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Drugs Feb 2017Ulcerative colitis (UC) is a chronic inflammatory bowel disease characterized by periods of remission and periods of relapse. Patients often present with symptoms such... (Review)
Review
Ulcerative colitis (UC) is a chronic inflammatory bowel disease characterized by periods of remission and periods of relapse. Patients often present with symptoms such as rectal bleeding, diarrhea and weight loss, and may require hospitalization and even colectomy. Long-term complications of UC include decreased quality of life and productivity and an increased risk of colorectal cancer. Mucosal healing (MH) has gained progressive importance in the management of UC patients. In this article, we review the endoscopic findings that define both mucosal injury and MH, and the strengths and limitations of the scoring systems currently available in clinical practice. The basic mechanisms behind colonic injury and MH are covered, highlighting the pathways through which different drugs exert their effect towards reducing inflammation and promoting epithelial repair. A comprehensive review of the evidence for approved drugs for UC to achieve and maintain MH is provided, including a section on the pharmacokinetics of anti-tumor necrosis factor (TNF)-α drugs. Currently approved drugs with proven efficacy in achieving MH in UC include salicylates, corticosteroids (induction only), calcineurin inhibitors (induction only), thiopurines, vedolizumab and anti-TNFα drugs (infliximab, adalimumab, and golimumab). MH is of crucial relevance in the outcomes of UC, resulting in lower incidences of clinical relapse, the need for hospitalization and surgery, as well as reduced rates of dysplasia and colorectal cancer. Finally, we present recent evidence towards the need for a more strict definition of complete MH as the preferred endpoint for UC patients, using a combination of both endoscopic and histological findings.
Topics: Colitis, Ulcerative; Humans; Intestinal Mucosa; Wound Healing
PubMed: 28078646
DOI: 10.1007/s40265-016-0676-y -
Gastroenterology Feb 2020Etrasimod (APD334) is an oral, selective sphingosine 1-phosphate receptor modulator in development for immune-mediated inflammatory disorders. We assessed the efficacy... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND & AIMS
Etrasimod (APD334) is an oral, selective sphingosine 1-phosphate receptor modulator in development for immune-mediated inflammatory disorders. We assessed the efficacy and safety of etrasimod in patients with moderately to severely active ulcerative colitis (UC).
METHODS
In a phase 2, proof-of-concept, double-blind, parallel-group study, adult outpatients with modified Mayo Clinic scores (MCSs) (stool frequency, rectal bleeding, and endoscopy findings) of 4-9, endoscopic subscores of 2 or more, and rectal bleeding subscores of 1 or more were randomly assigned to groups given once-daily etrasimod 1 mg (n = 52), etrasimod 2 mg (n = 50), or placebo (n = 54) for 12 weeks. The study was performed from October 15, 2015, through February 14, 2018, at 87 centers in 17 countries. The primary endpoint was an increase in the mean improvement in modified MCS from baseline to week 12. Secondary endpoints included the proportion of patients with endoscopic improvement (subscores of 1 or less) from baseline to week 12. Exploratory endpoints, including clinical remission, are reported in the article, although the study was statistically powered to draw conclusions only on the primary endpoint.
RESULTS
At week 12, the etrasimod 2 mg group met the primary and all secondary endpoints. Etrasimod 2 mg led to a significantly greater increase in mean improvement in modified MCS from baseline than placebo (difference from placebo, 0.99 points; 90% confidence interval, 0.30-1.68; P = .009), and etrasimod 1 mg led to an increase in mean improvement from baseline in modified MCS of 0.43 points more than placebo (90% confidence interval, reduction of 0.24 to increase of 1.11; nominal P = .15). Endoscopic improvement occurred in 41.8% of patients receiving etrasimod 2 mg vs 17.8% receiving placebo (P = .003). Most adverse events were mild to moderate. Three patients had a transient, asymptomatic, low-grade atrioventricular block that resolved spontaneously all patients had evidence of atrioventricular block before etrasimod exposure.
CONCLUSIONS
In patients with moderately to severely active ulcerative colitis, etrasimod 2 mg was more effective than placebo in producing clinical and endoscopic improvements. Further clinical development is warranted. Clinicaltrials.gov, Number: NCT02447302.
Topics: Acetates; Adult; Asymptomatic Diseases; Atrioventricular Block; Colitis, Ulcerative; Colon; Colonoscopy; Dose-Response Relationship, Drug; Double-Blind Method; Female; Gastrointestinal Hemorrhage; Humans; Indoles; Induction Chemotherapy; Intestinal Mucosa; Male; Middle Aged; Placebos; Proof of Concept Study; Rectum; Severity of Illness Index; Sphingosine-1-Phosphate Receptors; Treatment Outcome
PubMed: 31711921
DOI: 10.1053/j.gastro.2019.10.035 -
Integrative Cancer Therapies Dec 2018Chemoradiotherapy-associated mucositis can manifest as pain, inflammation, dysphagia, diarrhea, weight loss, rectal bleeding, and infection. Mucositis is a major...
BACKGROUND
Chemoradiotherapy-associated mucositis can manifest as pain, inflammation, dysphagia, diarrhea, weight loss, rectal bleeding, and infection. Mucositis is a major dose-limiting side effect of chemotherapy, affecting nutritional intake and oral and intestinal function. Despite several interventions being available, there is a need for safe and effective preventative and treatment options for treatment-induced mucositis. The goals of this review are to discuss interventions based on foods and natural products and present the research to date.
METHODS
A narrative literature review identified 60 clinical studies examining various nutritional compounds and 20 examining probiotics. 9 studies on probiotics for the prevention of diarrhea were also assessed on methodological quality and limitations identified.
RESULTS
Several compounds have been posited as useful adjuvants for cancer treatment-related mucositis. Probiotics demonstrate efficacy for the prevention and treatment of chemoradiotherapy-induced gastrointestinal toxicity without significant side effects. Glutamine and activated charcoal were reported to reduce chemotherapy-induced diarrhea but not radiation-induced intestinal mucositis. Honey has been reported to decrease treatment interruptions, weight loss, and delays the onset of oral mucositis. Zinc, glutamine, and topical vitamin E were demonstrated efficacy for oral mucositis.
CONCLUSION
There is plausible clinical evidence for the administration of several adjunctive treatments for the prevention and treatment of mucositis. Probiotics were reported to reduce the burden of intestinal mucositis and treatment-induced diarrhea. Activated charcoal and glutamine are beneficial for chemotherapy-induced diarrhea, whereas the administration of honey, zinc, and glutamine reduce the risk of developing oral mucositis during chemotherapy or radiotherapy.
Topics: Chemotherapy, Adjuvant; Diarrhea; Drug-Related Side Effects and Adverse Reactions; Humans; Mucositis; Neoplasms; Probiotics; Radiation Injuries; Radiotherapy
PubMed: 30136590
DOI: 10.1177/1534735418794885 -
Pharmaceutics Mar 2019Prevention strategies play a key role in the fight against HIV/AIDS. Vaginal and rectal microbicides hold great promise in tackling sexual transmission of HIV-1, but... (Review)
Review
Prevention strategies play a key role in the fight against HIV/AIDS. Vaginal and rectal microbicides hold great promise in tackling sexual transmission of HIV-1, but effective and safe products are yet to be approved and made available to those in need. While most efforts have been placed in finding and testing suitable active drug candidates to be used in microbicide development, the last decade also saw considerable advances in the design of adequate carrier systems and formulations that could lead to products presenting enhanced performance in protecting from infection. One strategy demonstrating great potential encompasses the use of nanosystems, either with intrinsic antiviral activity or acting as carriers for promising microbicide drug candidates. Polymeric nanoparticles, in particular, have been shown to be able to enhance mucosal distribution and retention of promising antiretroviral compounds. One important aspect in the development of nanotechnology-based microbicides relates to the design of pharmaceutical vehicles that allow not only convenient vaginal and/or rectal administration, but also preserve or even enhance the performance of nanosystems. In this manuscript, we revise relevant work concerning the selection of vaginal/rectal dosage forms and vehicle formulation development for the administration of microbicide nanosystems. We also pinpoint major gaps in the field and provide pertinent hints for future work.
PubMed: 30917532
DOI: 10.3390/pharmaceutics11030145 -
Actas Dermo-sifiliograficas Mar 2015Mucosal melanoma is a rare melanoma subtype that differs from the cutaneous form of the tumor in its biology, clinical manifestations, and management. Diagnosis is... (Review)
Review
Mucosal melanoma is a rare melanoma subtype that differs from the cutaneous form of the tumor in its biology, clinical manifestations, and management. Diagnosis is usually late due to a lack of early or specific signs and the location of lesions in areas that are difficult to access on physical examination. Surgical excision is the treatment of choice for localized disease. The value of sentinel lymph node biopsy and lymphadenectomy is still unclear. Radiotherapy can be used as adjuvant therapy for the control of local disease. c-KIT mutations are more common than in other types of melanoma and this has led to significant advances in the use of imatinib for the treatment of metastatic mucosal melanoma.
Topics: Humans; Melanoma; Mucous Membrane
PubMed: 25042176
DOI: 10.1016/j.ad.2014.04.012 -
Prostaglandins, Leukotrienes, and... May 2023Aspirin and eicosapentaenoic acid (EPA) have colorectal polyp prevention activity, alone and in combination. This study measured levels of plasma and rectal mucosal... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Aspirin and eicosapentaenoic acid (EPA) have colorectal polyp prevention activity, alone and in combination. This study measured levels of plasma and rectal mucosal oxylipins in participants of the seAFOod 2 × 2 factorial, randomised, placebo-controlled trial, who received aspirin 300 mg daily and EPA 2000 mg free fatty acid, alone and in combination, for 12 months.
METHODS
Resolvin (Rv) E1, 15-epi-lipoxin (LX) A and respective precursors 18-HEPE and 15-HETE (with chiral separation) were measured by ultra-high performance liquid chromatography-tandem mass spectrometry in plasma taken at baseline, 6 months and 12 months, as well as rectal mucosa obtained at trial exit colonoscopy at 12 months, in 401 trial participants.
RESULTS
Despite detection of S- and R- enantiomers of 18-HEPE and 15-HETE in ng/ml concentrations, RvE1 or 15‑epi-LXA were not detected above a limit of detection of 20 pg/ml in plasma or rectal mucosa, even in individuals randomised to both aspirin and EPA. We have confirmed in a large clinical trial cohort that prolonged (12 months) treatment with EPA is associated with increased plasma 18-HEPE concentrations (median [inter-quartile range] total 18-HEPE 0.51 [0.21-1.95] ng/ml at baseline versus 0.95 [0.46-4.06] ng/ml at 6 months [P<0.0001] in those randomised to EPA alone), which correlate strongly with respective rectal mucosal 18-HEPE levels (r = 0.82; P<0.001), but which do not predict polyp prevention efficacy by EPA or aspirin.
CONCLUSION
Analysis of seAFOod trial plasma and rectal mucosal samples has not provided evidence of synthesis of the EPA-derived specialised pro-resolving mediator RvE1 or aspirin-trigged lipoxin 15‑epi-LXA. We cannot rule out degradation of individual oxylipins during sample collection and storage but readily measurable precursor oxylipins argues against widespread degradation.
Topics: Humans; Aspirin; Eicosapentaenoic Acid; Oxylipins; Lipoxins; Mucous Membrane
PubMed: 37003144
DOI: 10.1016/j.plefa.2023.102570 -
Journal of Virology Apr 2020Zika virus (ZIKV) is a major human pathogen. ZIKV can replicate in female and male reproductive organs, thus facilitating the human-human transmission cycle. Viral...
Zika virus (ZIKV) is a major human pathogen. ZIKV can replicate in female and male reproductive organs, thus facilitating the human-human transmission cycle. Viral shedding in the semen can increase the risk of ZIKV transmission through sexual mode. Therefore, the vaginal and anorectal mucosa are relevant sites for ZIKV infection. However, the pathobiology of ZIKV transmission through the rectal route is not well understood. Here, we utilize a mouse model system to investigate the immunopathological consequences following ZIKV infection of the rectal mucosa compared to a subcutaneous route of infection. We show that ZIKV-rectal inoculation results in viremia with subclinical infection. ZIKV infects the mucosal epithelium and submucosal dendritic cells, inducing immune and inflammatory cell infiltration. Rectal transmission of ZIKV resulted in the generation of serum-neutralizing antibody responses. Mass cytometry analyses of splenocytes showed a significantly reduced level of inflammatory monocyte and neutrophil cellular responses in the rectal route group. Furthermore, immunological priming through the rectal mucosa with an attenuated ZIKV strain resulted in significant protection from lethal subcutaneous ZIKV challenge, further eliciting robust memory CD4-positive (CD4) and CD8 T-cell and ZIKV-specific serum-neutralizing antibody responses. Thus, our study provides deeper immunopathobiological insights on rectal transmission and highlights a rational strategy for mucosal immunization. This model system recapitulates clinical aspects of human ZIKV disease outcome, where most infections are well controlled and result in subclinical and asymptomatic outcomes. Zika virus is a clinically significant human pathogen that is primarily transmitted and spread by species mosquitoes but is also sexually transmissible. The recent pandemic in the Americas led to an unprecedented increase of newborn babies with developmental brain and eye abnormalities. To date, there is no licensed vaccine or therapeutic intervention available for the fight against ZIKV. Understanding the sexual transmission of ZIKV through vaginal and rectal routes is necessary to restrict virus transmission and spread. This study examines the early immunological and pathological consequences of rectal and subcutaneous routes of ZIKV infection using a mouse model. We characterized the primary target cells of ZIKV infection and the subsequent mucosal immune responses to infection, and we demonstrate the protective effect of mucosal rectal immunization using an attenuated ZIKV strain. This mucosal vaccination approach can be further developed to prevent future ZIKV outbreaks.
Topics: Aedes; Animals; Antibodies, Neutralizing; Antibodies, Viral; Cell Line; Chlorocebus aethiops; Disease Models, Animal; Epithelial Cells; Epithelium; Female; Immunity; Immunization; Male; Mice; Mice, Inbred C57BL; Mucous Membrane; Rectum; Semen; T-Lymphocytes; Vaccination; Vero Cells; Zika Virus; Zika Virus Infection
PubMed: 32051274
DOI: 10.1128/JVI.00067-20 -
Gut Microbes 2021Most studies examining correlations between the gut microbiota and disease states focus on fecal samples due to ease of collection, yet there are distinct differences...
Most studies examining correlations between the gut microbiota and disease states focus on fecal samples due to ease of collection, yet there are distinct differences when compared to samples collected from the colonic mucosa. Although fecal microbiota has been reported to be altered in cirrhosis, correlation with mucosal microbiota characterized via rectal swab has not been previously described in this patient population. We conducted a cross-sectional analysis using 39 stool and 39 rectal swabs from adult patients with cirrhosis of different etiologies and performed shotgun metagenomic sequencing. Bacterial growth studies were performed with . Two asaccharolytic bacterial taxa, and , were increased in rectal swabs relative to stool (FDR < 0.01). Genomic analysis of the microbiome revealed 58 genes and 16 pathways that differed between stool and rectal swabs (FDR < 0.05), where rectal swabs were enriched for pathways associated with protein synthesis and cellular proliferation but decreased in carbohydrate metabolism. Although no features in the fecal microbiome differentiated cirrhosis etiologies, the mucosal microbiome revealed decreased abundances of and Enterobacteriaceae in alcohol-related cirrhosis relative to non-alcohol related cirrhosis (FDR < 0.05). bacterial culture studies showed that physiological concentrations of ethanol and its oxidative metabolites inhibited growth in a pH- and concentration-dependent manner. Characterization of the mucosally associated gut microbiome via rectal swab revealed findings consistent with amino acid/nitrogen abundance versus carbohydrate limitation in the mucosal microenvironment as well as unique features of alcohol-related cirrhosis possibly consistent with the influence of host-derived metabolites on the composition of mucosally adherent microbiota.
Topics: Adult; Aged; Aged, 80 and over; Bacteria; Bacterial Adhesion; Bacterial Physiological Phenomena; Cross-Sectional Studies; Female; Gastrointestinal Microbiome; Humans; Intestinal Mucosa; Liver Cirrhosis, Alcoholic; Male; Middle Aged; Rectum; Young Adult
PubMed: 34747331
DOI: 10.1080/19490976.2021.1987781 -
Journal of Acquired Immune Deficiency... Jul 2013Strategies to prevent HIV infection using preexposure prophylaxis are required to curtail the HIV pandemic. The mucosal tissues of the genital and rectal tracts play a... (Review)
Review
Strategies to prevent HIV infection using preexposure prophylaxis are required to curtail the HIV pandemic. The mucosal tissues of the genital and rectal tracts play a critical role in HIV acquisition, but antiretroviral (ARV) disposition and correlates of efficacy within these tissues are not well understood. Preclinical and clinical strategies to describe ARV pharmacokinetic-pharmacodynamic relationships within mucosal tissues are currently being investigated. In this review, we summarize the physicochemical and biologic factors influencing ARV tissue exposure. Furthermore, we discuss the necessary steps to generate relevant pharmacokinetic-pharmacodynamic data and the challenges associated with this process. Finally, we suggest how preclinical and clinical data might be practically translated into optimal preexposure prophylaxis dosing strategies for clinical trials testing using mathematical modeling and simulation.
Topics: Animals; Anti-HIV Agents; Colon; Computer Simulation; Drug Dosage Calculations; Female; Genitalia, Female; HIV Infections; Humans; Male; Models, Theoretical; Mucous Membrane; Rectum; Treatment Outcome
PubMed: 23764642
DOI: 10.1097/QAI.0b013e3182986ff8 -
The Journal of Clinical Investigation Aug 2021BackgroundVRC01, a potent, broadly neutralizing monoclonal antibody, inhibits simian-HIV infection in animal models. The HVTN 104 study assessed the safety and...
BackgroundVRC01, a potent, broadly neutralizing monoclonal antibody, inhibits simian-HIV infection in animal models. The HVTN 104 study assessed the safety and pharmacokinetics of VRC01 in humans. We extend the clinical evaluation to determine intravenously infused VRC01 distribution and protective function at mucosal sites of HIV-1 entry.MethodsHealthy, HIV-1-uninfected men (n = 7) and women (n = 5) receiving VRC01 every 2 months provided mucosal and serum samples once, 4-13 days after infusion. Eleven male and 8 female HIV-seronegative volunteers provided untreated control samples. VRC01 levels were measured in serum, secretions, and tissue, and HIV-1 inhibition was determined in tissue explants.ResultsMedian VRC01 levels were quantifiable in serum (96.2 μg/mL or 1.3 pg/ng protein), rectal tissue (0.11 pg/ng protein), rectal secretions (0.13 pg/ng protein), vaginal tissue (0.1 pg/ng protein), and cervical secretions (0.44 pg/ng protein) from all recipients. VRC01/IgG ratios in male serum correlated with those in paired rectal tissue (r = 0.893, P = 0.012) and rectal secretions (r = 0.9643, P = 0.003). Ex vivo HIV-1Bal26 challenge infected 4 of 21 rectal explants from VRC01 recipients versus 20 of 22 from controls (P = 0.005); HIV-1Du422.1 infected 20 of 21 rectal explants from VRC01 recipients and 12 of 12 from controls (P = 0.639). HIV-1Bal26 infected 0 of 14 vaginal explants of VRC01 recipients compared with 23 of 28 control explants (P = 0.003).ConclusionIntravenous VRC01 distributes into the female genital and male rectal mucosa and retains anti-HIV-1 functionality, inhibiting a highly neutralization-sensitive but not a highly resistant HIV-1 strain in mucosal tissue. These findings lend insight into VRC01 mucosal infiltration and provide perspective on in vivo protective efficacy.FundingNational Institute of Allergy and Infectious Diseases and Bill & Melinda Gates Foundation.
Topics: Adult; Antibodies, Monoclonal; Broadly Neutralizing Antibodies; Female; HIV Antibodies; HIV Infections; HIV-1; Humans; In Vitro Techniques; Infusions, Intravenous; Male; Middle Aged; Mucous Membrane; Rectum; Vagina; Young Adult
PubMed: 34166231
DOI: 10.1172/JCI146975