, double-blind, crossover study. Each volunteer was examined during intravenous infusion of glyceryl trinitrate 1 microg/kg x min or saline. A gamma camera technique was used to measure gastric emptying and small intestinal transit after a 1600-kJ mixed liquid and solid meal. Furthermore, duodenal motility was assessed by manometry. RESULTS: Glyceryl trinitrate did not change gastric mean emptying time, gastric half emptying time, gastric retention at 15 min or small intestinal mean transit time. Glyceryl trinitrate did not influence the frequency of duodenal contractions, the amplitude of duodenal contractions or the duodenal motility index. CONCLUSIONS: Intravenous infusion of glyceryl trinitrate 1 microg/kg x min does not induce major changes in gastric or small intestinal motor function after a 1600-kJ meal in healthy volunteers.

Cross-Over Studies↗

PubMed2006

[Argatroban].

Explore the source record for details and available documents.

Anticoagulants↗

PubMed2005

An updated study of mortality among North American synthetic rubber industry workers.

AIM: This study evaluated the mortality experience of workers from the styrene-butadiene industry. METHODS: The authors added seven years of follow up to a previous investigation of mortality among 17 924 men employed in the North American synthetic rubber industry. Analyses used the standardised mortality ratios (SMRs) to compare styrene-butadiene rubber workers' cause specific mortality (1943-98) with those of the United States and the Ontario general populations. RESULTS: Overall, the observed/expected numbers of deaths were 6237/7242 for all causes (SMR = 86, 95% CI 84 to 88) and 1608/1741 for all cancers combined (SMR = 92, 95% CI 88 to 97), 71/61 for leukaemia, 53/53 for non-Hodgkin's lymphoma, and 26/27 for multiple myeloma. The 16% leukaemia increase was concentrated in hourly paid subjects with 20-29 years since hire and 10 or more years of employment in the industry (19/7.4, SMR = 258, 95% CI 156 to 403) and in subjects employed in polymerisation (18/8.8, SMR = 204, 95% CI 121 to 322), maintenance labour (15/7.4, SMR = 326, 95% CI 178 to 456), and laboratory operations (14/4.3, SMR = 326, 95% CI 178-546). CONCLUSION: The study found that some subgroups of synthetic rubber workers had an excess of mortality from leukaemia that was not limited to a particular form of leukaemia. Uncertainty remains about the specific agent(s) that might be responsible for the observed excesses and about the role of unidentified confounding factors. The study did not find any clear relation between employment in the industry and other forms of lymphohaematopoietic cancer. Some subgroups of subjects had more than expected deaths from colorectal and prostate cancers. These increases did not appear to be related to occupational exposure in the industry.

Aged↗

PubMed2004

Effect of sildenafil on gastric emptying and postprandial frequency of antral contractions in healthy humans.

BACKGROUND: Sildenafil is known to block phosphodiesterase type 5, which degrades nitric oxide-stimulated cyclic guanosine monophosphate, thereby relaxing smooth muscle cells in various organs. The effect of sildenafil on gastric motor function after a meal was investigated in healthy humans. METHODS: Ten healthy male volunteers (21-28 years) participated in a placebo-controlled, double-blind, cross-over study. In random order and on two separate days each volunteer ingested either 50 mg sildenafil (Viagra, Pfizer, New York, N.Y., USA) or placebo. A gamma camera technique was used to measure gastric emptying and postprandial frequency of antral contractions. RESULTS: The area under the curve of gastric retention versus time of liquid or solid radiolabelled marker was not changed by sildenafil intake, nor was the postprandial frequency of antral contractions affected by sildenafil. CONCLUSION: A single dose of 50 mg sildenafil does not change gastric emptying or postprandial frequency of antral contractions in healthy volunteers.

Adult↗

PubMed2003

[Rupture of a renal artery aneurysm during delivery].

INTRODUCTION: Renal artery aneurysms represent a rare entity with an incidence of 0.3 - 1.3% in angiographies. Rupture of such aneurysms are rare. During pregnancy there is an increased risk of rupture with a high mortality for mother and child. We report the first case of rupture of a left renal artery aneurysm during delivery with survival of mother and child. CASE REPORT: Due to arrest of labor during a home birth, the patient was admitted to the hospital, where an immediate forceps extraction on account of fetal asphyxia was performed. Immediately after delivery a hypovolemic shock developed. Ultrasound examination showed a huge subsplenic hematoma. Emergency laparotomy revealed a ruptured renal artery aneurysm. The renal artery was ligated on the assumption of a lower pole vessel. Despite hemodynamic stability a drop in hemoglobin occurred the following day. Angiography showed no perfusion of the left kidney. A left nephrectomy was performed without complications. The further course was uneventful. Mother and child survived. CONCLUSIONS: Rupture of aneurysms of the splenic and renal artery during later stages of pregnancy, during delivery or after childbirth are possible etiologies in cases of unexplained shock and abdominal pain. An emergency angiography in such cases helps to reveal the underlying cause and renders possible a targeted operative approach.

Adult↗

PubMed2002

Short-term administration of glucagon-like peptide-2. Effects on bone mineral density and markers of bone turnover in short-bowel patients with no colon.

BACKGROUND: Glucagon-like peptide 2 (GLP-2) is a newly discovered intestinotrophic hormone. We have recently reported that a 5-week GLP-2 treatment improved the intestinal absorptive capacity of short-bowel patients with no colon. Additionally, GLP-2 treatment was associated with changes in body composition that included a significant increase in total body bone mass. This article describes the effect of GLP-2 on spinal and hip bone mineral density (BMD) and biochemical markers of bone turnover in these patients. METHODS: In an open-labelled pilot study, eight short-bowel patients (3M, 5F; mean age 49 years) with small-bowel resection and no colon received 400 microg s.c. of GLP-2 twice daily for 5 weeks. Four received home parenteral nutrition (mean length of residual jejunum 83 cm) and 4 did not (mean length of ileum resected 106 cm). The outcome measures were the mean percent change from baseline in spinal and hip BMD measured by dual-energy X-ray absorptiometry, changes in four biochemical markers of bone-turnover, PTH, 25-hydroxy vitamin-D, and the intestinal absorption of calcium. RESULTS: Mean +/- s(x) (SEM) percent changes in spinal and hip BMD were 1.1+/-0.4% (P < 0.05) and 1.9+/-0.8% (P = 0.06), respectively. The intestinal calcium absorption increased by 2.7% (P = 0.87). Serum ionized calcium increased in 5/8 patients with a concomitant decrease in serum PTH values. Three of the four markers of bone turnover decreased. CONCLUSION: A 5-week GLP-2 administration significantly increased spinal BMD in short-bowel patients with no colon. The mechanism by which GLP-2 affects bone metabolism remains unclear, but may be related to an increased mineralization of bone resulting from an improved intestinal calcium absorption.

Absorptiometry, Photon↗

PubMed2002

Radioisotope-guided surgical biopsy of costal metastases in breast cancer patients.

Radioisotope bone scanning is a sensitive indicator of metastatic disease. Localization of the hot spot for biopsy is difficult. Today, a hand-held gamma probe enables the surgeon intraoperatively to accomplish the localization procedure easily. As this technique is described in American literature exclusively, more recent European findings is presented here. During one month two patients were diagnosed with breast cancer. Bone scanning disclosed minor hot spots in the ribs. On the day of surgical biopsy the localization of the hot spots was guided by a gamma probe. For the biopsy a dermal punch biopsy needle was employed, and fine needle aspiration biopsies were also taken. The procedures were easy and completed within a few minutes. The post-operative courses were uneventful. In one patient, final histology showed malignancy in both biopsies. In the other patient, only the fine needle aspiration biopsy was malignant. The punch biopsy was abnormal, but did not contain malignant tissue. The gamma probe is an important tool in the performance of rib biopsies of nonpalpable lesions. The punch biopsy technique is simple and combined with fine needle aspiration biopsy the method has proven to be sensitive and accurate. The punch biopsy technique furthermore reduces the risk of postoperative pneumothorax.

Biopsy, Needle↗

PubMed2002

Effects of antiplatelet agents on platelet-induced thrombin generation.

OBJECTIVES: The influence of antiplatelet agents on platelet-induced thrombin generation may increase the risk of bleeding. Assessment of the endogenous thrombin potential (ETP), is therefore a parameter deserving attention in early pharmacodynamic studies with antiplatelet drugs. The aim ofthis study was to assess whether an automated ETP-assay can be used to determine possible inhibitory effects of antiplatelet drugs on platelet-associated thrombin generation. METHODS: We first characterized the in vitro dose-response relationship of several platelet agonists (ADP, collagen, U46619, TRAP (amino acid sequence: SFLLRNP) and tissue factor (TF) using the generation of ETP. One submaximal concentration of each agonist was then used to assess the influence of in vivo treatment with aspirin (single oral dose of 500 mg as inhibitor of thromboxane synthesis) and clopidogrel (given orally for 6 days, as an inhibitor of the purinergic P2Y12-receptor on platelets) and in vitro treatment with abciximab (which inhibits the platelet glycoprotein IIb/IIIa-receptor for fibrinogen), on the ETP. RESULTS: The effect of TF and the other platelet inducers on thrombin generation was dose-dependent. Repeat measurements on samples from the same subject, with the same inducer concentration on 2 different occasions showed a variability of approx. 22% (absolute difference between 2 measurements as % of mean). The coefficient on variation of repeat measurements of one sample varied between 7% and 17%, depending on the inducer. After a single dose of aspirin, ETP was reduced by 25-40%, depending on the platelet activating agent used. The reduction in ETP with abciximab in vitro was more pronounced. In contrast, TF-induced ETP was not influenced by aspirin or abciximab. Clopidogrel, administered for 6 days, reduced the ETP by 60% when platelets were stimulated using 20 microM ADP, whereas collagen-induced ETP and TF-induced ETP remained unchanged. CONCLUSIONS: The ETP-method is a sensitive and reproducible method for the detection of drug effects on platelet-induced thrombin generation of high throughput, and can be recommended for studies on the pharmacodynamic profile of drugs interfering with platelet function.

Adult↗

PubMed2001

In vitro dose response to different GPIIb/IIIa-antagonists: inter-laboratory comparison of various platelet function tests.

AIMS: The aim of this study was to assess the inter- and intra-laboratory variation of the concentration-response to the GPIIb/IIIa-antagonists abciximab and eptifibatide on platelet aggregometry and to compare results with flow cytometric tests as well as the rapid platelet function analyser (RPFA). METHODS: In five different laboratory sites, blood from three to five healthy donors was spiked with abciximab or eptifibatide, followed by the assessment of: (1) aggregometry (anticoagulant: sodium citrate 3.18% or hirudin 5 microg/ml); (2) flow cytometry (fibrinogen binding or PAC1-expression), or (3) RPFA. Dose-response curves were established on the basis of a sigmoidal Imax)-model [I=(Imax)*Cg)/(IC50g + Cg)]. RESULTS: For citrated blood, aggregation induced by 20 microM ADP was blocked up to 100% by both GPIIb/IIIa-antagonists, IC50 values varied between 0.11-0.22 microg/ml for eptifibatide and 1.25-2.3 microg/ml for abciximab. I(max) of the response to 5 microg/ml collagen ranged from 46% to 100%, and IC50 values varied between 0.28-0.34 microg/ml for eptifibatide and 2.3-3.8 microg/ml for abciximab. In hirudinized blood, IC50 values for eptifibatide were 1.5- to 3-fold higher than those obtained with citrated plasma. Inhibition of PAC1-expression by abciximab (IC50) 0.84 microg/ml) showed results similar those of the RPFA (approx. 1.0 microg/ml); larger differences between PAC1 and RPFA results were observed for eptifibatide. Based on aggregometry, eptifibatide concentrations for 80% inhibition varied from 0.27 to 0.55 microg/ml, and were considerably less when the RPFA was taken as basis (0.15 or 0.22 microg/ml). A similar pattern was observed for abciximab. CONCLUSIONS: We found quite a low inter- and intra-laboratory variation in the in vitro pharmacodynamic characterization of GPIIb/IIIa-antagonists by aggregometry, making results of these tests obtained from different laboratories during clinical trials at least comparable. The RPFA exhibits a higher sensitivity to inhibitory GPIIb/IIIa-effects, in keeping with the "real" inhibition of the activated receptor (PAC1) as assessed with more elaborate flow cytometry.

Abciximab↗

PubMed2001

Pharmacodynamic characterization of the interaction between abciximab or tirofiban with unfractionated or a low molecular weight heparin in healthy subjects.

AIMS: The objective of our study was to define the interaction between either unfractionated heparin (UFH) or a low molecular weight heparin, reviparin (REV), and the pharmacodynamic profile of the GPIIb/IIIa-antagonists abciximab (ABC) or tirofiban (T). METHODS: Two studies each containing 18 healthy subjects were performed, and all were pretreated with aspirin (ASA) for 3 days. Volunteers then received UFH (5000 IU bolus/infusion 7 IU kg(-1) h(-1) for 7 h, n = 6), REV (4200-anti-Xa-IU s.c., n = 6) or placebo (n = 6). One hour later, ABC (study I) or T (study II) were given by i.v. infusion for 6 h. The pharmacodynamic effects measured were bleeding time (BT), fibrinogen-binding at the GPIIb/IIIa-receptor (FIB), expression of the platelet secretion marker CD62, and ADP (20 microM)- and collagen (5 microg ml(-1))-induced platelet aggregation. RESULTS: After treatment with both GPIIb/IIIa-antagonists, prolongation of BT occurred to a similar magnitude (approximately 25-30 min) and was not affected by UFH or REV-comedication. ABC or T with ASA alone resulted in nearly the same magnitude of reduction in FIB and platelet aggregation. After coadministration with UFH, FIB was significantly higher (thus less inhibited) than after after T + ASA alone (19 +/- 16% vs 55 +/- 36%) or ABC + ASA alone (8 +/- 9% vs 32 +/- 11%). This attenuation of FIB was not seen with REV. Inhibition of ADP-and collagen-induced aggregation tended to be attenuated by treatment with UFH (e.g. ADP-induced aggregation at 0.25 h after ABC + ASA alone =13 +/- 4%; after coadministration with UFH = 40 +/- 26%). No such changes were noted with REV. Minor reductions in CD62-expression were seen in subjects given ABC or T alone, but expression was not affected by UFH or REV. CONCLUSIONS: Co-medication with UFH attenuated platelet inhibition during treatment with GPIIb/IIIa-antagonists, but these effects were not seen with the low molecular weight heparin reviparin. The results show that administration of reviparin together with abciximab or tirofiban did not adversely affect the pharmacodynamic profile of these GPIIb/IIIa-antagonists.

Abciximab↗

PubMed2001

Platelet CD62 expression and PDGFAB secretion in patients undergoing PTCA and treatment with abciximab.

AIMS: To investigate a correlation of the platelet activation marker CD62 and secretion of the growth factor PDGF from platelets in coronary patients under therapy with the GPIIb/IIIa-inhibitor abciximab. METHODS: Flow cytometric assessment of fibrinogen binding (GPIIb/IIIa-binding site) and CD62 expression, as well as PDGF release of human platelets (immunoassay) and platelet aggregation with 20 microM ADP and 2 microg ml(-1) collagen were evaluated in nine patients with stable coronary artery disease. Patients were undergoing elective balloon angioplasty and were treated with aspirin (100 mg day(-1)), heparin (ACT < 220 s) and abciximab (bolus and infusion over 12 h). Blood samples were obtained before initiation of abciximab therapy (under aspirin and heparin) (I), 3 h after angioplasty under abciximab (II) and 12 h after termination of abciximab infusion (III). RESULTS: Compared with sample I before abciximab therapy, fibrinogen binding was reduced to 37% (+/- 34 s.d., P < 0.05) (II) and 55% (+/- 40 s.d., P < 0.05) (III). Reduced fibrinogen binding also led to a significant reduction of the aggregation response to ADP (down to 37% +/- 20) and collagen (down to 0%). Mean fluorescence intensity of CD62-expression was 78 units (+/- 20 s.d.) (I), 72 units (+/- 14 s.d.) (II) and 64 units (+/- 12 s.d., P < 0.05) (III). PDGF release from isolated, washed platelets was 99 (+/- 33 s.d.) ng/10(9) platelets at (I), 82 (+/- 31 s.d.) ng/10(9) platelets and 96 (+/- 30 s.d.) ng/10(9) platelets. CONCLUSIONS: The results indicate that despite a strong reduction of GPIIb/IIIa-binding and platelet aggregation, CD62 as a marker of platelet secretion and the secretion product PDGF were only slightly reduced under abciximab treatment. No direct correlation between CD62 expression and PDGF release could be demonstrated.

Abciximab↗

PubMed2001

Gastrointestinal mean transit times in young and middle-aged healthy subjects.

To investigate the effects of age and gender on gastric, small intestinal and colonic mean transit times, a study was conducted in 32 healthy volunteers: eight young women (22-30 years), eight young men (20-28 years), eight middle-aged women (43-51 years) and eight middle-aged men (38-53 years). After ingestion of a meal containing 111Indium-labelled water and 99mTechnetium-labelled omelette imaging of the abdomen was performed at intervals of 30 min until all radioactivity was located in the colon and henceforth at intervals of 24 h until all radioactivity had cleared from the colon. Gastric, small intestinal and colonic mean transit times were calculated. The gastric, small intestinal and colonic mean transit times were significantly longer in women. Ageing was shown to accelerate the gastric and small intestinal transit significantly. In the group of men the colonic mean transit time was unaffected by age, but middle-aged women had a significantly slower colonic transit than young women. We therefore conclude that both age and gender have to be considered when reference values for gastric, small intestinal and colonic mean transit times have to be established.

Adult↗

PubMed2001

Glucagon-like peptide 2 improves nutrient absorption and nutritional status in short-bowel patients with no colon.

BACKGROUND & AIMS: Glucagon-like peptide 2 (GLP-2) is intestinotrophic, antisecretory, and transit-modulating in rodents, and it is mainly secreted from the intestinal mucosa of the terminal ileum and colon after food ingestion. We assessed the effect of GLP-2 on the gastrointestinal function in patients without a terminal ileum and colon who have functional short-bowel syndrome with severe malabsorption of wet weight (>1.5 kg/day) and energy (>2.3 MJ/day) and no postprandial secretion of GLP-2. METHODS: Balance studies were performed before and after treatment with GLP-2, 400 microg subcutaneously twice a day for 35 days, in 8 patients (4-17 years from last bowel resection; 6 with Crohn's disease). Four patients received home parenteral nutrition (mean residual jejunum, 83 cm), and 4 did not (mean ileum resection, 106 cm). Biopsy specimens were taken from jejunal/ileal stomas, transit was measured by scintigraphy, and body composition was measured by dual-energy x-ray absorptiometry. RESULTS: Treatment with GLP-2 improved the intestinal absorption of energy 3.5% +/- 4.0% (mean +/- SD) from 49.9% to 53.4% (P = 0.04), wet weight 11% +/- 12% from 25% to 36% (P = 0.04), and nitrogen 4.7% +/- 5.4% from 47.4% to 52.1% (P = 0.04). Body weight increased 1.2 +/- 1.0 kg (P = 0.01), lean body mass increased 2.9 +/- 1.9 kg (P = 0.004), fat mass decreased 1.8 +/- 1.3 kg (P = 0.007), and 24-hour urine creatinine excretion increased (P = 0.02). The time to 50% gastric emptying of solids increased 30 +/- 16 minutes from 89 to 119 minutes (P < 0.05). Small bowel transit time was not changed. Crypt depth and villus height were increased in 5 and 6 patients, respectively. CONCLUSIONS: Treatment with GLP-2 improves intestinal absorption and nutritional status in short-bowel patients with impaired postprandial GLP-2 secretion in whom the terminal ileum and the colon have been resected.

Adult↗

PubMed2001

Levodopa pharmacokinetic-pharmacodynamic modeling and 6-[18F]levodopa positron emission tomography in patients with Parkinson's disease.

OBJECTIVE: Parameters of a pharmacokinetic-pharmacodynamic (PK-PD) model of levodopa have been claimed to reflect the magnitude of the dopaminergic deficit in patients with Parkinson's disease. The aim of this study was to correlate such parameters with positron emission tomography (PET) with levodopa tagged with 6-fluorine 18, an established imaging method for striatal dopaminergic neurons. METHODS: Twenty-three patients in different disease stages (Hoehm and Yahr stage 2.5-5 [Hoehn MM, Yahr MD. Parkinsonism: onset, progression and mortality. Neurology 1967;4:427-42]; median duration, 12 years) were studied. PK-PD modeling followed a single oral dose of levodopa/benserazide. The sum score of the Columbia Rating Scale (CURSSigma) was used for clinical assessments. A nonparametric effect compartment approach assuming a sigmoidal E(max) model was applied to the PK-PD analysis of plasma levodopa concentrations and corresponding CURSSigma. Thereafter 6-[18F]levodopa PET was performed, and the influx rate constants (k(c)) for the putamen and the caudatus region were correlated with the median effective concentration (EC(50)) and the equilibrium half-life (T(eq)) of the PK-PD model. RESULTS: (1) A significant correlation was observed between PK-PD parameters or with k(c) putamen as the dependent variable and the duration of the disease as the independent variable, which explains 33% of the variability of the EC(50), 42% of the variability of T(eq), and 36% of the variability of k(c). (2) Significant correlations were observed between k(c) and either EC(50) or T(eq), yielding the closest correlation for the putamen region (r = -0.47, P <.05; and r = 0.55, P <.01; respectively). CONCLUSIONS: Our findings show that key parameters of a PK-PD model of levodopa were in fairly close agreement with imaging of dopaminergic neurons by 6-[18F]levodopa PET. However, although PK-PD modeling of levodopa has been proven as a useful investigation of approaches aimed to restore dopaminergic deficits or to monitor disease progression, this modeling cannot serve as a pathomorphologic surrogate for the loss of striatal dopaminergic neurons.

Adult↗

PubMed2001

Impact of race in lung cancer: analysis of temporal trends from a surveillance, epidemiology, and end results database.

STUDY OBJECTIVES: We analyzed data from a community-based cancer database over a 26-year period in order to characterize clinicopathologic differences between black and white patients with lung cancer, and to identify relevant temporal trends in incidence and survival. DESIGN, SETTING, AND PATIENTS: Data on demographics, stage, histology, and survival were obtained on all black and white patients with primary bronchogenic carcinoma registered in the community-based metropolitan Detroit Surveillance, Epidemiology, and End Results database from 1973 to 1998. RESULTS: Of 48,318 eligible patients, 23% were black. Lung cancer incidence rates decreased for men of both races from 1985 to 1998, with a greater decline occurring in black men (p < 0.0001). Although incidence rates declined over time for men of both races < 50 years of age, this decrease was greater in white men, resulting in an increase in the racial differential in younger men. Temporal trends in incidence rates were similar for women of both races. The incidence of distant-stage disease was higher among blacks throughout the study period. The incidence of local-stage disease decreased for both races, though this decline was greater in blacks. A significant racial difference in 2-year and 5-year survival rates developed during the study period, due to a distinct lack of improvement in black patients. In a multivariate model, the relative risks of death for black patients, relative to white patients, were 1.24 (p < 0.0001) for local stage, 1.14 (p < 0.0001) for regional stage, and 1.03 (p = 0.045) for distant stage. CONCLUSION: Significant racial differences exist in the incidence and survival rates for lung cancer in metropolitan Detroit. Since 1973, several disturbing trends have developed, particularly with regard to the lack of improvement in overall survival in black patients. Further study is required to determine the factors responsible for these temporal trends.

Adenocarcinoma↗

PubMed2000

Differential in vitro effects of the platelet glycoprotein IIb/IIIa inhibitors abixicimab or SR121566A on platelet aggregation, fibrinogen binding and platelet secretory parameters.

The aim of this study was to compare fibrinogen binding, inhibition of platelet aggregation and secretory potential of the MAb abciximab (0.5-5 microg/mL) and the peptidomimetic compound SR121566A (15-250 ng/mL) in vitro in whole blood. Fibrinogen binding was followed by flow cytometry; platelet function was evaluated by light transmittance and by impedance aggregometry. Secretory functions of platelets were evaluated using ATP as marker for early secretion by dense granulae and P-selectin (CD62) for alpha-granular secretion as well as CD63 for lysosomal degranulation. Results showed that fibrinogen binding induced by 5 microM TRAP was maximally inhibited greater than 80% at 3 microg/mL abciximab or at 250 ng/mL SR121566A. At these concentrations of antagonists, platelet aggregation induced by 5 microM ADP or 2 microg/mL collagen was inhibited completely. Expression of CD62 was reduced 34% with abciximab or 15% with SR121566A; CD63 expression was reduced 22% with both agents. With both agents, the EC50 for inhibition of CD62 and CD63 expressions was in similar magnitudes than the EC50 for fibrinogen binding inhibition. With 3 microg/mL abciximab, ATP secretion was maximally reduced to 50% of the control, whereas SR121566A at 250 ng/mL had no inhibitory effect on this parameter. A slight increase in ATP secretion was seen with 0.5 microg/mL abciximab and with SR121566A in concentrations of less than 45 ng/mL. The data suggest a discoupling between the anti-aggregatory and the antisecretory effects of IIb/IIIa antagonists. Because it is not established to what extend CD62 or CD63 expression can be reduced by any means, the reduction by 20-30% obtained by 3 microg/mL abciximab or 250 ng/mL SR121566A might already be the maximum possible inhibition by these agents.

Adenosine Triphosphate↗

PubMed2000

Simplified scintigraphic methods for measuring gastrointestinal transit times.

To investigate whether simple transit measurements based on scintigraphy performed only 0, 2, 4 and 24 h after intake of a radiolabelled meal can be used to predict the mean transit time values for the stomach, the small intestine, and the colon, a study was conducted in 16 healthy volunteers. After ingestion of a meal containing 111indium-labelled water and 99mtechnetium-labelled omelette, imaging was performed at intervals of 30 min until all radioactivity was located in the colon and henceforth at intervals of 24 h until all radioactivity had cleared from the colon. Gastric, small intestinal and colonic mean transit times were calculated for both markers and compared with fractional gastric emptying at 2 h, fractional colonic filling at 4 h, and geometric centre of colonic content at 24 h, respectively. Highly significant correlations were found between gastric mean transit time and fractional gastric emptying at 2 h (111In: r=0.95, P<0.00001; 99mTc: r=0.96, P<0.00001), between small intestinal mean transit time and fractional colonic filling at 4 h (111In: r=-0.97, P<0.00001; 99mTc: r=-0.89, P<0. 00001), and between colonic mean transit time and geometric centre of colonic content at 24 h (111In: r=- 0.88, P<0.00001). We therefore conclude that reliable regional gastrointestinal transit times can be estimated from scintigraphic images taken 0, 2, 4 and 24 h after intake of radiolabelled markers.

Adult↗

PubMed2000

Ex vivo--in vitro interaction between aspirin, clopidogrel, and the glycoprotein IIb/IIIa inhibitors abciximab and SR121566A.

OBJECTIVES: To assess the interaction between aspirin and clopidogrel in healthy male volunteers and the interaction of the glycoprotein IIb/IIIa (GPIIb/IIIa) inhibitors abciximab and SR121566A with blood from those pretreated subjects (ex vivo-in vitro). METHODS: Aspirin (300 mg/day), clopidogrel (75 mg/day), or the combination of both drugs were administered orally for 8 days. Group 1 (n = 5) started with aspirin and group 2 (n = 5) with clopidogrel. From day 4 to day 8, subjects of both groups received the combined treatment. Blood from these subjects was spiked with abciximab (0.5 and 1.5 microg x mL(-1)) and SR121566A (31 and 62 ng x mL(-1)). RESULTS: In vivo, average bleeding times were 6.8 minutes at baseline, 20.3 minutes for clopidogrel alone (P < .01), 10.9 minutes for aspirin alone (difference not significant), and 24.0 minutes (P < .01) for the combined treatment. Fibrinogen binding to the platelet GPIIb/IIIa receptor was reduced for aspirin to 69% (difference not significant), to 63% for clopidogrel (difference not significant), and to 63% for the clopidogrel plus aspirin combination (P < .01). CD62 expression as a marker of platelet granular secretion was reduced to 66% by clopidogrel (P < .01) and to 41% by the combination of clopidogrel and aspirin; aspirin alone had no effect. In vitro, with pretreatment with aspirin and clopidogrel, inhibitory effects of the GPIIb/IIIa inhibitors on fibrinogen binding were additive to changes observed with aspirin or clopidogrel alone. No effect on CD62 expression was observed with either GPIIb/IIIa inhibitor. Aspirin and clopidogrel reinforced effects of the GPIIb/IIIa inhibitors on adenosine diphosphate (5 micromol/L)-induced aggregation in an additive manner, a supra-additive effect was observed with collagen (2 microg x mL(-1))-induced aggregation. CONCLUSION: The augmentation of the antiaggregatory effects of GPIIb/IIIa inhibitors by aspirin and clopidogrel and the lack of antisecretory effects of GPIIb/IIIa inhibitors may favor their combination with clopidogrel.

Abciximab↗