Efficacy and Safety of Peppermint Oil in a Randomized, Double-Blind Trial of Patients With Irritable Bowel Syndrome.

BACKGROUND & AIMS: Peppermint oil is frequently used to treat irritable bowel syndrome (IBS), despite a lack of evidence for efficacy from high-quality controlled trials. We studied the efficacy and safety of small-intestinal-release peppermint oil in patients with IBS and explored the effects of targeted ileocolonic-release peppermint oil. METHODS: We performed a double-blind trial of 190 patients with IBS (according to Rome IV criteria) at 4 hospitals in The Netherlands from August 2016 through March 2018; 189 patients were included in the intent-to-treat analysis (mean age, 34.0 years; 77.8% female; 57.7% in primary care), and 178 completed the study. Patients were randomly assigned to groups given 182 mg small-intestinal-release peppermint oil, 182 mg ileocolonic-release peppermint oil, or placebo for 8 weeks. The primary endpoint was abdominal pain response, as defined by the US Food and Drug Administration: at least a 30% decrease in the weekly average of worst daily abdominal pain compared with baseline in at least 4 weeks. The co-primary endpoint was overall relief of IBS symptoms, as defined by the European Medicines Agency. Secondary endpoints included abdominal pain, discomfort, symptom severity, and adverse events. RESULTS: Abdominal pain response did not differ significantly between the peppermint oil and placebo groups: 29 of 62 patients in the small-intestinal-release peppermint oil group had a response (46.8%, P = .170 vs placebo), 26 of 63 patients in the ileocolonic-release peppermint oil group had a response (41.3%, P = .385 vs placebo), and 22 of 64 patients in the placebo group had a response (34.4%). We did not find differences among the groups in overall relief (9.7%, P = .317 and 1.6%, P = .351 vs 4.7% for placebo). The small intestinal peppermint oil did, however, produce greater improvements than placebo in secondary outcomes of abdominal pain (P = .016), discomfort (P = .020), and IBS severity (P = .020). Adverse events, although mild, were more common in both peppermint oil groups (P < .005). CONCLUSIONS: In a randomized trial of patients with IBS, we found that neither small-intestinal-release nor ileocolonic-release peppermint oil (8 weeks) produced statistically significant reductions in abdominal pain response or overall symptom relief, when using US Food and Drug Administration/European Medicines Agency recommended endpoints. The small-intestinal-release peppermint oil did, however, significantly reduce abdominal pain, discomfort, and IBS severity. These findings do not support further development of ileocolonic-release peppermint oil for treatment of IBS. Clinicaltrials.gov, Number: NCT02716285.

A Novel Ileocolonic Release Peppermint Oil Capsule for Treatment of Irritable Bowel Syndrome: A Phase I Study in Healthy Volunteers.

INTRODUCTION: Peppermint oil (PO) has been shown to reduce abdominal pain in patients with irritable bowel syndrome (IBS). PO is assumed to induce intestinal smooth muscle relaxation and desensitization of nociceptive nerve afferents. To increase colonic PO concentration, an ileocolonic release peppermint oil (IC-PO) capsule has been developed. The aim of this study was to compare pharmacokinetic parameters of the currently available small intestinal release PO (SI-PO) and the novel IC-PO. METHODS: In this randomized, double-blind, crossover study, subjects received 182 mg of either SI-PO or IC-PO in a crossover design with a washout period of more than 14 days. Blood samples were collected to determine menthol glucuronide concentrations. RESULTS: Eight healthy volunteers (50% female, median age 22) were included. The time to reach the maximum concentration (Tmax) of IC-PO was significantly longer compared to SI-PO with a median (IQR) of 360 (360-405) versus 180 (120-180) min. The lag time (Tlag) was significantly longer with a median (IQR) of 225 (204-284) for IC-PO compared to 37 (6-65) min for SI-PO. The areas under the menthol glucuronide plasma concentration-time curves were significantly smaller with a median (IQR) of 2331 µg h/L (2006-2510) for IC-PO compared to 2623 µg h/L (2471-2920) for SI-PO. No significant differences were found in peak concentrations and elimination half-lives. CONCLUSION: IC-PO has a significantly delayed peak menthol glucuronide concentration and Tlag, both pointing to the release of PO in the more distal part of the intestine. This may enhance therapeutic efficacy as it results in increased exposure of colonic mucosal afferents to the PO. A randomized controlled trial investigating the efficacy of SI and IC-PO in IBS is currently ongoing. TRIAL REGISTRATION: ClinicalTrials.gov identifier, NCT02291445, EudraCT database 2014-004195-32.

Calcium and vitamin D supplementation: state of the art for daily practice.

BACKGROUND: Calcium and vitamin D play an essential role in bone metabolism but deficiency and/or inadequate intake are common. OBJECTIVES: To describe a practical approach based on the literature regarding clinically important aspects of calcium and vitamin D supplementation. METHODS: A systematic evaluation of relevant literature in Medline was conducted. We included physiological studies, publications on relevant guidelines, meta-analysis, randomized clinical trials, and cohort studies. RESULTS: An adequate calcium intake and vitamin D supplementation is recommended in most guidelines xon fracture prevention. Daily supplementation with 800 IU is advocated in most guidelines, appears to be safe, and with this approach it is generally not necessary to determine vitamin D levels. There are no data on additional effects of loading doses of vitamin D on fracture or fall prevention. Calcium supplementation should be tailored to the patient's need: usually 500 mg per day is required. The intestinal absorption of calcium citrate is approximately 24% better than that of calcium carbonate independent of intake with meals. Data on difference between calcium absorption with calcium carbonate compared to calcium citrate with simultaneous use of proton pump inhibitors are lacking. Concern has arisen about a possible link between calcium supplementation and an increased risk of myocardial infarction. Probably only well-designed prospective randomized controlled trials will be able to allow definite conclusions on this subject. CONCLUSION: Daily supplementation with 800 IU vitamin D is a practical and safe strategy without the need for prior determination of vitamin D levels. Calcium supplementation should be tailored to the patient's need based on total daily dietary calcium intake. In most patients 500 mg per day is required to achieve a total intake of 1,200 mg, or in some 1,000 mg per day. More calcium is absorbed from calcium citrate compared to calcium carbonate.

Vietnamese traditional medicine from a pharmacist's perspective.

Traditional medicine plays an important role in the healthcare system of Vietnam. Vietnamese traditional medicine (VTM) is underpinned by the oriental philosophy and theory of healing. VTM is largely influenced by traditional Chinese medicine, but differs to a certain extent. VTM is largely not evidence-based from a clinical perspective but subclinical research data from the past decades support the traditional use of many herbal VTM drugs. For safe use, knowledge of the occurrence of adverse reactions and herb-drug interactions is necessary. The Vietnamese government supports further development of VTM in a scientific way and integration of VTM with Western medicine. This article first gives an overview of the general aspects of VTM (historical perspective, regulatory aspects, comparison with traditional Chinese medicine, philosophical background, the Vietnamese market situation, quality assurance and formulations), and subsequently focuses on its safe and effective use in Vietnamese clinical pharmacy and medical practice.

An evidence-based assessment of the clinical significance of drug-drug interactions between disease-modifying antirheumatic drugs and non-antirheumatic drugs according to rheumatologists and pharmacists.

BACKGROUND: Clinically relevant drug-drug interactions (DDIs) must be recognized in a timely manner and managed appropriately to prevent adverse drug reactions or therapeutic failure. Because the evidence for most DDIs is based on case reports or poorly documented clinical information, there is a need for better assessment of their clinical relevance. OBJECTIVE: This study evaluates the interdisciplinary agreement between rheumatologists and clinical (hospital) pharmacists in assessing the clinical relevance of DDIs with disease-modifying antirheumatic drugs (DMARDs) and non-DMARD medications. METHODS: Potential DDIs were identified from the medical literature using MEDLINE and EMBASE for the years 1968-2009. The following search terms were used for the key word, title, and abstract sections of the publications: interaction(s), DMARD, disease-modifying antirheumatic drug(s), antirheumatic, rheumatology, rheumatoid arthritis, and the names of the individual DMARDs of interest (abatacept, adalimumab, anakinra, auranofin, aurothioglucose, aurothiomalate, d-penicillamine, etanercept, gold, [hydroxy]-chloroquine, interleukin-1 receptor antagonist, IL1-RA, infliximab, leflunomide, methotrexate, rituximab, and sulfasalazine/sulphasalazine). Reference lists of the retrieved publications were searched for further information on potential DDIs. All pharmacodynamic or pharmacokinetic DDIs between a DMARD and a non-DMARD identified were included in the study, with the exception of evidence regarding DMARD doses higher than used in the treatment of rheumatoid arthritis and interactions with phytotherapeutic or homeopathic preparations. Using a standard information set for each DDI (eg, from product labeling, textbooks, and the medical literature), a group of rheumatologists and a group of clinical pharmacists independently assessed whether the individual drug-DMARD combinations interacted and whether they required immediate intervention. Both groups consisted of 3 members (2 men and 1 woman), aged 40 to 60 years, who had >5 years of clinical experience and were currently involved in clinical practice in large, nonacademic teaching hospitals in the Netherlands. RESULTS: Forty potential DDIs with DMARDs were retrieved and assessed by the 2 groups. For 30 (75%) of these, rheumatologists and clinical pharmacists agreed about the requirement for immediate intervention. Specifically, 17 drug combinations (43%) were judged to interact and to require immediate intervention, and 13 combinations (33%) were judged either not to interact or to interact but not to require immediate intervention. For 10 combinations (25%), rheumatologists and clinical pharmacists were not in agreement. Overall, agreement between the groups was good (kappa = 0.80) for judging whether the drug combinations were interactions, and agreement was fair (kappa = 0.39) for judging whether immediate intervention was required. Prospective analysis of the data showed that rheumatologists tended to recommend immediate intervention more often when the adverse reaction to the DDI involved an increased risk of toxicity of the DMARD. In contrast, clinical pharmacists more often advocated immediate intervention when the adverse reaction involved decreased effectiveness of the DMARD. CONCLUSION: For a subset of DMARD-drug combinations, rheumatologists and clinical pharmacists differed in their assessments of clinical relevance.

Cost-benefit analysis of capecitabine versus 5-fluorouracil/leucovorin in the treatment of colorectal cancer in the Netherlands.

BACKGROUND: Capecitabine is an oral prodrug of 5-fluorouracil and has been studied for the treatment of colorectal cancer. In 2 Phase III trials, capecitabine was at least as effective as 5-fluorouracil plus leucovorin and had a more favorable toxicity profile. OBJECTIVE: A cost-benefit analysis was used to assess the pharmacoeconomic profile of capecitabine compared with 5-fluorouracil/leucovorin, given according to the Mayo regimen, for colorectal cancer patients treated in the Netherlands. METHODS: The medical files of patients treated for colorectal cancer at a single center from 1999 to 2002 were examined to determine the numbers of outpatient visits for 5-fluorouracil/leucovorin administration, health care use and medication to manage adverse effects, and travel distance to and from the hospital. The costs of capecitabine treatment were simulated by assuming that the same patients were treated with capecitabine instead of 5-fluorouracil/leucovorin. Toxicity data for capecitabine were derived from 2 Phase III studies that compared capecitabine and 5-fluorouracil/leucovorin. RESULTS: The files of 65 patients were reviewed. Thirty-two patients received adjuvant treatment and 33 patients were treated palliatively for metastatic disease. The mean total costs of palliative treatment were Euro 4004 with capecitabine and Euro 5614 with 5-fluorouracil/leucovorin. These results were robust in sensitivity analyses. The cost savings were primarily related to the number of outpatient visits for capecitabine versus the number of day-care treatment days for 5-fluorouracil/leucovorin, despite the higher acquisition costs of capecitabine. CONCLUSIONS: Based on this analysis, treatment of colorectal cancer with oral capecitabine is cost saving in the Netherlands compared with 5-fluorouracil plus leucovorin administered according to the Mayo regimen. Baseline savings were estimated at Euro 1610 for palliative treatment and Euro 934 for adjuvant treatment.