Briefly noted: GR D’Haens, C Jobin. Gastroenterol 2019; 157: 624-36. This review sums up the emerging evidence for use of fecal microbial transplantation for conditions besides recurrent Clostridium difficile infection.
Table 2 succinctly provides list of disease, types of study/evidence, and potential effect.
- Among gastrointestinal diseases, the authors note that there is an “overall positive” effect for ulcerative colitis, “suggestive” benefits for IBS, GVHD, post-antibiotic diarrhea, constipation, and hepatic encephalopathy. No effect has been evident with Crohn’s disease or pouchitis.
- Among nongastrointestinal diseases, the authors note a “suggestive” benefit in autism and metabolic syndrome and “unknown” effect with psoriasis and multiple sclerosis.
My take: The review indicates a need for more studies and the need to define which factors in fecal material mediate the therapeutic effects.
Related article: OC Aroniadis. Lancet Gastroenterology and Hepatology; 2019. https://doi.org/10.1016/S2468-1253(19)30198-0. In this double-blind, randomized, placebo-controlled crossover trial in patients aged 18–65 years with moderate-to-severe IBS-D with 48 patients, FMT (capsule study) was safe, but did not induce symptom relief at 12 weeks compared with placebo.
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Here’s the link: Talking to your patients about ranitidine Thanks to John Pohl for sharing this information.
Talking to your patients about ranitidine
The recent FDA safety alert might be causing concern among your patients about their heartburn treatment.
The FDA recently released several safety alerts on ranitidine formulations, including the brand-name drug Zantac, that were found to contain a nitrosamine impurity called N-nitrosodimethylamine (NDMA) at low levels. NDMA is classified as a probable human carcinogen (a substance that could cause cancer) based on results from laboratory tests and animal studies. NDMA is a known environmental contaminant and found in water and foods, including meats, dairy products, and vegetables. This contaminant is similar to was recently found in losartan, an angiotensin II receptor blocker used to treat hypertension, that was recalled by the FDA.
The FDA is continuing to test ranitidine products from multiple manufacturers and is assessing the potential impact on patients who have been taking ranitidine.
With the voluntary recall of 14 lots of prescription ranitidine capsules distributed by Sandoz Inc., as well as the voluntary recall of over-the-counter (OTC) ranitidine tablets (75 mg and 150 mg), labeled by Walgreens, Walmart, and Rite-Aid and manufactured by Apotex Corp, your patients might be asking a lot of questions about whether to continue to using their medicines and what alternatives are available.
TALKING TO YOUR PATIENTS
The FDA safety alerts have been covered by various media outlets since early September. This may cause your patients to question whether they should stay on or start using ranitidine products. When discussing the recall with your patients, let them know that:
- Ranitidine is an H2 blocker (antihistamine) — available OTC and in prescription strength — used to prevent and relieve heartburn associated with acid ingestion and sour stomach. It reduces stomach acid and works longer but not as quickly as antacids.
- Not all ranitidine medicines marketed in the U.S. are being recalled and the FDA is not recommending individuals stop taking all ranitidine medicines at this time.
- It might be prudent to hold off taking Zantac until a final FDA conclusion.
- Multiple drugs are approved for the same or similar uses as ranitidine. Other treatment options are available, both prescription and OTC, for patients who are concerned about ranitidine.
- Life-style modifications may reduce or eliminate the need for heartburn drugs for long-term use. These may include weight loss, avoiding tobacco or a change in eating patterns. Share AGA’s patient education content on gastroesophageal reflux disease (GERD) for more tips for your patients.
Related blog post: Preliminary Recommendations from NASPGHAN on Ranitidine Warnings
A recent study (ID Croall, et al. Gastroenterol 2019; 157: 881-3) provides additional data indicating that a gluten-free diet does not confer health benefits to healthy individuals.
A double-blind randomized placebo 2-week trial with 30 healthy adults divided subjects into two groups –some received flour sachets to consume with organic gluten (14 g) and some received a gluten-free blend (rice, potato, tapioca, maize, buckwheat flour). Both groups were instructed to take their flour sachets twice a day along with a gluten-free diet (GFD).
Key finding: The group receiving gluten did not experience any increase in gastrointestinal symptoms or fatigue compared to the placebo group.
My take: While this study lasted only 2 weeks and had a small sample size, nevertheless, it adds to the literature indicating that a GFD is unlikely to be beneficial in otherwise healthy individuals. Those who stick with a GFD should seek the help of a well-qualified dietician.
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There is speculation that the use of therapeutic drug monitoring (TDM) may obviate the advantages of combination therapy. However, there is plenty of data supporting combination therapy including a recent retrospective population-based study (LE Targownik et al. Clin Gastroenterol Hepatol 2019; 17: 1788-98).
This ‘real-world’ study (2001-2016) utilized the Manitoba IBD database and included 852 persons with Crohn’s disease (CD) and 303 with ulcerative colitis (UC).
- In persons with CD, combination therapy (immunomodulator with a TNF antagonist) was associated with lower treatment ineffectiveness with an adjusted hazard ratio (aHR) for ineffectiveness at 0.62. The ineffectiveness in UC persons was lower at 0.82 but did not reach statistical significance.
- When looking at specific time frames, among patients with CD, at 1 year, combination therapy the rate of ineffectiveness-free treatment was 74.2% for combination therapy compared to 68.6% for monotherapy; at 2 years, the rates were 64.0% and 54.5% respectively.
- Combination therapy in CD was associated with increased time to first IBD-related hospitalization with aHR of 0.53 and with lower rates of switching anti-TNF agents (aHR 0.63). Lower rate of surgery (aHR 0.76) did not reach statistical significance.
- The choice of immunomodulator (6-MP/AZA vs MTX) and the choice of anti-TNF agent (IFX or ADA) did not significantly influence the overall benefit of combination therapy. Though, AZA was the main concomitant treatment (92%).
- 90% of the patients in the study who received combination therapy had received immunomodulator therapy prior to combination therapy. This is in contrast to the SONIC study in which patients were naive to both agents.
- 57% of IFX users and 43% of ADA users received concomitant therapy.
My take: Combination therapy has been associated with higher response rates to IBD therapy. This advantage has to be weighed against potential adverse effects.
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Disclaimer: These blog posts are for educational purposes only. Specific dosing of medications/diets (along with potential adverse effects) should be confirmed by prescribing physician/nutritionist. This content is not a substitute for medical advice, diagnosis or treatment provided by a qualified healthcare provider. Always seek the advice of your physician or other qualified health provider with any questions you may have regarding a condition.
Wizard Island. Crater Lake, OR
This blog post and tomorrow’s post highlights two articles on proactive therapeutic drug monitoring (pTDM) for inflammatory bowel disease. The first article (K Papmichael et al. Clin Gastroenterol Hepatol 2019; 17: 1655-68) summarizes a meeting of 13 international IBD specialists who reached consensus on 24 statements after a review of the literature.
Full Text Link: Appropriate Therapeutic Drug Monitoring of Biologic Agents for Patients With Inflammatory Bowel Diseases
- For anti-tumor necrosis factor (anti-TNF) therapies, proactive TDM was found to be appropriate after induction and at least once during maintenance therapy, but this was not the case for the other biologics.
- Reactive TDM was appropriate for all biologic agents both for primary non-response and secondary loss of response
Background/Rationale for pTDM:
- “Numerous studies have demonstrated a positive correlation between serum biologic drug.concentrations and favorable therapeutic outcomes”
- “Low or undetectable drug concentrations can lead to immunogenicity and treatment failures”
- “TDM…is an important tool for optimizing biologic therapy…Data suggest that pTDM, with drug titration to a target trough concentration, performed in patients with clinical response/remission can also improve the efficacy of anti-TNFs”
Table 4 Scenarios of Applying Therapeutic Drug Monitoring of Biological Therapy in Patients With Inflammatory Bowel Disease
- It is appropriate to order drug/antibody concentration testing in responders at the end of induction for all anti-TNFs.
- It is appropriate to order drug/antibody concentration testing at least once during maintenance for patients on all anti-TNFs.
- It is appropriate to order drug/antibody concentration testing of anti-TNFs at the end of induction in primary non-responders.
- It is appropriate to order drug/antibody concentration testing for all anti-TNFs in patients with confirmed secondary loss of response.
5-8: Vedolizumab -agreement only on ordering TDM in non-responders or those with loss of response
9-12: Ustekinumab -agreement only on ordering TDM in non-responders or those with loss of response
From Table 5: Biological Drug Concentrations and Anti-Drug Antibodies When Applying Therapeutic Drug Monitoring in Inflammatory Bowel Disease
- Infliximab: 15. In the presence of adequate trough drug concentrations, anti-drug antibodies are unlikely to be clinically relevant.
- Infliximab: 19. The minimal trough concentration for infliximab post-induction at week 14 should be greater than 3 μg/mL, and concentrations greater than 7 μg/mL are associated with an increased likelihood of mucosal healing.
- Adalimumab: 22. The minimum drug concentration at week 4 for adalimumab should at least be 5 μg/mL. Drug concentrations greater than 7 μg/ml are associated with an increased likelihood of mucosal healing.
- Certolizumab: 24 & 25: The minimum concentrations for certolizumab pegol at week 6 should be greater than 32 μg/mL and 15 μg/mL during maintenance.
- Golimumab 26 & 27: The minimum drug concentration at week 6 for golimumab should at least be 2.5 μg/mL and 1 μg/mL.during maintenance
My take: This article provides extensive literature to reinforce their recommendations. Most of the trough levels mentioned are minimum levels that need to be achieved.
A recent letter to the editor (A Khoruts, LJ Brandt, Am J Gastroenterol 114: 1176) suggests that the terms “Fecal Transplant” or “Fecal Microbiota Transplantation” (FMT) should be abandoned in favor of “intestinal microbiota transplant.”
- First of all, the authors argue that the word “fecal” is no longer accurate as some transplants occur by swallowing capsules of purified microbiota and the days of “blending raw stool near the bedside are largely over.”
- Secondly, the term “fecal” is highly problematic. “We are hard-wired to perceive feces to be disgusting.”
- Third, the media sensation from the terms FMT or fecal transplant “has not translated into substantial positive consequences, such as funding research…[or] philanthropic fundraising.”
Thus, the authors advocate “Intestinal Microbiota Transplant” or IMT.
My take: (borrowed from authors) It is time to “abandon the scatologic humor that is arguably threatening further development of this promising therapeutic approach.”
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Sunrise at Crater Lake, OR
A recent study (LLD Zhong et al. Clin Gastroenterol Hepatol 2019; 17: 1303-10) shows that a Chinese remedy MaZiRenWan (MZRW) which is a combination of 6 herbs is an effective agent for constipation based on a double-blind, double-dummy trial of 291 patients with functional constipation. Thanks to Ben Gold for this reference.
MZRW was dosed at 7.5 mg BID and Senna was dosed at 15 mg per day. Mean age of study participants was 45 years.
- Complete response, defined as an increase of stooling by 1 or more BM per week, was similar between MZRW (68%) and Senna (58%) at week 8. Both were superior to placebo which had a 33% complete response.
- At week 16, MZRW had better response than senna or placebo, with complete responses of 47%, 21%, and 18% respectively.
- No serious adverse effects were reported and there were no significant differences in renal or liver function between the groups.
My take: The authors note that this remedy has been around for 2000 years. Their data show it appears to be a well-tolerated alternative for the management of constipation in adults.
Mount Batchelor, OR