Drug-disease interaction: Crohn's disease elevates verapamil plasma concentrations but reduces response to the drug proportional to disease activity

AIM

Inflammation is involved in the pathogenesis of cardiovascular diseases that includes reduced response to pharmacotherapy due to altered pharmacokinetics and pharmacodynamics. It is not known if these effects exist in general in all inflammatory conditions. It also remains unknown whether in a given population the effect is a function of disease severity. We investigated whether pharmacokinetics and pharmacodynamics of a typical calcium channel inhibitor are influenced by Crohn''s disease (CD), a disease for which the disease severity can be readily ranked.

METHODS

We administered 80 mg verapamil orally to (i) healthy control subjects (n = 9), (ii) patients with clinically quiescent CD (n = 22) and (iii) patients with clinically active CD (n = 14). Serial analysis of verapamil enantiomers (total and plasma unbound), blood pressure and electrocardiograms were recorded over 8 h post dose. The severity of CD was measured using the Harvey-Bradshaw Index.

RESULTS

CD substantially and significantly increased plasma verapamil concentration and in a stereoselective fashion (S, 9-fold; R, 2-fold). The elevated verapamil concentration, however, failed to result in an increased verapamil pharmacodynamic effect so that the patients with elevated verapamil concentration demonstrated no significant increase in response measured as PR interval and blood pressure. Instead, the greater the disease severity, the lower was the drug potency to prolong PR interval (r = 0.86, P < 0.0006),

CONCLUSIONS

CD patients with severe disease may not respond to cardiovascular therapy with calcium channel blockers. Reducing the severity increases response despite reduced drug concentration. This observation may have therapeutic implication beyond the disease and the drug studies herein.     

Prevalence of Internal Hernias After Laparoscopic Colonic Surgery

Introduction  Laparoscopic approach for colorectal resections is gaining popularity. Internal small bowel herniation (SBH) through a mesenteric defect has been described and, although rare, is a severe complication. The aim of this study was to evaluate the incidence and outcome of internal hernias after laparoscopic colorectal resection. Material and methods  During a 5-year period, all patients who underwent laparoscopic left colon resection were included in the study. A retrospective data base query was performed searching for all patients in whom SBH required surgical reintervention. Results  A total of 436 laparoscopic left colorectal resections were performed from January 2000 to July 2006. Five male patients presented symptomatic internal hernias and required re-operation. Four had a resection for cancer and one for sigmoiditis. The mesenteric defect was not initially closed in three cases. In all cases, we found small bowel hernias through the mesocolon defect. One patient was re-operated on post-op day 2 for mesenteric ischemia and died after 24 h. Discussion  Internal hernia is a rare but fatal complication after laparoscopic colonic resection. Suspicion of this diagnosis requires emergency re-operation because symptoms are nonspecific. Conclusion  All mesenteric defects created during colorectal laparoscopy surgery should be meticulously closed. SAGES April 2007, Las Vegas     

Early jejunojejunostomy obstruction after laparoscopic gastric bypass: case series and treatment algorithm

BackgroundTo review our experience with early jejunojejunostomy obstruction (JJO) at a large academic teaching hospital and provide a management algorithm. Early JJO is a known and often overlooked complication of laparoscopic Roux-en-Y gastric bypass.MethodsFrom 2003 to 2007, 1097 patients underwent laparoscopic Roux-en-Y gastric bypass at our institution. Data, including patient demographics, co-morbidities, intraoperative data, peri- and postoperative complications, and outcomes, were prospectively recorded and retrospectively reviewed.ResultsEarly post-laparoscopic Roux-en-Y gastric bypass JJO occurred in 13 patients (1.2%). The average time to presentation was 15 days (range 5–27). Patients presented with a combination of nausea, vomiting, and abdominal pain; all underwent computed tomography to confirm the diagnosis. The causes of JJO included dietary noncompliance (46%), anastomotic edema (23%), narrowing of the jejunojejunostomy at surgery (23%), and luminal clot (8%). Management was determined using our proposed treatment algorithm. Three patients (23%) required operative intervention, with the remainder successfully treated conservatively.ConclusionFrom our experience, we propose a treatment algorithm for standardized management of early JJO, reserving reoperation for those who are acutely ill on presentation or those in whom conservative management fails. A review of our series using this algorithm has suggested that most patients can be successfully treated nonoperatively; however, bariatric surgeons must maintain a low threshold for surgical re-intervention in cases in which rapid recovery is not seen.     

Activated alphavbeta3 integrin targeting in injury-induced vascular remodeling

There is currently no imaging modality to track the remodeling process, a common feature of a broad spectrum of vasculopathies, in vivo. alphavbeta3 Integrin is up-regulated in proliferating vascular cells. RP748, a novel peptidomimetic tracer, binds specifically to the activated alphavbeta3 conformer and exhibits favorable binding characteristics for in vivo imaging. In a model of injury-induced vascular remodeling in apoE null mice, RP748 localization to the injured carotid arteries parallels vascular cell proliferation, providing an opportunity to image the remodeling process in vivo.