Colorectal endoscopic full-thickness resection using a novel, flat-base over-the-scope clip: a prospective study.

Background and study aims We aimed to evaluate the feasibility and safety of a new, flat-based over-the-scope clip (Padlock Clip) for colorectal endoscopic full-thickness resection (eFTR). Patients and methods We prospectively included 26 patients with lesions < 20 mm. Indications for eFTR were re-resection of the scar of a low risk malignant polyp (n = 11), recurrent adenoma in a non-lifting scar (n = 10), non-lifting polyp (n = 4), and an adenoma located in a diverticulum (n = 1). Results Technical success rate and full-thickness resection rate were 100 % (26/26) and 92 % (24/26), respectively. Median procedure time was 43 minutes (IQR 27 - 56). No complications occurred during the procedure; 3 complications (12 %) occurred within 48 hours, of which one was a perforation requiring laparoscopic suturing. Specimen volumes from eFTR of scar tissue where the original polyp had been ≥ 20 mm (n = 13) were smaller compared with those from non-scar resections or scars where the original polyps had been < 20 mm (n = 13) (median 0.8 vs. 1.5 cm3, P = 0.03). Conclusions In this first series of colorectal eFTR using the Padlock Clip, feasibility was demonstrated. It was relatively safe in view of surgery as the alternative treatment, but could still benefit from technical refinement. Future studies should explore for which indication this technique is most suitable. TRIAL REGISTRATION: NTR5562 (Dutch Trial Register).

Effects of hypothermia on propranolol kinetics.

Propranolol may be uniquely useful in cardiac surgical procedures, since beta adrenergic blockade can prevent the hypokalemia and associated arrhythmias which result from systemic hypothermia. To determine the effects of hypothermic cardiopulmonary bypass (HCPB) on the in vivo handling of propranolol, serial drug plasma concentrations (Cp) were measured during HCPB in 12 patients who had been treated chronically with propranolol prior to surgery. Although no further propranolol was given during the procedure, Cp values (corrected for plasma volume dilution) were higher during hypothermia than in the preoperative period, falling to or below control levels after rewarming. Due to the variables inherent in patient surgery, meaningful kinetic analysis could not be carried out. Therefore, intravenous propranolol (1 mg/kg) was given twice to each of 5 dogs, first after anesthesia only, then after anesthesia and systemic cooling to 26 degrees in a water bath Cp values measured serially over 2 hr after drug administration were consistently higher during hypothermia. Compared with the paired normothermic control studies, hypothermia markedly reduced the apparent volume of distribution (6.78 +/- 1.65 vs 2.08 +/- 0.58 L/kg; p less than 0.001) and the total body clearance of propranolol (64.4 +/- 11.0 vs 32.3 +/- 7.2 ml/kg/min; p less than 0.005). These data show that hypothermia substantially alters the pharmacokinetics of propranolol, resulting in plasma drug levels higher than those predicted from kinetic patterns derived under normothermic conditions.

Cardiovascular and pharmacokinetic consequences of combined administration of verapamil and propranolol in dogs.

Verapamil and propranolol, alone and in combination, were given intravenously to anesthetized dogs to analyze the interaction between drug-induced cardiovascular effects and the resulting changes in pharmacokinetics. Dosing regimens were used that produced steady state plasma levels of both drugs, and the observed effects were clearly related to the plasma concentrations of the agents. When given alone, at stable "therapeutic" levels in plasma, verapamil or propranolol decreased spontaneous heart rate, increased atrioventricular conduction time, and had opposite effects on cardiac output. At the same doses, the combined infusion of the 2 drugs rapidly resulted in profound depression in cardiac function; in addition, plasma concentrations of both agents increased into ranges associated with cardiovascular toxicity. When verapamil doses were reduced, combined infusion with propranolol decreased atrioventricular conduction and cardiac output, but drug plasma concentrations (and associated effects) remained stable. When reduced doses of propranolol were added to infusion of verapamil, similar effects on cardiovascular function occurred, but plasma drug levels increased progressively throughout the remainder of the study period. In all combinations studied, beta blockade with propranolol decreased liver plasma flow and, therefore, the systemic clearance of verapamil. The in vitro effects of propranolol on verapamil metabolism were small, although significant, and not clinically relevant. These acute studies suggest that the hemodynamic effects resulting from verapamil and propranolol in combination may significantly diminish clearance of 1 or both drugs, thereby resulting in accumulation during continued administration, increased drug effects with increasing plasma concentrations, and potentially lethal drug toxicity.

Ranitidine bismuth citrate with clarithromycin versus omeprazole with amoxycillin in the cure of Helicobacter pylori infection.

AIM: To compare the efficacy of ranitidine bismuth citrate plus clarithromycin (RBC-C) vs. omeprazole plus amoxycillin (OME-AMO) in the cure of Helicobacter pylori infection. METHODS: In this double-blind, multicentre, parallel-group study 122 H. pylori-positive patients with active duodenal ulcer or gastritis, with confirmed history of duodenal ulcer, were randomized to treatment with ranitidine bismuth citrate 400 mg b.d. plus clarithromycin 500 mg b.d. or omeprazole 20 mg b.d. plus amoxycillin 1000 mg b.d. for 14 days, followed by 14 days of ranitidine bismuth citrate 400 mg b.d. or omeprazole 20 mg once daily, respectively, to facilitate ulcer healing. Endoscopy was carried out at the start of the study and 28 days after the end of treatment. At each endoscopy four biopsies were obtained from the antrum and four biopsies from the corpus, for rapid urease test, histology and culture. H. pylori infection was defined as a positive urease test, confirmed by histology or culture. Cure of H. pylori infection was defined as negative urease test, histology or culture from both sites. RESULTS: Per-protocol, all-patients-treated and intention-to-treat cure rates (95% confidence interval) were, respectively, 90% (81-89%), 90% (82-89%) and 84% (74-93%) for ranitidine bismuth citrate plus clarithromycin, and 39% (27-54%), 44% (31-57%) and 41% (29-53%) for omeprazole plus amoxycillin, P < 0.00001. Both regimens were well tolerated. Eight patients were lost to follow-up, for lack of efficacy (one patient), adverse events (three patients) or refusal of second endoscopy (four patients). CONCLUSION: Ranitidine bismuth citrate 400 mg b.d. with clarithromycin 500 mg b.d. is superior to omeprazole 20 mg b.d. with amoxycillin 1000 mg b.d. Ranitidine bismuth citrate with clarithromycin is the first dual therapy with high cure rates and good tolerance, and is easy to take. It may therefore prove a suitable first-line treatment in H. pylori infection.

A double-blind, randomized comparison of omeprazole Multiple Unit Pellet System (MUPS) 20 mg, lansoprazole 30 mg and pantoprazole 40 mg in symptomatic reflux oesophagitis followed by 3 months of omeprazole MUPS maintenance treatment: a Dutch multicentre trial.

BACKGROUND: Proton pump inhibitors (PPIs) have proved to be effective in treating reflux oesophagitis. Until now, no study had compared the PPIs omeprazole Multiple Unit Pellet System (MUPS), lansoprazole and pantoprazole in patients with reflux oesophagitis. AIM: To compare omeprazole MUPS 20 mg, lansoprazole 30 mg and pantoprazole 40 mg for treatment effect in symptomatic reflux oesophagitis. METHOD: Patients with grade I-IV symptomatic reflux oesophagitis were randomized to double-blind omeprazole 20 mg once morning, lansoprazole 30 mg o.m. or pantoprazole 40 mg o.m. Patient satisfaction and symptoms were evaluated after 4 and 8 weeks. Patients not satisfied after 8 weeks were treated for another 4 weeks with omeprazole 40 mg MUPS (open). Successful treatment was followed by 3 months' maintenance treatment with omeprazole MUPS 20 mg (patients satisfied after 4 or 8 weeks) or omeprazole MUPS 40 mg (patients satisfied after 12 weeks). RESULTS: On intention-to-treat (ITT) analysis (n = 461) at 4 and 8 weeks, respectively, 84% and 87% (omeprazole MUPS), 78% and 81% (lansoprazole), and 84% and 89% (pantoprazole) were free of heartburn. Equivalence was found between omeprazole MUPS and pantoprazole (heartburn relief), but not with lansoprazole. Patient satisfaction after 4 and 8 weeks, respectively, was 79% and 89% (omeprazole MUPS), 76% and 86% (lansoprazole), and 79% and 91% (pantoprazole). Patient satisfaction was similar in all treatment groups. During maintenance, 87% in the omeprazole MUPS 20 mg group and 81% in the omeprazole MUPS 40 mg group were satisfied after 3 months. CONCLUSIONS: Omeprazole MUPS 20 mg and pantoprazole 40 mg have equivalent efficacy in the treatment of reflux oesophagitis. Based on patient satisfaction, omeprazole MUPS 20 mg, lansoprazole 30 mg and pantoprazole 40 mg are equally effective.

GLC assay of verapamil in plasma: identification of fluorescent metabolites after oral drug administration.

The fluorometric assay for verapamil in plasma is not useful after oral drug administration because of interference by inactive, but fluorescent, metabolites extracted along with the parent drug. A GLC method using a flame-ionization detector after silylation allows the separation of unchanged active verapamil from the metabolites and quantitation to a sensitivity of 0.025 microgram/ml. After a single oral dose of drug in dogs, up to 80% of "fluorescent verapamil" represented inactive metabolites.

Exoplanet detection. A terrestrial planet in a ~1-AU orbit around one member of a ~15-AU binary.

Using gravitational microlensing, we detected a cold terrestrial planet orbiting one member of a binary star system. The planet has low mass (twice Earth's) and lies projected at ~0.8 astronomical units (AU) from its host star, about the distance between Earth and the Sun. However, the planet's temperature is much lower, <60 Kelvin, because the host star is only 0.10 to 0.15 solar masses and therefore more than 400 times less luminous than the Sun. The host itself orbits a slightly more massive companion with projected separation of 10 to 15 AU. This detection is consistent with such systems being very common. Straightforward modification of current microlensing search strategies could increase sensitivity to planets in binary systems. With more detections, such binary-star planetary systems could constrain models of planet formation and evolution.

Randomised clinical trial: once- vs. twice-daily prolonged-release mesalazine for active ulcerative colitis.

BACKGROUND: Aminosalicylates are first-choice treatment for mild-to-moderately active ulcerative colitis (UC); however, multi-dosing regimens are inconvenient. AIM: To compare the efficacy and safety of once- (OD) vs. twice- (BD) daily prolonged-release mesalazine (Pentasa, Ferring, Saint-Prex, Switzerland) for active mild-to-moderate UC in a non-inferiority study. METHODS: Eligible patients (n = 206) were randomised to 8 weeks of mesalazine (4 g/day), either OD with two sachets of 2 g mesalazine granules in the morning (n = 102) or BD with one 2 g sachet in the morning and one in the evening (n = 104). Patients also received 4 weeks of mesalazine enema 1 g/day. Disease activity was assessed at randomisation, weeks 4, 8 and 12 using the UC Disease Activity Index (UC-DAI). Clinical and endoscopic remission (primary endpoint) was assessed after 8 weeks. Patients recorded stool frequency and rectal bleeding in a daily diary. RESULTS: The primary endpoint, non-inferiority in clinical and endoscopic remission with OD vs. BD mesalazine at 8 weeks, was met (intent-to-treat population: 52.1% vs. 41.8%, respectively, 95% confidence interval -3.4, 24.1; P = 0.14). Improvement of UC-DAI score (92% vs. 79%; P = 0.01) and mucosal healing (87.5% vs. 71.1%; P = 0.007) were significantly better, time to remission significantly shorter (26 vs. 28 days; P = 0.04) and safety similar with OD vs. BD dosing. CONCLUSIONS: When combined with mesalazine enema, prolonged-release mesalazine once-daily 4 g is as effective and well tolerated as 2 g twice-daily for inducing remission in patients with mild-to-moderately active ulcerative colitis (Clinicaltrials.gov: NCT00737789).

Combined oral and enema treatment with Pentasa (mesalazine) is superior to oral therapy alone in patients with extensive mild/moderate active ulcerative colitis: a randomised, double blind, placebo controlled study.

BACKGROUND AND AIMS: Oral aminosalicylates are well established in the treatment of active mild/moderate ulcerative colitis (UC) when the disease is extensive (that is, beyond the splenic flexure). The majority of clinical symptoms relate to disease activity in the distal part of the colon and therefore this study was designed to investigate if adding a mesalazine enema to oral mesalazine has additional benefit for patients with extensive mild/moderate active UC. METHODS: A randomised double blind study was performed in 127 ambulatory patients. All received 4 g/day (twice daily dosing) oral mesalazine for eight weeks. During the initial four weeks, they additionally received an enema at bedtime containing 1 g of mesalazine or placebo. Disease activity was assessed using the ulcerative colitis disease activity index, with clinical and endoscopic signs at four and eight weeks. RESULTS: Remission was obtained in 44% (95% confidence interval (CI) 31%, 58%) of the mesalazine enema group (Me) and in 34% (95% CI 21%, 49%) of the placebo enema group (Pl) at four weeks (p = 0.31) and in 64% (95% CI 50%, 76%) of the Me group versus 43% (95% CI 28%, 58%) of the Pl group at eight weeks (p = 0.03). Improvement was obtained in 89% (95% CI 78%, 96%) of the Me group versus 62% (95% CI 46%, 75%) of the Pl group at four weeks (p = 0.0008) and in 86% (95% CI 75%, 94%) of the Me group versus 68% (95% CI 53%, 81%) of the Pl group at eight weeks (p = 0.026). CONCLUSION: In patients with extensive mild/moderate active UC, the combination therapy is superior to oral therapy. It is safe, well accepted, and may be regarded as firstline treatment.

Effect of hypothermia on drug metabolism. In vitro studies with propranolol and verapamil.

Propranolol and verapamil are cardioactive drugs which may be useful during surgical procedures involving hypothermic cardiopulmonary bypass. Previous in vivo studies have shown that the pharmacokinetics of propranolol are altered by hypothermia, and that clearance of the drug is significantly reduced by lowered body temperature. Since both propranolol and verapamil are eliminated largely by hepatic metabolic activity, the effect of hypothermia on the ability of the liver to metabolize both drugs was studied in vitro with rat hepatic microsome preparations. Known quantities of the drugs were added after preincubation of microsomes at 37 degrees C (normothermia) or 26 degrees C (hypothermia), and the amount of drug substrate remaining after an additional incubation period was measured. Hypothermic microsomes metabolized significantly less of each drug at all substrate concentrations studies (p less than 0.001). Double-reciprocal plots showed similar results for experiments with both propranolol and verapamil: the extrapolated Vmax was the same for both temperature conditions, but the Km values were significantly increased by hypothermia (p less than 0.001), indicating reduced affinity for drug substrate by the microsomal enzymes. These in vitro studies show that hepatic metabolic elimination of both propranolol and verapamil is decreased by hypothermia.

Glucuronidation of bilirubin and the occurrence of pigment gallstones in patients with chronic haemolytic diseases.

A group of thirty-seven patients with increased haem catabolism has been studied to gain insight in their bilirubin conjugating capacity. Bilirubin UDP-glucuronyl transferase activity (GlcATa) in the liver and bilirubin monoconjugates in bile were measured and the hepatic bilirubin clearance was calculated from the radio-chromium-survival data. In the present group, 41% of the patients clearly had a deficiency in bilirubin conjugation similar to what is classically found in Gilbert's syndrome. The association may facilitate detection of these patients as serum bilirubin levels were higher (65.8 microM +/- 19) (m +/- 1 SD) in the fifteen patients with associated Gilbert's syndrome versus thirteen having only haemolysis (43.6 microM +/- 15). A fair correlation was found between the percentage of monoconjugates in bile and the GlcATa levels in the liver as well as with the calculated hepatic bilirubin clearance, although some discrepancies exist. Using these determinations, a clearcut separation from normal values was not obtained, suggesting at least in the present group of patients that Gilbert' syndrome represents only one end of a continuum of bilirubin conjugation rates and not a separate entity. Pigment stones in the gall-bladder were documented in 51% of the patients and usually at an early age. There was no relationship towards sex, serum bilirubin, GlcATa in liver, total bilirubin or monoconjugates in bile. Age played some role as well as the type of haemolysis as all patients with congenital dyserythropoiesis (n = 4) or acquired haemolysis (n = 3) had lithiasis. Moderate chronic cholecystitis was present, whereas an accumulation of iron and bile pigment was evident in the liver.

Massive hemorrhage caused by a perforating Gianturco-Z stent resulting in an aortoesophageal fistula.

Endoscopic placement of self-expanding metal stents is regarded as a safe and effective method of palliating obstructive esophageal malignancies. We report here the case of a 49-year-old woman with an inoperable squamous-cell carcinoma located in the mid-esophagus. After two courses of chemotherapy, a silicone-covered Gianturco-Z stent was placed because of progressive tumor growth. Eighteen days after the stent placement, the patient presented with hematemesis, and died 24 hours after admission. At autopsy, the proximal end of the stent was found to have perforated through the normal esophageal mucosa into the aorta, resulting in an aortoesophageal fistula. This complication should be considered in patients who present with massive hemorrhage after undergoing radiotherapy or chemotherapy, or both, before stent placement in the mid-esophagus.

Effects of hemodynamic changes on the elimination kinetics of verapamil and nifedipine.

This study used a steady-state approach to evaluate the relationships between the pharmacodynamic and pharmacokinetic characteristics of nifedipine and verapamil. In anesthetized and instrumented dogs, i.v. bolus/infusion dosing regimens were used for each drug to achieve and maintain stable drug concentrations in four different ranges rapidly. For both compounds, increases in doses were associated with disproportionate higher plasma drug concentrations, greater hemodynamic effects and significant reductions in systemic drug clearance. Progressive increases in the dose of nifedipine produced reductions in arterial pressure and reflex augmentation in cardiac output, together with decreases in calculated hepatic plasma flow which closely paralleled the decline in mean aortic pressure. Increasing doses of verapamil also resulted in decreased hepatic plasma flow, which was associated with both systemic hypotension and drug-induced decreases in cardiac output. These data imply that the hemodynamic effects of both nifedipine and verapamil result in changes in hepatic plasma flow which, in turn, result in significant alterations in systemic drug clearance. In this experimental model, the calculated hepatic plasma flow and observed systemic clearance values for nifedipine and verapamil were closely related to concentrations of the respective drugs in plasma.

The pharmacology of verapamil. III. Pharmacokinetics in normal subjects after intravenous drug administration.

The pharmacokinetics of verapamil were determined in 8 normal male subjects (age range, 24-28 years) after administration of 0.2 mg/kg over a 3-4 min period. Plasma drug concentrations were measured by a gas-chromatographic method using a nitrogen-specific detector with a sensitivity of 5 ng/ml. Verapamil levels fell in a biexponential pattern, and the data were fitted to a two-compartment model with the NONLIN computer program. The distribution phase half-life was 3.51 min and that of the elimination phase, 110.5 min; the volume of distribution was 178 +/- 26 liters, and the plasma clearance ws 1.06 +/- 0.27 liters/min. The P-R interval of the surface electrocardiogram was increased in each subject in direct proportion to the verapamil plasma level, but with considerable between-subject variability. One subject developed transient Mobitz I block at a plasma drug concentration of 162 ng/ml. At peak verapamil concentrations, mean T-wave amplitude decreased 35 +/- 11% from control height. The results of this study suggest that P-R interval prolongation can be used as an indication of verapamil effect in patients with sinus rhythm.