BackgroundThe total effect of a medication is the sum of its drug effect, placebo effect (meaning response), and their possible interaction. Current interpretation of clinical trials' results assumes no interaction. Demonstrating such an interaction has been difficult due to lack of an appropriate study design.Methods180 adults were randomized to caffeine (300 mg) or placebo groups. Each group received the assigned intervention described by the investigators as caffeine or placebo, in a randomized crossover design. 4-hour-area-under-the-curve of energy, sleepiness, nausea (on 100 mm visual analog scales), and systolic blood pressure levels as well as caffeine pharmacokinetics (in 22 volunteers nested in the caffeine group) were determined. Caffeine drug, placebo, placebo-plus-interaction, and total effects were estimated by comparing outcomes after, receiving caffeine described as placebo to receiving placebo described as placebo, receiving placebo described as caffeine or placebo, receiving caffeine described as caffeine or placebo, and receiving caffeine described as caffeine to receiving placebo described as placebo, respectively.ResultsThe placebo effect on area-under-the-curve of energy (mean difference) and sleepiness (geometric mean ratio) was larger than placebo-plus-interaction effect (16.6 [95% CI, 4.1 to 29.0] vs. 8.4 [-4.2 to 21.0] mm*hr and 0.58 [0.39 to 0.86] vs. 0.69 [0.49 to 0.97], respectively), similar in size to drug effect (20.8 [3.8 to 37.8] mm*hr and 0.49 [0.30 to 0.91], respectively), and its combination with the later was larger than total caffeine effect (29.5 [11.9 to 47.1] mm*hr and 0.37 [0.22 to 0.64]). Placebo-plus-interaction effect increased caffeine terminal half-life by 0.40 [0.12 to 0.68] hr (P = 0.007).ConclusionsDrug and placebo effects of a medication may be less than additive, which influences the interpretation of clinical trials. The placebo effect may increase active drug terminal half-life, a novel mechanism of placebo action.Trial RegistrationClinicalTrials.gov identification number - NCT00426010.
Half of patients with inflammatory bowel disease (IBD) are men, yet less attention has been focused on their sexual issues despite higher rates of sexual dysfunction and infertility than the general population. Depression and IBD disease activity are the most consistently reported risk factor for sexual dysfunction among men with IBD. Methotrexate and sulfasalazine have been rarely associated with impotence. Sulfasalazine reversibly reduces male fertility. No other medications used in IBD significantly affect fertility in humans. There is no increase in adverse fetal outcomes among offspring of fathers with IBD. Patients with IBD seem to be at a higher risk for prostate cancer; therefore, screening as recommended for high-risk patients should be considered.
Multiple myeloma (MM) is the most common indication for autologous hematopoietic stem cell transplantation (HSCT) in North America. Despite occurring in up to 50% of patients undergoing allogeneic HSCT, the incidence of graft-versus-host disease (GVHD) after autologous HSCT is reportedly only 5-20%. Gastrointestinal involvement with graft-versus-host disease (GI GVHD) is a common and serious complication of allogeneic HSCT. GI GVHD after autologous transplant, which is referred to as autologous GVHD (auto-GVHD), has also been described. Auto-GVHD is usually less severe than allogeneic GVHD, and it can be one of the manifestations of engraftment syndrome with release of inflammatory cytokines and infiltration of auto-reactive T cells into affected tissue. Seventy-nine percent of patients respond well to corticosteroids without evidence of recurrence. However, cases of severe auto-GVHD lacking good response to corticosteroids have been reported, most notably in MM patients. Here we present two cases of autologous GI GVHD in recipients of autologous HSCT for treatment of MM. Our cases demonstrate two distinct clinical and endoscopic presentations of this uncommon entity. In the first case, the patient had more severe clinical symptoms accompanied by radiographic, endoscopic, and pathologic findings. The hospital course was complicated by cryptosporidium enteritis and acute cholecystitis in the setting of increased immunosuppression with a corticosteroid for presumed auto-GVHD. In contrast, the second case presented a patient with normal radiologic and endoscopic findings. Pathology revealing frequent apoptotic bodies led to auto-GVHD as a diagnosis. Both our patients received similar courses of chemotherapy prior to autologous HSCT (four cycles of a proteasome inhibitor, lenalidomide, and dexamethasone). Our work highlights the importance of maintaining a high level of clinical suspicion for auto-GVHD in patients presenting with GI symptoms after autologous HSCT, as it is a potentially treatable pathology that may be easily confused with other conditions. Health care providers should be aware of the potential complications of auto-GVHD after autologous HSCT and should be suspicious of auto-GVHD if GI symptoms occur, especially in patients receiving immunomodulatory therapy for MM, even in the absence of gross endoscopic findings.
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