Comparative Effectiveness of Biologic Therapies in Preventing Penetrating Complications in Patients With Crohn's Disease.

BACKGROUND & AIMS: Comparative effectiveness of biologics in preventing penetrating disease (PD) in Crohn's disease (CD) is not well established. We compared the risk of developing luminal and perianal PD (LPD and PPD) between biologics used as first-line therapies. METHODS: Adults (>17 years) with CD who initiated their first biologic (anti-tumor necrosis factor [anti-TNF], ustekinumab [UST], or vedolizumab [VDZ]) were identified from Merative Commercial Database (2006 and 2020). We excluded preexisting PD using a minimum look-back period of 1 year. Cohorts were balanced by inverse probability of treatment weighting based on age, sex, comorbidities, prior CD surgery, and CD severity. Pairwise comparisons were performed by Cox proportional hazards models, adjusted for immunomodulator exposure, and with biologic exposure treated as a time-dependent variable based on a medication possession ratio of 0.8. RESULTS: Our analysis included 40,693 patients: 93% anti-TNF, 3% UST, and 4% VDZ. After inverse probability of treatment weighting all comparisons were well balanced. Anti-TNF was protective against LPD (hazard ratio, 0.66; 95% confidence interval, 0.55-0.78; P < .0001) and PPD (hazard ratio, 0.88; 95% confidence interval, 0.80-0.96; P = .0045) compared with VDZ and LPD (hazard ratio, 0.37; 95% confidence interval, 0.30-0.46; P < .0001) compared with UST. There were no significant differences in the risk of LPD and PPD between VDZ and UST. These results were similar after limiting the study period to after 2016. CONCLUSIONS: Anti-TNF therapy was associated with a lower risk of LPD and PPD compared with VDZ, and lower risk of LPD compared with UST. Further studies are needed to validate these findings and to determine potential reasons for these differences.

Comparison of Complication Risk Following Trigger Digit Release Performed in the Office Versus the Operating Room: A Population-Based Assessment.

PURPOSE: Trigger digit release (TDR) performed in an office-based procedure room (PR) setting minimizes surgical costs compared with that performed in an operating room (OR); yet, it remains unclear whether the rates of major complications differ by setting. We hypothesized that surgical setting does not have an impact on the rate of major complications after TDR. METHODS: Adult patients who underwent isolated TDR from 2006 to 2015 were identified from the MarketScan commercial database (IBM) using the provider current procedural terminology code 26055 with a concordant diagnosis on the same claim line (International Classification of Diseases, ninth revision, clinical modification 727.03). The PR cohort was defined by presence of a place-of-service code for an in-office procedure without OR or ambulatory center revenue codes, or anesthesiologist claims, on the day of the surgery. The OR cohort was defined by presence of an OR revenue code. We identified major medical complications, surgical site complications, as well as iatrogenic neurovascular and tendon complications within 90 days of the surgery using International Classification of Diseases, ninth revision, clinical modification diagnosis and/or current procedural terminology codes. Multivariable logistic regression was used to compare the risk of complications between the PR and OR groups while controlling for Elixhauser comorbidities, smoking, and demographics. RESULTS: For 7,640 PR and 29,962 OR cases, the pooled rate of major medical complications was 0.99% (76/7,640) and 1.47% (440/29,962), respectively. The PR setting was associated with a significantly lower risk of major medical complications in the multivariable analysis (adjusted odds ratio 0.76; 95% confidence interval 0.60-0.98). The pooled rate of surgical site complications was 0.67% (51/7,640) and 0.88% (265/29,962) for the PR and OR cases, respectively, with no difference between the surgical settings in the multivariable analysis (adjusted odds ratio 0.81; 95% confidence interval 0.60-1.10). Iatrogenic complications were infrequently observed (PR 5/7,640 [0.07%]; OR 26/29,962 [0.09%]). CONCLUSIONS: Compared with performing TDR in the OR using a spectrum of commonly used anesthesia types, performing TDR in the PR using local-only anesthesia was associated with a comparably low risk of major medical complications, surgical complications, and iatrogenic complications. TYPE OF STUDY/LEVEL OF EVIDENCE: Prognostic II.

Use of Medical Therapy and Success of Laser Surgery and Transurethral Resection of the Prostate for Benign Prostatic Hyperplasia.

OBJECTIVE: To assess the impact of surgery for benign prostatic hyperplasia (BPH) on use of medication (5-alpha reductase inhibitors, alpha blockers, antispasmodics), we assessed preoperative and postoperative medication utilization among surgically treated men. PATIENTS AND METHODS: Using the Truven Health Analytics MarketScan Commercial Claims Database, we defined a cohort of men aged <65 years who had surgical therapy for BPH with either transurethral resection of the prostate (TURP) or laser procedures from 2007 through 2009. Primary outcomes included freedom from medical or surgical intervention by 4 months after surgery (chi-square and multivariable logistic regression) and subsequent use of medical or surgical intervention in initial responders (Kaplan-Meier and multivariable Cox regression). RESULTS: We identified 6430 patients treated with either TURP (3096) or laser procedure (3334) for BPH. Presurgical antispasmodic use was associated with the highest risk of medication use at 4 months after surgery (odds ratio, 5.19; 95% confidence interval (CI), 3.16-8.53 vs no medication use before surgery). At 3 years after surgery, 6% (95% CI, 4%-8%) of laser-treated and 4% (95% CI, 2%-5%) of TURP-treated patients had repeat surgical intervention, and both laser- and TURP-treated patients had an estimated new use of medication rate of 22% (95% CI, 18%-25% laser and 20%-25% TURP). The strongest predictor of intervention after surgery was preoperative antispasmodic use (hazard ratio, 2.49; 95% CI, 1.41-4.43). CONCLUSION: Our results show a need for effective patient counseling about continued or new use of medical therapy after laser and TURP procedures. However, most patients experience durable improvement after surgical intervention for BPH.

Lactoferrin enhanced efficacy of the BCG vaccine to generate host protective responses against challenge with virulent Mycobacterium tuberculosis.

Tuberculosis (TB), caused by Mycobacterium tuberculosis (MTB), is a disease with world wide consequences, affecting nearly a third of the world's population. The established vaccine for TB, an attenuated strain of Mycobacterium bovis Calmette Guerin (BCG), has existed since 1921. Lactoferrin, an iron-binding protein found in mucosal secretions and granules of neutrophils was hypothesized to be an ideal adjuvant to enhance the efficacy of the BCG vaccine, specifically because of previous reports of lactoferrin enhancement of IL-12 production from macrophages infected with BCG. Different vaccination protocols were investigated for generation of host protective responses against MTB infection using lactoferrin admixed to the BCG vaccine. Resulting effects demonstrate that BCG/lactoferrin increased host protection against MTB infection by decreasing organ bacterial load and reducing lung histopathology; significant reduction in tissue CFUs and pathology were observed post-challenge compared to those seen with BCG alone. Addition of lactoferrin to the vaccine led to reduced pathological damage upon subsequent infection with virulent MTB, with positive results demonstrated when admixed in oil-based vehicle (incomplete Freund's adjuvant, IFA) or when given with BCG in saline. The observed post-challenge results paralleled increasing production of IFN-gamma and IL-6, but only limited changes to proinflammatory mediators TNF-alpha or IL-1beta from BCG-stimulated splenocytes. Overall, these studies indicate that lactoferrin is a useful and effective adjuvant to improve efficacy of the BCG vaccine, with potential to reduce related tissue damage and pulmonary histopathology.

Drug-herb interaction: effect of St John's wort on bioavailability and metabolism of procainamide in mice.

CONTEXT: St John's wort induces the activity of the cytochrome P450 enzyme system causing treatment failure because of increased metabolism of many drugs. Procainamide is metabolized by a different pathway to N-acetyl procainamide. OBJECTIVE: To study St John's wort-procainamide interaction using a mouse (Swiss Webster) model. DESIGN: One group of mice (group A, 4 mice in each group) was fed St John's wort each day for 2 weeks (last dose 1 day before administration of procainamide); another group (group B) received the same dose of St John's wort for 1 week. The third group (group C) received only a single dose 1 hour before administration of procainamide, and the control group (group D) received no St John's wort. All groups later received a single oral dose of procainamide. Blood was drawn 1, 4, and 24 hours after administration of procainamide and concentrations in serum of procainamide as well as N-acetyl procainamide were measured using immunoassays. RESULTS: The procainamide concentrations 1 hour after administration was highest in group C (mean, 11.59 microg/mL) followed by group A (9.92 microg/mL), whereas group B (7.44 microg/mL) and control group D (7.36 microg/mL) showed comparable values. The concentration in group C was significantly greater than the control group D (P = .03, 2-tailed independent t test). N-Acetyl procainamide concentrations and estimated half-life of procainamide among groups were comparable. In a separate experiment when mice were fed purified hypericin, the active component of St John's wort, a significant increase in bioavailability (53%) of procainamide was observed compared with the control group. CONCLUSIONS: St John's wort has an acute effect to increase bioavailability of procainamide but has no effect on its metabolism.

Interference of Asian, American, and Indian (Ashwagandha) ginsengs in serum digoxin measurements by a fluorescence polarization immunoassay can be minimized by using a new enzyme-linked chemiluminescent immunosorbent or turbidimetric assay.

CONTEXT: Ginsengs are widely used by the general population. These herbs interfere with serum digoxin measurement using the fluorescence polarization immunoassay. OBJECTIVE: To assess potential interference of different ginsengs (Asian, American, and Indian, also known as Ashwagandha) in vitro and in vivo in a mouse model by using a new enzyme-linked chemiluminescent immunosorbent digoxin assay and an existing turbidimetric assay. Comparisons were made with the fluorescence polarization immunoassay. DESIGN: Aliquots of drug-free serum pools were supplemented with ginseng and apparent digoxin concentrations were measured using enzyme-linked chemiluminescent immunosorbent digoxin assay, turbidimetric assay, and fluorescence polarization immunoassay digoxin assays. Mice were fed with different ginseng preparations and apparent digoxin concentrations were measured 1 and 3 hours later. In a separate experiment, aliquots of serum digoxin pools were further supplemented with ginsengs and the serum digoxin concentrations were measured again. RESULTS: A significant apparent digoxin concentration was observed both in vitro and in vivo using the fluorescence polarization immunoassay, but no apparent digoxin concentration was observed using enzyme-linked chemiluminescent immunosorbent digoxin assay and turbidimetric assay. No interference was observed with enzyme-linked chemiluminescent immunosorbent digoxin assay and turbidimetric assay when digoxin serum pools were further supplemented with various ginsengs. CONCLUSIONS: It was concluded that both enzyme-linked chemiluminescent immunosorbent and turbidimetric digoxin assays are free from ginseng interferences.

New enzyme-linked chemiluminescent immunosorbent digoxin assay is free from interference of Chinese medicine DanShen.

DanShen is a traditional Chinese medicine indicated for cardiovascular diseases. The potential interference of DanShen with serum digoxin measurement was investigated using a new enzyme-linked chemiluminescent immunosorbent (ECLIA) digoxin assay. Aliquots of drug-free serum were supplemented with ethyl acetate extract of DanShen (4 different brands studied), and apparent digoxin concentrations were measured by the ECLIA as well as fluorescence polarization immunoassay (FPIA) and a turbidimetric assay for comparison. Mice were also fed 4 DanShen preparations and apparent digoxin concentrations were subsequently measured. In another experiment, serum pools containing digoxin were further supplemented with DanShen extracts and digoxin concentrations were measured again by all 3 assays. No apparent digoxin concentration was observed when aliquots of drug-free serum pools were supplemented with DanShen and digoxin concentrations were measured by the ECLIA or the turbidimetric assay. In contrast, significant apparent digoxin concentrations were observed using FPIA, and the highest apparent digoxin concentration was observed with brand 4 of DanShen extract. Similarly, when mice were fed with this herb, significant apparent digoxin concentrations were also observed using FPIA, but neither ECLIA nor turbidimetric assay showed any apparent digoxin concentration. When aliquots of digoxin pool were further supplemented with various DanShen extract, the apparent digoxin concentrations were significantly increased when FPIA was used. In contrast, digoxin concentrations in the presence of DanShen extract compared well with the digoxin concentration of the original pool when ECLIA or turbidimetric assay was used. We conclude that DanShen does not interfere with serum digoxin measurement using a more recently released ECLIA digoxin assay.

Effect of Asian and Siberian ginseng on serum digoxin measurement by five digoxin immunoassays. Significant variation in digoxin-like immunoreactivity among commercial ginsengs.

Asian and Siberian ginsengs contain glycosides with structural similarities to digoxin. We studied potential interference of ginseng in 5 digoxin immunoassays in 3 Asian (2 liquid extracts, 1 capsule) and 3 Siberian ginseng preparations (1 liquid extract, 2 capsules). With the fluorescence polarization immunoassay (FPIA), we observed apparent digoxin activity in 1 Asian liquid preparation and in the liquid extract and 1 capsule form of Siberian ginseng. In mice fed ginseng, we observed digoxin activities in the serum (Asian, 0.48-0.68 ng/mL [0.6-0.9 nmol/L]; Siberian, 0.20-0.47 ng/mL [0.3-0.6 nmol/L]), indicating that such interferences also occur in vivo. Serum pools prepared from samples from patients receiving digoxin and then supplemented with Asian or Siberian ginseng showed falsely increased digoxin values using the FPIA (e.g., for Asian ginseng, 1.54 ng/mL [2.0 nmol/L] vs control value, 1.10 ng/mL [1.4 nmol/L]) and falsely decreased values using the microparticle enzyme immunoassay (MEIA; 0.73 ng/mL [0.9 nmol/L] vs control value, 1.04 ng/mL [1.3 nmol/L]). Digoxin-like immunoreactive substances (DLISs) showed synergistic effects with ginsengs in interfering with the FPIA and MEIA for digoxin. No interference was observed with 3 other digoxin assays, even in the presence of elevated DLISs.

Asian and Siberian ginseng as a potential modulator of immune function: an in vitro cytokine study using mouse macrophages.

BACKGROUND: Ginseng is a widely used herbal product in China, other Asian countries, and in the Unites States. There is a traditional belief that ginseng stimulates immune functions. In this study, the innate effects of Asian and Siberian ginsengs on cytokines and chemokines produced by cultured macrophages were examined. MATERIALS AND METHODS: The effects of Asian and Siberian ginseng on cytokines and chemokines produced by cultured macrophages were examined. Mouse macrophages (J774A.1) were incubated with Asian or Siberian ginseng at varying concentrations (1, 10, 100, and 1000 microg/ml) for 24 h and then harvested for RNA isolation. The expression levels of IL-1beta, IL-12, TNF-alpha, MIP-1 alpha, and MIP-2 mRNA were measured by quantitative PCR. RESULTS: Our data showed that Asian ginseng induced a statistically significant increase in IL-12 expression at both mRNA and protein levels. However, the minor twofold increase is probably biologically insignificant. No significant increase of IL-12 by Siberian ginseng was observed at any dose level studied. No significant change in IL-1beta, IL-15, TNF-alpha, or MIP-1alpha mRNA was observed by either Asian or Siberian ginseng treatment. CONCLUSIONS: Our data showed statistically significant differential regulation of IL-12 by Asian ginseng. Siberian ginseng did not show a statistically significant increase. We conclude that both Asian ginseng and Siberian ginseng cannot significantly stimulate innate macrophage immune functions that influence cellular immune responses. Therefore, contrary to the popular belief, Asian and Siberian ginseng may not stimulate immune function.

Activated charcoal is more effective than equilibrium dialysis in removing Chinese medicines Chan Su and Dan Shen from serum and activated charcoal also prevents further absorption of these agents from G.I. tract in mice: monitoring the effect in clinical laboratory by measuring digoxin activity in serum.

BACKGROUND: Chinese medicines are freely available without prescription and are widely used by the general population. Chan Su and Dan Shen are both indicated for the treatment of cardiac diseases. Severe toxicity from Chan Su has been reported. We studied the possibility of removing Chan Su and Dan Shen from human sera using activated charcoal and equilibrium dialysis, and also examined the potential benefit of preventing absorption of these agents from the G.I. tract in the mouse model. METHODS: For in vitro studies, drug-free serum pools were supplemented with Chan Su or Dan Shen and then either treated with activated charcoal (10 and 25 mg/ml), or passed through a column packed with activated charcoal. Serum pools supplemented with Chan Su or Dan Shen were also subjected to equilibrium dialysis against phosphate buffer (pH 7.4) using dialysis membrane with molecular cut-off of 25,000 Da. Removal of Chan Su or Dan Shen from the serum was monitored by measuring the apparent digoxin concentration using the fluorescence polarization immunoassay (FPIA) for digoxin (Abbott Laboratories). RESULTS: We observed the fast and effective removal of both Chan Su and Dan Shen from the serum by activated charcoal. We also observed significant removal of both Chan Su and Dan Shen when the serum pools containing these Chinese medicines were passed through columns packed with activated charcoal. Although equilibrium dialysis was also effective in removing these Chinese medicines from the serum, 24 h was required for complete removal of Dan Shen activity, and for Chan Su, complete removal was not achieved even after 24 h. In our in vivo model, we observed significantly less digoxin activity in the group of mice that received activated charcoal compared to the control group. CONCLUSIONS: Activated charcoal is effective in preventing absorption of these Chinese medicines from the G.I. tract and can also remove these agents from the serum.

In vivo digoxin-like immunoreactivity in mice and interference of Chinese medicine Danshen in serum digoxin measurement: elimination of interference by using a chemiluminescent assay.

BACKGROUND: Danshen, a traditional Chinese medicine used in the management of cardiovascular diseases, is available without prescription in the US. Because Danshen is used to treat cardiovascular diseases, we studied the potential interference of Danshen with serum digoxin measurement using various immunoassays. METHODS: Blood was collected 1 day before and then 1 and 2 h after feeding mice with Danshen. The apparent digitoxin activities were measured by the fluorescence polarization immunoassay (FPIA). We also added microliter amounts of Danshen extract to digoxin pools prepared from patients receiving digoxin. The digoxin concentrations were measured using the fluorescence polarization immunoassay (FPIA), microparticle enzyme immunoassay (MEIA) and chemiluminescent assay (CLIA). The observed values were compared with original values. We also fed mice with Danshen. RESULTS: We observed measurable digoxin-like immunoreactivity in sera of mice after feeding with Danshen. We also observed falsely lower digoxin concentrations (negative interference) when MEIA was used for digoxin measurement. However, serum digoxin concentrations were falsely elevated with FPIA. We observed no interference of Danshen in serum digoxin measurement using the CLIA. CONCLUSION: Danshen appears to contain digoxin-like immunoreactivity but does not interfere with serum digoxin measurement when CLIA was used.