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Biomedical subjects

G R May

Publications and source records attributed to G R May.

At least 19 recordsLinked to original sources
PubMed1995

Azathioprine and 6-mercaptopurine in Crohn disease. A meta-analysis.

PURPOSE: To assess the effectiveness of azathioprine and 6-mercaptopurine in inducing remission of active Crohn disease and the effectiveness of azathioprine in maintaining remission of quiescent disease. DATA SOURCES: Pertinent studies were selected from the MEDLINE database (1966 to May 1994), abstracts from major gastrointestinal meetings, and references from published articles and reviews. STUDY SELECTION: Nine randomized, placebo-controlled trials of azathioprine or 6-mercaptopurine therapy were identified: Four addressed active disease, two addressed quiescent disease, and three had multiple therapeutic arms. DATA EXTRACTION: Data were extracted by three independent observers on the basis of the intention-to-treat principle and were analyzed with logistic regression. Each study was given a quality score on the basis of predetermined criteria. DATA SYNTHESIS: Compared with placebo, azathioprine or 6-mercaptopurine therapy had an odds ratio of response of 3.09 (95% CI, 2.45 to 3.91) in patients with active Crohn disease. When the single trial that used 6-mercaptopurine in active disease was excluded from the analysis, the odds ratio of response was 1.45 (CI, 1.12 to 1.87). No trials of quiescent disease used 6-mercaptopurine; the odds ratio of response in these trials of quiescent disease was 2.27 (CI, 1.76 to 2.93). For active disease, continuation of therapy for at least 17 weeks improved response (P = 0.03). For quiescent disease, a higher dose improved response (P = 0.008). Increased cumulative dose improved response in both groups (P < 0.001 for active disease and P = 0.01 for quiescent disease). A steroid-sparing effect was seen in active disease (odds ratio, 3.69 (CI, 2.12 to 6.42) and in quiescent disease (odds ratio, 4.64 [CI, 1.00 to 21.54]). Fistulae improved with therapy (odds ratio, 4.44 [CI, 1.50 to 13.20]). Adverse events requiring withdrawal from a trial, primarily allergy, leukopenia, pancreatitis, and nausea, were increased with therapy (odds ratio, 5.26 [CI, 2.20 to 12.60]). CONCLUSIONS: Azathioprine and 6-mercaptopurine are effective in treating active Crohn disease and in maintaining remission. Cumulative dose was an important factor in predicting response. Adverse effects were more common among patients receiving therapy.

Azathioprine↗
PubMed1995

Neuroprotective profile of lifarizine (RS-87476) in rat cerebrocortical neurones in culture.

1. The ability of the neuroprotective agent, lifarizine (RS-87476), to mitigate veratridine-, cyanide- and glutamate-induced toxicity in rat embryonic cerebrocortical neurones in primary culture has been compared with that of tetrodotoxin (TTX), nitrendipine, (+)-MK-801 and (-)-MK-801. Lactate dehydrogenase (LDH) released into the culture medium was used as the indicator of cell viability. 2. Incubation of cultures for 16 h in a medium containing veratridine (10(-4) M), sodium glutamate (10(-3) M) or sodium cyanide (10(-3) M) resulted in consistent elevations of LDH activity in the culture medium. The ability of compounds to attenuate these elevations was expressed as the concentration required to inhibit the increases in LDH release by 50% (IC50). 3. Neurotoxicity induced by veratridine was inhibited by lifarizine (IC50 = 4 x 10(-7) M), TTX (IC50 = 3 x 10(-8) M) and nitrendipine (IC50 = 3 x 10(-5) M). In contrast, (+)-MK-801 (up to 3 x 10(-5) M) was ineffective against this insult. 4. Glutamate-induced neurotoxicity was inhibited by (+)-MK-801 (IC50 = 1.4 x 10(-8) M) and to a lesser extent by (-)-MK-801 (IC50 = 1 x 10(-7) M), but was unaffected by lifarizine, TTX or nitrendipine (up to 10(-6) M). 5. (+)-MK-801 was effective against sodium cyanide-induced neurotoxicity (IC50 = 1.9 x 10(-8) M), whereas lifarizine and TTX (up to 10(-6) M) and nitrendipine (up to 3 x 10(-6) M) were without protective activity against this insult. 6. The results demonstrate that lifarizine potently protects rat cortical neurones in vitro against a neurotoxic insult that requires activation of sodium channels for its expression, and that the compound is ineffective against insults mediated by N-methyl-D-aspartate receptor activation. The weak efficacy of nitrendipine against veratridine-induced cell death argues against the involvement of L-type calcium channels in this insult. These data are consistent with the notion that the neuroprotective activity oflifarizine observed in vivo may be mediated by inhibition of neuronal sodium currents.

Animals↗
PubMed1995

Meta-analysis of the role of oral contraceptive agents in inflammatory bowel disease.

Numerous epidemiological studies have been performed to determine factors that might contribute to the development of inflammatory bowel disease. Although the role of oral contraceptive agents in Crohn's disease (CD) and ulcerative colitis (UC) have been assessed, most studies were of small sample size and characterised by low statistical precision. A meta-analysis was performed to increase the statistical power and to investigate the association between the use of oral contraceptives and the development of CD and UC. The study was based on a search of a Medline database from 1975 to October 1993 and a review of reference lists from published articles, reviews, symposia proceedings, and abstracts from major gastrointestinal meetings. All studies specifically designed to evaluate this association were selected. The combined results of nine studies--two cohort studies (30,379 unexposed and 30,673 exposed patients) and seven case-control studies (482 CD, 237 UC, and 3198 controls)--which satisfied our selection criteria were evaluated. The pooled relative risk (adjusted for smoking) associated with oral contraceptive use was 1.44 (1.12, 1.86) for CD and 1.29 (0.94, 1.77) for UC. These results suggest modest associations between the use of oral contraceptives and the development of CD and UC. As these associations are weak, non-causal explanations for the findings cannot be eliminated.

Case-Control Studies↗
PubMed1994

The effect of propofol on the canine sphincter of Oddi.

To assess the effect of propofol on the canine sphincter of Oddi(SO), sphincter of Oddi manometry (SOM) was performed in fasting dogs which had undergone cholecystectomy and placement of modified Thomas duodenal cannulae. Using two water-perfused, single-lumen manometric catheters, SO and duodenal pressures were measured simultaneously. Baseline SO activity was recorded for at least one complete interdigestive cycle followed by bolus injections of propofol (Diprivan) (N = 31) from 0.1 to 4.0 mg/kg during Phase I of the Migrating Motor Complex (MMC). When propofol was administered in bolus doses < or = 0.4 mg/kg, no change in SO or duodenal motor function was seen. In doses > or = 0.5 mg/kg, SO basal pressure, amplitude, and frequency of contractions increased significantly. Increases in duodenal activity paralleled SO activity. Our results suggest that propofol in low doses may be useful for sedation during Sphincter of Oddi manometry in humans. Further studies of the effect of propofol on the human sphincter of Oddi are warranted.

Animals↗
PubMed1993

Sulfasalazine revisited: a meta-analysis of 5-aminosalicylic acid in the treatment of ulcerative colitis.

PURPOSE: To assess the effectiveness of the newer 5-aminosalicylic acid (5-ASA) delivery systems compared with placebo or sulfasalazine for the treatment of active ulcerative colitis and for the maintenance of remission. DATA SOURCES: Pertinent studies were selected using the MEDLINE and BIOS (1981 to 1992) data bases, reference lists from published articles, reviews, symposia proceedings, and abstracts from major gastrointestinal meetings. STUDY SELECTION: Randomized controlled trials of 5-ASA compared with placebo or sulfasalazine of a minimum of 4 weeks duration for active disease and a minimum of 6 months for maintenance of disease remission. Sixteen trials of 5-ASA for active disease, published either in abstract or full manuscript, were available. Eleven trials of 5-ASA for maintenance of remission were also reviewed. DATA EXTRACTION: Crude rates for either induction of remission (active disease studies) or maintenance of remission (relapse-prevention trials) based on the intention-to-treat principle were extracted from the studies by two independent observers. Each study was given a quality score, based on predetermined criteria. RESULTS: Studies were placed in three groups: 5-ASA compared with placebo, 5-ASA compared with sulfasalazine for active disease, and 5-ASA compared with sulfasalazine for maintenance of remission. 5-Aminosalicylic acid was superior to placebo in the treatment of active ulcerative colitis (pooled odds ratio, 2.02; 95% CI, 1.50 to 2.72). A dose-response effect for 5-ASA existed (P < 0.001). For active disease, the pooled odds ratio for 5-ASA compared with sulfasalazine was 1.15 (CI, 0.83 to 1.61). When 5-ASA was compared with sulfasalazine for maintenance of disease remission, the pooled odds ratio was 0.85 (CI, 0.64 to 1.15). Withdrawal rates and reported side effects were similar for 5-ASA compared with placebo- or sulfasalazine-treated patients. CONCLUSIONS: Although the newer 5-ASA preparations in a dose of at least 2 g/d are more effective than placebo in the treatment of ulcerative colitis, insufficient evidence exists to suggest that they are superior to sulfasalazine. Although they offer a benefit to the sulfasalazine-sensitive patient, use of 5-ASA preparations instead of sulfasalazine in the treatment of ulcerative colitis cannot yet be substantiated.

Aminosalicylic Acids↗
PubMed1993

Gastrointestinal symptoms in ambulatory HIV-infected patients.

Gastrointestinal symptoms are commonly seen in patients with established AIDS. We examined the charts of 258 HIV-infected patients attending our HIV outpatient clinic to determine: (1) the frequency of gastrointestinal symptoms in unselected HIV-infected patients and (2) if there are any predictors of the development of symptoms in initially asymptomatic patients. We found the overall frequency of gastrointestinal symptoms at initial presentation in our ambulatory, predominantly homosexual population of HIV-infected patients was 35% (95% CI 30-40%) with 19% having anorexia, 15% weight loss, 14% diarrhea, and 5% dysphagia. There was no association between the presence of symptoms and stool parasites, which were found in 51% of patients. In 165 patients who were initially asymptomatic, 72% subsequently developed symptoms over 36 months of actuarial follow-up. Patients with initial T4 counts < 500 were more likely to develop symptoms. Patients with a greater degree of immunosuppression as indicated by a lower T4 count, are more likely to develop gastrointestinal symptoms.

Ambulatory Care↗
PubMed1993

Is small intestinal permeability really increased in relatives of patients with Crohn's disease?

BACKGROUND: Patients with Crohn's disease have increased intestinal permeability, which may precede the development of clinical disease and be involved in disease pathogenesis. Subsequent studies have suggested that, as a group, first-degree relatives of patients with Crohn's disease do not have significantly increased small intestinal permeability rates. The present study proposes that conventional data analysis, used in these studies, may be inappropriate and has overlooked an important observation. METHODS: Lactulose and mannitol permeabilities were defined in healthy controls and in patients with Crohn's disease and their first-degree relatives. RESULTS: Intestinal permeability in relatives was similar to that in the control group, but a subpopulation had abnormally high permeability rates in the absence of clinical evidence for disease. Raw data from another investigator confirmed this finding in an additional study; consequently, it is concluded that the original hypothesis is still viable. A small proportion of individuals, at high risk of developing Crohn's disease, have increased intestinal permeability. CONCLUSIONS: Increased intestinal permeability may precede clinical manifestations of Crohn's disease.

Crohn Disease↗
PubMed1993

Efficacy of bile acid therapy for gallstone dissolution: a meta-analysis of randomized trials.

To define better the efficacy of bile acid therapy for dissolution of radiolucent gallstones, we performed a meta-analysis of published trials from January 1966 to September 1992. Studies were identified using a MEDLINE computer search followed by an extensive manual search. The inclusion criteria used were: randomized trial, radiolucent gallstones in a visualizing gallbladder on oral cholecystography, and complete stone dissolution confirmed by oral cholecystography or ultrasound. Study results were pooled into 6 groups: placebo: high- and low-dose chenodeoxycholic acid (CDCA) (> or = 10 mg.kg/day and < 10 mg.kg/day); high- and low-dose ursodeoxycholic acid (UDCA) (> or = 7 mg.kg/day and < 7 mg.kg/day) and combined CDCA plus UDCA. Homogeneity calculations were performed and the percentage of complete stone dissolution calculated for each group with 95% confidence intervals. Of 66 trials identified, 23 comprising 1949 patients met the inclusion criteria. A total of 1062 patients were treated with CDCA, 819 with UDCA and 78 combination therapy. In studies > 6 months' duration, high-dose UDCA completely dissolved stones in 37.3% of patients (95% C.I. 33-42%), low-dose UDCA in 20.6%) and high-dose CDCA 18.2% (95% C.I. 15-21%). Based on only two studies, combination therapy achieved dissolution in 62.8% (95% C.I. 51-74%) of patients. Stones less than 10 mm dissolved significantly more frequently than stones larger than 10 mm. This analysis shows that UDCA in doses greater than 7 mg.kg/day taken for greater than 6 months will dissolve radiolucent gallstones in 38% of patients. The combination of UDCA and CDCA may be more efficacious but this observation is based upon only 78 patients and requires confirmation in further randomized trials.

Chenodeoxycholic Acid↗
PubMed1992

The pharmacological modulation of thrombin-induced cerebral thromboembolism in the rabbit.

1. Intracarotid (i.c.) administration of thrombin induced a marked accumulation of 111indium-labelled platelets and 125I-labelled fibrinogen within the cranial vasculature of anaesthetized rabbits. 2. Thrombin (100 iu kg-1, i.c.) - induced platelet accumulation was completely abolished by pretreatment with desulphatohirudin (CGP 39393; 1 mg kg-1 i.c., 1 min prior to thrombin). Administration of CGP 39393 1 or 20 min after thrombin produced a significant reduction in platelet accumulation. 3. Intravenous (i.v.) administration of the platelet activating factor (PAF) receptor antagonist BN 52021 (10 mg kg-1) 5 min prior to thrombin (100 iu kg-1, i.c.) had no effect on platelet accumulation. 4. An inhibitor of NO biosynthesis, L-NG-nitro arginine methyl ester (L-NAME; 100 mg kg-1, i.c.), had no significant effect on the cranial platelet accumulation response to thrombin (10 iu kg-1, i.c.) when administered 5 min prior to thrombin. 5. Defibrotide (32 or 64 mg kg-1 bolus i.c. followed by 32 or 64 mg kg-1 h-1, i.c., infusion for 45 min) treatment begun 20 min after thrombin (100 iu kg-1, i.c.) did not significantly modify the cranial platelet accumulation response. 6. Cranial platelet accumulation induced by thrombin (100 iu kg-1, i.c.) was significantly reversed by the fibrinolytic drugs urokinase (20 iu kg-1, i.c., infusion for 45 min), anisoylated plasminogen streptokinase activator complex (APSAC) (200 micrograms kg-1, i.v. bolus) or recombinant tissue plasminogen activator (rt-PA; 100 micrograms kg-1, i.c. bolus followed by 20 micrograms kg-1 min-1, i.c., infusion for 45 min) administered 20 min after thrombin.8. These results suggest that neither endogenous PAF nor NO modulate thrombin-induced intracranial platelet accumulation in the rabbit. However, fibrin deposition appears to play an important role as shown by the ability of fibrinolytic agents to reverse platelet and fibrinogen accumulation induced by i.c. thrombin.

Animals↗
PubMed1991

Should elective endoscopic sphincterotomy replace cholecystectomy for the treatment of high-risk patients with gallstone pancreatitis?

Since the introduction of endoscopic sphincterotomy approximately 15 years ago, the indications for this procedure have expanded. Currently endoscopic sphincterotomy is the procedure of choice for management of retained common bile duct stones following cholecystectomy. It is also being used more frequently for choledocholithiasis with an intact gallbladder in high-risk patients and in some patients with acute gallstone pancreatitis. In patients recovering from an episode of gallstone pancreatitis, standard practice has been subsequent cholecystectomy with possible exploration of the common bile duct. To avoid surgery in high-risk patients, we propose that an elective endoscopic sphincterotomy may be a reasonable therapeutic option regardless of whether common bile duct stones are present at the time of ERCP. A prospective trial is needed to examine this issue since to date there is no literature on endoscopic sphincterotomy in the absence of choledocholithiasis for gallstone pancreatitis in patients with intact gallbladders.

Cholecystectomy↗
PubMed1991

The role of nitric oxide as an endogenous regulator of platelet and neutrophil activation within the pulmonary circulation of the rabbit.

1. Intravenous (i.v.) administration of adenosine diphosphate (ADP), platelet activating factor (PAF) and thrombin induced a dose-related accumulation of 111indium-labelled platelets within the thoracic region of anaesthetized rabbits. 2. I.v. administration of the inhibitor of NO biosynthesis, L-NG-nitro arginine methyl ester (L-NAME; 10 mg kg-1) significantly potentiated the peak platelet accumulation induced by ADP, PAF and thrombin. Additionally L-NAME prolonged the disaggregation of platelets in comparison to D-NAME (10 mg kg-1). Such changes were reversible by the administration of L-arginine (900 mg kg-1). 3. I.v. administration of PAF induced a small accumulation of 111indium-labelled neutrophils within the pulmonary circulation which could be greatly potentiated by pretreatment of the animals with L-NAME. In contrast, thrombin administration did not cause significant accumulation of 11indium-labelled erythrocytes in the pulmonary circulation of anaesthetized rabbits. 4. Intracarotid (i.c.) administration of thrombin induced a marked accumulation of radiolabelled platelets within the cranial vasculature which was not potentiated by the prior administration of L-NAME (at either 10 mg kg-1 or 100 mg kg-1). 5. These results suggest that endogenous NO may regulate platelet and polymorphonuclear leukocyte activation within the pulmonary but not the cerebral circulation of rabbits.

Adenosine Diphosphate↗
PubMed1990

Radioisotopic model for investigating thromboembolism in the rabbit.

111Indium (111In)-oxine labeled platelets have been used in a variety of species to assess platelet behavior in vivo. We have shown that 111In-oxine is a suitable label for rabbit platelets and, using a noninvasive technique for the automated, continuous, external imaging of these radiolabeled platelets, we have shown that intravenous adenosine disphosphate (ADP), collagen, platelet activating factor (PAF), and thrombin all elicit dose-related accumulation of platelet-(but not erythrocyte-)associated radioactivity in the thoracic region and a concomitant fall in both the cranial and hindlimb regions of the anesthetized rabbit. Intracarotid (i.c.) ADP, collagen, PAF, and thrombin also produce dose-related increases in platelet-associated radioactivity in the thoracic and decreases in the cranial and hindlimb regions. However, the initial fall in cranial counts induced by i.c. thrombin was followed by a marked increase that was sustained for up to 3 hr. These results suggest this may be a useful model for investigating the mechanisms of platelet activation in the arterial and venous circulations in vivo and may provide a novel model for investigating thromboembolic events in the cerebral circulation.

Adenosine Diphosphate↗
PubMed1990

Safety of same-day sequential extracorporeal shock wave lithotripsy and dissolution of gallstones by methyl tert-butyl ether in dogs.

Passage of stone fragments after extracorporeal shock wave lithotripsy (ESWL) of gallstones has resulted in biliary colic, duct obstruction, and pancreatitis in some patients. Rapid dissolution of these fragments with methyl tert-butyl ether (MTBE) may prevent such side effects and achieve complete clearance of gallstones within hours rather than several months to a year or longer. This study examines the safety of same-day ESWL fragmentation and MTBE dissolution of surgically implanted human gallstones in 15 dogs. The animals were randomly assigned to one of four treatment groups to assess MTBE absorption from the gallbladder and to observe hematology and chemistry profiles after 0, 400, and 1,200 shock waves from a lithotriptor followed by MTBE dissolution therapy. They were sacrificed either immediately after treatment (12 dogs) or 2 weeks later (3 dogs). The results demonstrated that although ESWL causes moderate trauma to the gallbladder, this did not result in increased MTBE absorption or histologic evidence of mucosal disruption. Blood profiles demonstrated an increase in only the level of aspartate aminotransferase. The three dogs that were sacrificed 2 weeks after the combined treatment had no residual evidence of gallbladder injury or remaining stone material. In all animals, severe injury occurred where shock waves passed through lung or air-filled colon. This study suggests that same-day sequential fragmentation of gallstones by ESWL followed by dissolution of stone fragments with use of MTBE may be associated with only mild to moderate and reversible gallbladder trauma and can rapidly achieve clearance of gallstones.

Animals↗
PubMed1990

Endothelin-1 inhibits platelet aggregation in vivo: a study with 111indium-labelled platelets.

1. A non-invasive technique for the scintigraphic determination of 111indium-labelled platelet aggregation stimulated with submaximal doses of adenosine diphosphate (ADP, 56 micrograms kg-1 i.v.), collagen (100 micrograms kg-1 i.v.), platelet-activating factor (PAF, 0.1 microgram kg-1 i.v.) or thrombin (18 iu kg-1 i.v.) was used to investigate the platelet-inhibitory effects of endothelin 1 (ET-1) in anaesthetized rabbits in vivo. 2. ET-1 (1 nmol kg-1 i.v.) inhibited ADP-stimulated platelet aggregation in vivo; a maximum inhibition of 78% of the control value was reached at 3 min, with 45% inhibition at 15 min, and a return to control values at 30 min after injection of the peptide. 3. ET-1 (1 nmol kg-1 i.v.) inhibited in vivo platelet aggregation in response to collagen or PAF by 86% and 52%, respectively, but had no effect on thrombin-induced platelet aggregation. 4. Indomethacin (5 mg kg-1 i.v.) abolished the ET-1-induced inhibition of ADP-stimulated platelet aggregation and significantly potentiated and prolonged the pressor response brought about by ET-1. 5. In conclusion, the data demonstrate that ET-1 potently inhibits platelet aggregation in the anaesthetized rabbit in vivo by releasing a hypotensive and anti-aggregatory cyclo-oxygenase product, presumably prostacyclin, into the circulation.

Adenosine Diphosphate↗
PubMed1989

Dissolution of cholesterol gallbladder stones by methyl tert-butyl ether administered by percutaneous transhepatic catheter.

We treated 75 patients with symptomatic cholesterol gallstones by dissolving the stones with methyl tert-butyl ether (MTBE) instilled into the gallbladder through a percutaneous transhepatic catheter. The MTBE was continuously infused and aspirated manually four to six times a minute, for an average of five hours per day for one to three days; the treatment was monitored by fluoroscopy. The placement of the catheter and the administration of MTBE caused few side effects or complications, and treatment did not have to be stopped in any patient for this reason. In 72 patients there was complete dissolution of stones or more than 95 percent dissolution. Among 21 patients who were completely free of stones after treatment, 4 had recurrence of stone formation 6 to 16 months later. The other 51 patients had residual debris, which spontaneously cleared completely in 15 patients within 6 to 35 months; only 7 with persisting debris have had symptoms. Five of the initial 6 patients treated, but only 1 of the next 69 patients, have required surgery during follow-up periods of 6 to 42 months. We conclude that the dissolution of gallstones by MTBE delivered through a percutaneous transhepatic catheter is a useful alternative to surgery in selected patients with symptomatic cholesterol stones. Further study will be necessary to establish the long-term effectiveness of this treatment and its appropriate role in the management of the various types of gallstones.

Adult↗
PubMed1988

Endothelium-derived relaxing factor inhibits platelet aggregation in human whole blood in vitro and in the rat in vivo.

Carbachol (0.03-10 microM) or histamine (0.06-10 microM) challenge of indomethacin-pretreated rat aortic rings inhibited ADP-induced aggregation of platelets suspended in anticoagulated human whole blood. The maximum inhibition of platelet aggregation achieved with either drug was approximately 50%. No such inhibition was observed in rat aortic rings rubbed to remove endothelial cells or in intact vessels preincubated with nordihydroguaiaretic acid (NDGA, 10 microM), mepacrine (10 microM) or methylene blue (100 microM). Intravenously (i.v.) injected carbachol (0.5-5 micrograms/kg) also inhibited ADP-induced accumulation of 111indium-labelled platelets in the pulmonary circulation of urethane-anaesthetised rats. This effect of carbachol was inhibited by i.v. injected methylene blue (10 mg/kg) but unaffected by indomethacin (3 mg/kg) or hexamethonium (10 mg/kg) suggesting that PGI2 or adrenaline release did not account for the inhibition of platelet activation observed. Similarly, the platelet inhibitory effect of carbachol in vivo was not related to increased pulmonary vascular blood flow (assessed by accumulation of 111indium-labelled erythrocytes) or blood fibrinolytic activity (measured by euglobulin clot bioassay). The present results suggest that endothelium-derived relaxing factor or a like substance inhibits human platelet aggregation in vitro and rat platelet aggregation in vivo.

6-Ketoprostaglandin F1 alpha↗