Indomethacin with or without prophylactic pancreatic stent placement to prevent pancreatitis after ERCP: a randomised non-inferiority trial.

BACKGROUND: The combination of rectally administered indomethacin and placement of a prophylactic pancreatic stent is recommended to prevent pancreatitis after endoscopic retrograde cholangiopancreatography (ERCP) in high-risk patients. Preliminary evidence suggests that the use of indomethacin might eliminate or substantially reduce the need for stent placement, a technically complex, costly, and potentially harmful intervention. METHODS: In this randomised, non-inferiority trial conducted at 20 referral centres in the USA and Canada, patients (aged ≥18 years) at high risk for post-ERCP pancreatitis were randomly assigned (1:1) to receive rectal indomethacin alone or the combination of indomethacin plus a prophylactic pancreatic stent. Patients, treating clinicians, and outcomes assessors were masked to study group assignment. The primary outcome was post-ERCP pancreatitis. To declare non-inferiority, the upper bound of the two-sided 95% CI for the difference in post-ERCP pancreatitis (indomethacin alone minus indomethacin plus stent) would have to be less than 5% (non-inferiority margin) in both the intention-to-treat and per-protocol populations. This trial is registered with ClinicalTrials.gov (NCT02476279), and is complete. FINDINGS: Between Sept 17, 2015, and Jan 25, 2023, a total of 1950 patients were randomly assigned. Post-ERCP pancreatitis occurred in 145 (14·9%) of 975 patients in the indomethacin alone group and in 110 (11·3%) of 975 in the indomethacin plus stent group (risk difference 3·6%; 95% CI 0·6-6·6; p=0·18 for non-inferiority). A post-hoc intention-to-treat analysis of the risk difference between groups showed that indomethacin alone was inferior to the combination of indomethacin plus prophylactic stent (p=0·011). The relative benefit of stent placement was generally consistent across study subgroups but appeared more prominent among patients at highest risk for pancreatitis. Safety outcomes (serious adverse events, intensive care unit admission, and hospital length of stay) did not differ between groups. INTERPRETATION: For preventing post-ERCP pancreatitis in high-risk patients, a strategy of indomethacin alone was not as effective as a strategy of indomethacin plus prophylactic pancreatic stent placement. These results support prophylactic pancreatic stent placement in addition to rectal indomethacin administration in high-risk patients, in accordance with clinical practice guidelines. FUNDING: US National Institutes of Health.

A Phase 1 Clinical Trial to Assess the Safety and Pharmacokinetics of a Tenofovir Alafenamide/Elvitegravir Insert Administered Rectally for HIV Prevention.

BACKGROUND: On-demand topical products could be an important tool for human immunodeficiency virus (HIV) prevention. We evaluated the safety, pharmacokinetics, and ex vivo pharmacodynamics of a tenofovir alafenamide/elvitegravir (TAF/EVG, 20 mg/16 mg) insert administered rectally. METHODS: MTN-039 was a phase 1, open-label, single-arm, 2-dose study. Blood, rectal fluid, and rectal tissue were collected over 72 hours following rectal administration of 1 and 2 TAF/EVG inserts for each participant. RESULTS: TAF/EVG inserts were safe and well tolerated. EVG and tenofovir (TFV) were detected in blood plasma at low concentrations: median peak concentrations after 2 inserts were EVG 2.4 ng/mL and TFV 4.4 ng/mL. Rectal tissue EVG peaked at 2 hours (median, 2 inserts = 9 ng/mg) but declined to below limit of quantification in the majority of samples at 24 hours, whereas tenofovir diphosphate (TFV-DP) remained high >2000 fmol/million cells for 72 hours with 2 inserts. Compared to baseline, median cumulative log10 HIV p24 antigen of ex vivo rectal tissue HIV infection was reduced at each time point for both 1 and 2 inserts (P < .065 and P < .039, respectively). DISCUSSION: Rectal administration of TAF/EVG inserts achieved high rectal tissue concentrations of EVG and TFV-DP with low systemic drug exposure and demonstrable ex vivo inhibition of HIV infection for 72 hours. Clinical Trials Registration . NCT04047420.

NSAIDs do not reduce severity among post-ERCP pancreatitis patients.

OBJECTIVE: Non-steroidal anti-inflammatory drugs (NSAIDs) are the most studied chemoprophylaxis for post-endoscopic retrograde cholangiopancreatography pancreatitis (PEP). While previous systematic reviews have shown NSAIDs reduce PEP, their impact on moderate to severe PEP (MSPEP) is unclear. We conducted a systematic review and meta-analysis to understand the impact of NSAIDs on MSPEP among patients who developed PEP. We later surveyed physicians' understanding of that impact. DESIGN: A systematic search for randomized trials using NSAIDs for PEP prevention was conducted. Pooled-prevalence and Odds-ratio of PEP, MSPEP were compared between treated vs. control groups. Analysis was performed using R software. Random-effects model was used for all variables. Physicians were surveyed via email before and after reviewing our results. RESULTS: 7688 patients in 25 trials were included. PEP was significantly reduced to 0.598 (95%CI, 0.47-0.76) in the NSAIDs group. Overall burden of MSPEP was reduced among all patients undergoing ERCP: OR 0.59 (95%CI, 0.42-0.83). However, NSAIDs didn't affect the proportion of MSPEP among those who developed PEP (p = 0.658). Rectal Indomethacin and diclofenac reduced PEP but not MSPEP. Efficacy didn't vary by risk, timing of administration, or bias-risk. Survey revealed a change in the impression of the effect of NSAIDs on MSPEP after reviewing our results. CONCLUSIONS: Rectal diclofenac or indomethacin before or after ERCP reduce the overall burden of MSPEP by reducing the pool of PEP from which it can arise. However, the proportion of MSPEP among patients who developed PEP is unaffected. Therefore, NSAIDs prevent initiation of PEP, but do not affect severity among those that develop PEP. Alternative modalities are needed to reduce MSPEP among patients who develop PEP.

Characterization of Pediatric Rectal Absorption, Drug Disposition, and Sedation Level for Midazolam Gel Using Physiologically Based Pharmacokinetic/Pharmacodynamic Modeling.

This study aims to explore and characterize the role of pediatric sedation via rectal route. A pediatric physiologically based pharmacokinetic-pharmacodynamic (PBPK/PD) model of midazolam gel was built and validated to support dose selection for pediatric clinical trials. Before developing the rectal PBPK model, an intravenous PBPK model was developed to determine drug disposition, specifically by describing the ontogeny model of the metabolic enzyme. Pediatric rectal absorption was developed based on the rectal PBPK model of adults. The improved Weibull function with permeability, surface area, and fluid volume parameters was used to extrapolate pediatric rectal absorption. A logistic regression model was used to characterize the relationship between the free concentrations of midazolam and the probability of sedation. All models successfully described the PK profiles with absolute average fold error (AAFE) < 2, especially our intravenous PBPK model that extended the predicted age to preterm. The simulation results of the PD model showed that when the free concentrations of midazolam ranged from 3.9 to 18.4 ng/mL, the probability of "Sedation" was greater than that of "Not-sedation" states. Combined with the rectal PBPK model, the recommended sedation doses were in the ranges of 0.44-2.08 mg/kg for children aged 2-3 years, 0.35-1.65 mg/kg for children aged 4-7 years, 0.24-1.27 mg/kg for children aged 8-12 years, and 0.20-1.10 mg/kg for adolescents aged 13-18 years. Overall, this model mechanistically quantified drug disposition and effect of midazolam gel in the pediatric population, accurately predicted the observed clinical data, and simulated the drug exposure for sedation that will inform dose selection for following pediatric clinical trials.

History of Rectal Product Use and Country of Residence Influence Preference for Rectal Microbicide Dosage Forms Among Young Sexual and Gender Minorities: A Multi-country Trial Comparing Placebo Douche, Suppository, and Insert Products.

The DESIRE Study (MTN-035) explored product preference among three placebo rectal microbicide (RM) formulations, a rectal douche (RD), a suppository, and an insert, among 210 sexually active transgender people and men who have sex with men in five counties: the United States, Peru, Thailand, South Africa, and Malawi. Participants used each product prior to receptive anal sex (RAS) for 1 month, following a randomly assigned sequence, then selected their preferred product via computer assisted self-interview. In-depth interviews examined reasons for preference. We compared product preference and prior product use by country to explore whether geographic location and experience with the similar products impacted preference. A majority in the United States (56%) and Peru (58%) and nearly half in South Africa (48%) preferred the douche. Most in Malawi (59%) preferred the suppository, while half in Thailand (50%) and nearly half in South Africa (47%) preferred the insert. Participants who preferred the douche described it as quick and easy, already routinized, and serving a dual purpose of cleansing and protecting. Those who preferred the insert found it small, portable, discreet, with quick dissolution. Those who preferred the suppository found the size and shape acceptable and liked the added lubrication it provided. Experience with product use varied by country. Participants with RD experience were significantly more likely to prefer the douche (p = 0.03). Diversifying availability of multiple RM dosage forms can increase uptake and improve HIV prevention efforts globally.

RESUMEN: El estudio DESIRE (MTN-035) exploró la preferencia de producto entre tres formulaciones de microbicida rectal (MR) de placebo, una ducha rectal, un supositorio y un inserto, entre 210 personas transgénero y hombres que tienen sexo con hombres en cinco países: los Estados Unidos, Perú., Tailandia, Sudáfrica y Malawi. Los participantes utilizaron cada producto antes del sexo anal receptive (SAR) durante un mes, siguiendo una secuencia asignada al azar, luego seleccionaron su producto preferido mediante una autoentrevista asistida por computadora. Las entrevistas en profundidad examinaron los motivos de preferencia. Comparamos la preferencia de producto y el uso previo del producto por país para explorar si la ubicación geográfica y la experiencia con la forma farmacéutica impactaron la preferencia. Una mayoría en los Estados Unidos (56%) y Perú (58%) y casi la mitad en Sudáfrica (48%) prefirieron la ducha rectal. La mayoría en Malawi (59%) prefirió el supositorio, mientras que la mitad en Tailandia (50%) y casi la mitad en Sudáfrica (47%) prefirió el inserto. Los participantes que prefirieron la ducha rectal la describieron como rápida y fácil, ya parte de su rutina y que tenía el doble propósito de limpiar y proteger. Los que prefirieron el inserto lo consideraron pequeño, portátil, discreto y de rápida disolución. Los que prefirieron el supositorio encontraron que tenía un tamaño y forma aceptables y proveía lubricación adicional. La experiencia con el uso del producto varió según el país. Los participantes con experiencia con duchas rectales tenían significativamente más probabilidades de preferir la ducha rectal (p = 0,03). Diversificar la disponibilidad de múltiples formas farmacéuticas de MR puede aumentar la aceptación y mejorar los esfuerzos de prevención del VIH a nivel mundial.

Effectiveness and tolerability of rectal ointment and suppositories containing sucralfate for hemorrhoidal symptoms: a prospective, observational study.

BACKGROUND AND AIMS: A high number of topical products are available for the treatment of hemorrhoidal symptoms. Sucralfate-based topical products constitute a new treatment alternative that act as a mechanical barrier to facilitate healing. The aim of this prospective, observational study was to determine patient- and physician-assessed effectiveness and tolerability of rectal ointment and suppositories containing sucralfate for the treatment of hemorrhoidal symptoms in routine clinical practice. METHODS: Adult patients with diagnosed, mild-to-moderate, symptomatic non-bleeding hemorrhoids treated with rectal ointment or suppositories containing sucralfate were enrolled. Patients were administered treatment twice per day for at least 1 week until symptom resolution and/or for a maximum of 4 weeks. The primary endpoint was patient-assessed effectiveness on a modified Symptom Severity Score (mSSS, range 0 to 14). Physician-assessed effectiveness (9 symptoms, 0 to 5 Likert scale), hemorrhoid grade, and patient satisfaction were also determined. RESULTS: Five investigators enrolled 60 patients; mean age was 48.4 ± 16.6 years and 72.4% were female. Pain or pressure sensitivity was reported as the most severe symptom by patients, and pressure sensitivity, discharge, soiling, and prolapse by physicians. Mean patient-assessed mSSS at baseline was 6.6 ± 1.9 and was significantly improved overall and in the ointment and suppository groups individually by -4.6 ± 2.0, -4.4 ± 1.8, and -4.8 ± 2.2, respectively (p < 0.0001). Investigator-assessed mean baseline symptom score was 18.1 ± 3.9 and improved by -7.1 ± 4.5, -6.9 ± 5.4, and -7.3 ± 3.5, respectively (p < 0.0001). Investigator-assessed symptoms of pressure sensitivity, swelling, and discharge were improved to the greatest extent. Hemorrhoid grade was improved in 38% of patients at the end of treatment. Compliance with treatment was 97.4% and patient satisfaction with application and onset of action was high (81.3% and 76.2%, respectively). Both the ointment and suppository were well tolerated. CONCLUSIONS: The effectiveness of topical ointment or suppository containing sucralfate on patient- and investigator-assessed hemorrhoidal symptoms in real-life clinical practice was demonstrated. Patient satisfaction was high and treatments were well tolerated. Larger controlled trials are warranted to confirm the results.

Intrarectal formalin treatment for haemorrhagic radiation-induced proctopathy: efficacy and safety.

AIM: Pelvic radiotherapy is limited by dose-dependent toxicity to surrounding organs. The aim of this prospective study was to evaluate the efficacy and safety of intrarectal formalin treatment for radiotherapy-induced haemorrhagic proctopathy (RHP) at the Royal Marsden Hospital. METHOD: Adult patients were enrolled. Haemoglobin was evaluated before and after formalin treatment. Antiplatelet and/or anticoagulation treatment and administration of transfusion were recorded. The interval between completion of radiotherapy and the first intrarectal 5% formalin treatment was assessed and the dose of radiotherapy was evaluated. Clinical assessment of the frequency and amount of rectal bleeding (rectal bleeding score 1-6) and endoscopic appearance (grade 0-3) were classified. Complications were recorded. RESULTS: Nineteen patients were enrolled, comprising 13 men (68%) and 6 women. The mean age was 75 ± 9 years. The median time between completion of radiotherapy and the first treatment was 20 months [interquartile range (IQR) 15 months] and the median dose of radiotherapy was 68 Gy (IQR 14 Gy). Thirty-two procedures were performed (average 1.7 per patient). In total, 9/19 (47%) patients were receiving anticoagulation and/or antiplatelet medication and 5/19 (26%) received transfusion prior to treatment. The mean value of serum haemoglobin before the first treatment was 110 ± 18 g/L and afterwards it was 123 ± 16 g/L (p = 0.022). The median rectal bleeding score before the first treatment was 6 (IQR 0) and afterwards 2 (IQR 1-4; p < 0.001), while the median endoscopy score on the day of first treatment was 3 (IQR 0) compared with 1 (IQR 1-2) on the day of the last treatment 1 (p < 0.001). One female patient with a persistent rectal ulcer that eventually healed (18 months of healing) subsequently developed rectovaginal fistula (complication rate 1/19, 5%). CONCLUSIONS: Treatment with intrarectal formalin in RHP is effective and safe.

Indomethacin Does Not Reduce Post-ERCP Pancreatitis in High-Risk Patients Receiving Pancreatic Stenting.

BACKGROUND: Rectal indomethacin reduces pancreatitis following endoscopic retrograde cholangiopancreatography (ERCP). However, there is insufficient evidence regarding its added benefits in patients already receiving prophylactic pancreatic stenting. Our goal was to evaluate the impact of indomethacin in high-risk patients undergoing pancreatic stenting. METHODS: A cohort study was conducted on all patients who underwent the rescue cannulation technique for challenging bile duct cannulation (selected high-risk patients). Patients were split into two groups based on the prophylaxis method for post-ERCP pancreatitis (PEP): one receiving a combination of indomethacin and pancreatic stenting, while the other received pancreatic stenting alone. Comparative analyses were carried out on PEP, hyperamylasemia, gastrointestinal bleeding, and postoperative hospital stay among post-ERCP pancreatitis patients. RESULTS: Between November 2017 and May 2023, a total of 607 patients with native papillae were enrolled, with 140 grouped into the indomethacin plus stent group and 467 into the stent alone group. The overall PEP rate was 4.4% in the entire cohort, with no statistical differences observed between the groups in terms of PEP rates (P = 0.407), mild PEP (P = 0.340), moderate to severe PEP (P = 1.000), hyperamylasemia (P = 0.543), gastrointestinal bleeding (P = 0.392), and postoperative hospital stay (P = 0.521). Furthermore, sensitivity analysis using multivariable analysis also validated these findings. CONCLUSIONS: Indomethacin did not reduce the incidence or severity of PEP in high-risk patients who routinely received prophylactic pancreatic stent placement. Therefore, the additional administration of rectal indomethacin to further mitigate PEP appears to be not necessary.

Methamphetamine Poisoning After "Plugging" Intentional Recreational Rectal Use.

BACKGROUND: Methamphetamine is a commonly used illicit substance. The route of administration is usually parenteral, oral ingestion, or snorting. A less common route of administration is placing in the rectum. CASE REPORT: A 28-year-old man presented to the emergency department with acute methamphetamine toxicity within 30 min after intentional rectal administration of methamphetamine for recreational purposes. The patient had hypertension, tachycardia, drug-induced psychosis, elevated creatine kinase, and required rapid sequence intubation and admission to the intensive care unit. Our patient had no clinical evidence of bowel ischemia or injury at the time of discharge. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: Rectal administration of methamphetamine is known as "plugging," "booty bumping," "keestering," and "butt whacking." The rectal administration of methamphetamine has the increased risk of severe acute methamphetamine toxicity, as rectal administration bypasses first-pass metabolism, allowing for a more acute onset and higher bioavailability of methamphetamine compared with oral administration. There is the potential for mesenteric ischemia and bowel injury after rectal methamphetamine. Close clinical monitoring for bowel and rectal ischemia or injury are recommended, in addition to management of the sympathomimetic toxidrome.

Effectiveness of preoperative micronized purified flavonoid fraction treatment and sucralfate-based rectal ointment on hemorrhoidal disease: A case-matched analysis.

BACKGROUND: Hemorrhoidal disease (HD) significantly impacts patients' quality of life. This study aimed to evaluate the effectiveness of preoperative treatment with the micronized purified flavonoid fraction (MPFF) and a sucralfate-based rectal ointment in managing HD symptoms and reducing interventions. METHODS: A prospective quasi-experimental study including consecutive cases and controls matched on the basis of sex was performed in a tertiary referral center. Cases received systemic and local therapy for HD, consisting of a rectal ointment containing 3% sucralfate and herbal extracts plus MPFF, in addition to conservative therapy, while controls received conservative therapy alone. The hemorrhoidal disease symptom score (HDSS), the Short Health Scale for HD (SHS-HD) score, and the Vaizey Incontinence Score were used to evaluate symptoms severity and their impact on quality of life and continence. Intervention requirements were assessed at baseline (T0) and after 60 days of treatment (T1). RESULTS: Between January and December 2023, a total of 98 patients were assessed for eligibility. After exclusions, 56 patients were enrolled, with 28 in each group. Significant improvements were observed in HD symptom scores from T0 to T1: the intervention group showed a mean change in HDSS of -9 [95% confidence interval (CI) -10 to -8], and the control group showed no significant change (mean change of 0; 95% CI -1.5 to 0). At T1, a higher proportion of patients in the intervention group underwent less invasive interventions compared with controls (18% versus 11%). Age, treatment group, and baseline symptom severity significantly predicted post-treatment symptom scores. CONCLUSIONS: In our study the preoperative treatment with MPFF and a sucralfate-based rectal ointment demonstrated clinical benefits in managing HD symptoms and reducing interventions. Further prospective trials are warranted to confirm and explore additional therapeutic strategies.

Lipid-Gelucire based rectal delivery of ramipril prodrug exhibits significant lowering of intra-ocular pressure in normotensive rabbit: sustained structural relaxation release kinetics and IVIVC.

Carboxylesterase enzymes convert a prodrug ramipril into the biologically active metabolite ramiprilat. It is prescribed for controlling ocular hypertension after oral administration. High concentrations of carboxylesterase enzymes in rectal and colon tissue can transform ramipril significantly to ramiprilat. Sustained rectal delivery of ramipril has been developed for intra-ocular pressure lowering effect using a normotensive rabbit model. Rectal suppositories have been formulated using a matrix base of HPMC K100-PEG 400-PEG 6000, incorporating varying amounts of Gelucire by the fusion moulding method. The presence of Gelucire in the suppository exhibited sustained structural relaxation-based release kinetics of RM compared to its absence. Intravenous and oral administration of ramipril has decreased IOP in the treated rabbit up to 90 and 360 min, respectively. Treated rabbits with suppositories have revealed decreased IOP for an extended period compared to the above. Formulation containing GEL 3% reduced intra-ocular pressure to 540 min, with the highest area under the decreased IOP curve. Compared to oral, the pharmacodynamic bioavailability of ramipril has been improved significantly using a sustained-release rectal suppository. A rectal suppository for sustained delivery of ramipril could be used to lower IOP significantly.

Effect of rectal indomethacin on the prevention of pancreatitis after endoscopic retrograde cholangiopancreatography for choledocholithiasis: a prospective randomized clinical trial.

BACKGROUND AND AIM: the aim of this study was to evaluate the efficacy and safety of rectal indomethacin for the prevention of post-endoscopic retrograde cholangiopancreatography (ERCP) pancreatitis (PEP) in patients with common bile duct (CBD) stones. METHODS: a total of 167 patients undergoing ERCP between November 2019 and November 2022 for CBD stones in the First Affiliated Hospital of Dalian Medical University were prospectively analyzed. The patients were divided into an indomethacin group (n = 58) and a control group (n = 109). The primary endpoint was the percent of patients who experienced PEP. RESULTS: PEP was observed in a total of 26 patients (15.57 %); four patients (6.90 %) in the indomethacin group and 22 (20.18 %) in the control group (p = 0.042). Mild, moderate and severe PEP was observed in three (5.17 %), one (1.72 %) and zero patients, respectively, in the indomethacin group, and in eleven (10.09 %), nine (8.26 %) and two (1.83 %) patients, respectively, in the control group. There was one case (0.92 %) of death due to PEP in the control group. No cases of moderate or severe bleeding were observed in either group. CONCLUSIONS: rectal indomethacin is an effective and safe method to prevent PEP for patients with CBD stones undergoing ERCP.

Rectal versus intravenous administration of acetaminophen; Clinical investigation of plasma level, analgesic, and antipyretic effects on 6-month to 6-year-old children in Zabol city, Iran.

OBJECTIVES: Acetaminophen is the most widely antipyretic analgesic medicine used in adults and children worldwide. Rectal acetaminophen is widely used in children who resist or cannot take oral medications. This study was designed to compare the efficacy of rectal and IV acetaminophen in children with fever and mild to moderate pain. PATIENTS AND METHODS: Total 60 children aged six months to 6 years, with fever and pain, that were treated with rectal or intravenous acetaminophen were selected and assigned in two groups. The IV group received 10mg/kg paracetamol as an IV infusion, and the rectal group received a 15mg/kg dose immediately after admission. Pain score was calculated using the FLACC method, and the axillary temperature was recorded at baseline and then 0.5, 1, 2, 4, and 6hours after drug administration. Blood samples were collected at baseline and then at 30min-intervals for the first 90minutes. RESULTS: The trend of changes in mean pain score at different time intervals was significantly different between the two groups. Body temperature decrease was more prominent in the IV group. The plasma concentration increased in both groups significantly with time. This increase was sharper in the IV group, just in the first 60minutes after drug administration. CONCLUSIONS: IV acetaminophen has more rapid onset of action, while rectal dosage form control fever and pain for longer duration. Considering its favorable effects with ease of administration and lower cost, rectal acetaminophen can be a reasonable option in selected patients with pain or fever.

Pre-referral rectal artesunate is no "magic bullet" in weak health systems.

Severe malaria is a potentially fatal condition that requires urgent treatment. In a clinical trial, a sub-group of children treated with rectal artesunate (RAS) before being referred to a health facility had an increased chance of survival. We recently published in BMC Medicine results of the CARAMAL Project that did not find the same protective effect of pre-referral RAS implemented at scale under real-world conditions in three African countries. Instead, CARAMAL identified serious health system shortfalls that impacted the entire continuum of care, constraining the effectiveness of RAS. Correspondence to the article criticized the observational study design and the alleged interpretation and consequences of our findings.Here, we clarify that we do not dispute the life-saving potential of RAS, and discuss the methodological criticism. We acknowledge the potential for confounding in observational studies. Nevertheless, the totality of CARAMAL evidence is in full support of our conclusion that the conditions under which RAS can be beneficial were not met in our settings, as children often failed to complete referral and post-referral treatment was inadequate.The criticism did not appear to acknowledge the realities of highly malarious settings documented in detail in the CARAMAL project. Suggesting that trial-demonstrated efficacy is sufficient to warrant large-scale deployment of pre-referral RAS ignores the paramount importance of functioning health systems for its delivery, for completing post-referral treatment, and for achieving complete cure. Presenting RAS as a "magic bullet" distracts from the most urgent priority: fixing health systems so they can provide a functioning continuum of care and save the lives of sick children.The data underlying our publication is freely accessible on Zenodo.

Rectal progesterone administration secures a high ongoing pregnancy rate in a personalized Hormone Replacement Therapy Frozen Embryo Transfer (HRT-FET) protocol: a prospective interventional study.

STUDY QUESTION: Can supplementation with rectal administration of progesterone secure high ongoing pregnancy rates (OPRs) in patients with low serum progesterone (P4) on the day of blastocyst transfer (ET)? SUMMARY ANSWER: Rectally administered progesterone commencing on the ET day secures high OPRs in patients with serum P4 levels below 35 nmol/l (11 ng/ml). WHAT IS KNOWN ALREADY: Low serum P4 levels at peri-implantation in Hormone Replacement Therapy Frozen Embryo Transfer (HRT-FET) cycles impact reproductive outcomes negatively. However, studies have shown that patients with low P4 after a standard vaginal progesterone treatment can obtain live birth rates (LBRs) comparable to patients with optimal P4 levels if they receive additionalsubcutaneous progesterone, starting around the day of blastocyst transfer. In contrast, increasing vaginal progesterone supplementation in low serum P4 patients does not increase LBR. Another route of administration rarely used in ART is the rectal route, despite the fact that progesterone is well absorbed and serum P4 levels reach a maximum level after ∼2 h. STUDY DESIGN, SIZE, DURATION: This prospective interventional study included a cohort of 488 HRT-FET cycles, in which a total of 374 patients had serum P4 levels ≥35 nmol/l (11 ng/ml) at ET, and 114 patients had serum P4 levels <35 nmol/l (11 ng/ml). The study was conducted from January 2020 to November 2022. PARTICIPANTS/MATERIALS, SETTING, METHODS: Patients underwent HRT-FET in a public Fertility Clinic, and endometrial preparation included oral oestradiol (6 mg/24 h), followed by vaginal micronized progesterone, 400 mg/12 h. Blastocyst transfer and P4 measurements were performed on the sixth day of progesterone administration. In patients with serum P4 <35 nmol/l (11 ng/ml), 'rescue' was performed by rectal administration of progesterone (400 mg/12 h) starting that same day. In pregnant patients, rectal administration continued until Week 8 of gestation, and oestradiol and vaginal progesterone treatment continued until Week 10 of gestation. MAIN RESULTS AND THE ROLE OF CHANCE: Among 488 HRT-FET single blastocyst transfers, the mean age of the patients at oocyte retrieval (OR) was 30.9 ± 4.6 years and the mean BMI at ET 25.1 ± 3.5 kg/m2. The mean serum P4 level after vaginal progesterone administration on the day of ET was 48.9 ± 21.0 nmol/l (15.4 ± 6.6 ng/ml), and a total of 23% (114/488) of the patients had a serum P4 level lower than 35 nmol/l (11 ng/ml). The overall, positive hCG rate, clinical pregnancy rate, OPR week 12, and total pregnancy loss rate were 66% (320/488), 54% (265/488), 45% (221/488), and 31% (99/320), respectively. There was no significant difference in either OPR week 12 or total pregnancy loss rate between patients with P4 ≥35 nmol/l (11 ng/ml) and patients with P4 <35 nmol/l, who received rescue in terms of rectally administered progesterone, 45% versus 46%, P = 0.77 and 30% versus 34%, P = 0.53, respectively. OPR did not differ whether patients had initially low P4 and rectal rescue or were above the P4 cut-off. Logistic regression analysis showed that only age at OR and blastocyst scoring correlated with OPR week 12, independently of other factors like BMI and vitrification day of blastocysts (Day 5 or 6). LIMITATIONS, REASONS FOR CAUTION: In this study, vaginal micronized progesterone pessaries, a solid pessary with progesterone suspended in vegetable hard fat, were used vaginally as well as rectally. It is unknown whether other vaginal progesterone products, such as capsules, gel, or tablet, could be used rectally with the same rescue effect. WIDER IMPLICATIONS OF THE FINDINGS: A substantial part of HRT-FET patients receiving vaginal progesterone treatment has lowserum P4. Adding rectally administered progesterone in these patients increases the reproductive outcome. Importantly, rectal progesterone administration is considered convenient, and progesterone pessaries are easy to administer rectally and of low cost. STUDY FUNDING/COMPETING INTEREST(S): Gedeon Richter Nordic supported the study with an unrestricted grant as well as study medication. B.A. has received unrestricted grant from Gedeon Richter Nordic and Merck and honoraria for lectures from Gedeon Richter, Merck, IBSA and Marckyrl Pharma. P.H. has received honoraria for lectures from Gedeon Richter, Merck, IBSA and U.S.K. has received grant from Gedeon Richter Nordic, IBSA and Merck for studies outside this work and honoraria for teaching from Merck and Thillotts Pharma AB and conference expenses covered by Merck. The other co-authors have no conflict of interest to declare. TRIAL REGISTRATION NUMBER (25): EudraCT no.: 2019-001539-29.

Rectal administration of tacrolimus protects against post-ERCP pancreatitis in mice.

OBJECTIVE: There is an unmet clinical need for effective, targeted interventions to prevent post-ERCP pancreatitis (PEP). We previously demonstrated that the serine-threonine phosphatase, calcineurin (Cn) is a critical mediator of PEP and that the FDA-approved calcineurin inhibitors, tacrolimus (Tac) or cyclosporine A, prevented PEP. Our recent observations in preclinical PEP models demonstrating that Cn deletion in both pancreatic and hematopoietic compartments is required for maximal pancreas protection, highlighted the need to target both systemic and pancreas-specific Cn signaling. We hypothesized that rectal administration of Tac would effectively mitigate PEP by ensuring systemic and pancreatic bioavailability of Tac. We have tested the efficacy of rectal Tac in a preclinical PEP model and in cerulein-induced experimental pancreatitis. METHODS: C57BL/6 mice underwent ductal cannulation with saline infusion to simulate pressure-induced PEP or were given seven, hourly, cerulein injections to induce pancreatitis. To test the efficacy of rectal Tac in pancreatitis prevention, a rectal Tac suppository (1 mg/kg) was administered 10 min prior to cannulation or first cerulein injection. Histological and biochemical indicators of pancreatitis were evaluated post-treatment. Pharmacokinetic parameters of Tac in the blood after rectal delivery compared to intravenous and intragastric administration was evaluated. RESULTS: Rectal Tac was effective in reducing pancreatic injury and inflammation in both PEP and cerulein models. Pharmacokinetic studies revealed that the rectal administration of Tac helped achieve optimal blood levels of Tac over an extended time compared to intravenous or intragastric delivery. CONCLUSION: Our results underscore the effectiveness and clinical utility of rectal Tac for PEP prophylaxis.

An Open-Label Randomized Controlled Trial Comparing Effectiveness of Aggressive Hydration Versus High-dose Rectal Indomethacin in the Prevention of Postendoscopic Retrograde Cholangiopancreatographic Pancreatitis (AHRI-PEP).

BACKGROUND: Although rectal administration of nonsteroidal anti-inflammatory drugs is recommended as the standard pharmacologic modality to prevent postendoscopic retrograde cholangiopancreatography (ERCP) post-ERCP pancreatitis (PEP), vigorous periprocedural hydration (vHR) with lactated Ringer's solution (LR) is emerging as an effective prophylaxis modality for PEP. There has been no head-to-head comparison between these 2. STUDY: This was a single-center, randomized, open-label, noninferiority, parallel-assigned, equal allocation, controlled clinical trial in a tertiary care hospital. Consecutive adults referred for ERCP, satisfying predefined inclusion criteria, underwent simple randomization and blinded allocation into 2 groups. Those allocated to vHR received intravenous LR at 3 mL/kg/h during procedure, 20 ml/kg bolus immediately afterward, and then at 3 mL/kg/h for another 8 hours. Those randomized to rectal Indomethacin received only per-rectal 100 mg suppository immediately post-ERCP. Assuming PEP of 9% in Indomethacin arm and noninferiority margin of 4%, we calculated sample size of 171 patients in each arm for 80% power and α-error 5%. Primary outcome was incidence of PEP, within 1 week, as defined by Cotton's criteria. All analysis were done by intention-to-treat. RESULTS: Between October, 2017 to February, 2018, 521 patients were assessed. In all, 352 were enrolled, 178 randomized to vHR, and 174 to per-rectal Indomethacin. Baseline details and ERCP outcomes were not different between 2 groups. PEP occurred in 6 (1.7%) overall, with 1 (0.6%) in hydration arm, and 5 (2.9%) in indomethacin arm; an absolute risk reduction of 2.3% (95% confidence interval: 0.9%-3.5%) and odds ratio of 0.19 (95% confidence interval: 0.02-1.65). Three patients developed severe PEP, all receiving indomethacin. CONCLUSIONS: vHR with LR is noninferior to postprocedure per-rectal Indomethacin for PEP prevention (ClinicalTrials.govID:NCT03629600).

Effect of Adding Intravenous Somatostatin to Rectal Indomethacin on Post-Endoscopic Retrograde Cholangiopancreatography (ERCP) Pancreatitis in High-risk Patients: A Double-blind Randomized Placebo-controlled Clinical Trial.

BACKGROUND: Endoscopic retrograde cholangiopancreatography (ERCP) has an important role in the treatment of pancreaticobiliary disorders. GOALS: Considering the high prevalence and importance of postendoscopic retrograde cholangiopancreatography pancreatitis (PEP) and the controversial findings, we aimed to determine the effect of adding intravenous somatostatin to rectal indomethacin on the incidence of PEP in high-risk patients. STUDY: In this prospective study, 530 patients underwent ERCP during March 2018 and February 2019. Patients were randomized into 2 groups. The intervention group received a bolus injection of 250 µg somatostatin followed by an infusion of 500 µg of somatostatin for 2 hours. In both groups, 100 mg of pre-ERCP suppository indomethacin was administrated. All patients were screened for PEP symptoms and signs for 24 hours after ERCP (Iranian Registry of Clinical Trials code: IRCT20080921001264N11). RESULTS: A total of 376 patients were finally analyzed. PEP was the most common adverse event with 50 (13.2%) episodes, including 21 (5.5%) mild, 23 (6.1%) moderate, and 6 (1.2%) severe. The rate of PEP was 15.2% in the control group and 11.4% in the intervention group ( P =0.666). The incidence of post-ERCP hyperamylasemia was 21.7% in the control group and 18.2% in the intervention group ( P =0.395). No death occurred. CONCLUSIONS: In this study administration of somatostatin plus indomethacin could safely reduce the rate of post-ERCP hyperamylasemia and PEP in the intervention group compared with the control group, but the differences were not significant. Further studies with larger sample sizes are required.

Combination Topical Epinephrine and Non-steroidal Inflammatory Drugs in the Prevention of Post-ERCP Pancreatitis: A Systematic Review.

BACKGROUND: The utility of combination rectal NSAID and topical epinephrine (EI) or rectal NSAID and normal saline (SI) sprayed on duodenal papilla in the prevention of post-ERCP pancreatitis (PEP) has been studied but results have been conflicting. AIMS: To evaluate the benefit of using combination prophylaxis in preventing PEP. METHODS: A literature search was performed using Scopus, PubMed/MEDLINE, and Cochrane databases in May 2021. Randomized controlled trials (RCTs) involving adults patients who underwent ERCP and received EI versus SI were eligible for inclusion. The pooled effect was expressed as odds ratio (OR) to assess the rate of PEP, severity of PEP, and specific adverse events. The results were pooled using Reviewer Manager 5.4 software. RESULTS: Six RCTs involving 4016 patients were included in the final analysis. The EI group did not demonstrate any significant benefit over SI group in preventing PEP (OR = 1.00, 95% CI [0.68, 1.45], P = 0.98), irrespective of gender or the epinephrine concentration used. The tests for subgroup differences were not statistically significant with P-values of 0.66 and 0.28, respectively. The addition of topical epinephrine to rectal NSAID did not improve the rate of moderate to severe PEP (OR = 0.94, P = 0.86) or PEP in high-risk patients (OR = 1.14, 95%, P = 0.73). The rates of infection, including cholangitis and sepsis (OR = 0.63, P = 0.07), gastrointestinal bleeding (OR = 1.25, P = 0.56) and procedure-related death (OR = 0.71, P = 0.59) were similar between both groups. CONCLUSION: The addition of topical epinephrine did not demonstrate any benefit over rectal NSAID alone in preventing PEP or reducing other procedure-related adverse events.

Rectal administration of low-dose diclofenac does not reduce post-endoscopic retrograde cholangiopancreatography pancreatitis: a propensity score matching analysis.

BACKGROUND: Endoscopic retrograde cholangiopancreatography (ERCP) is a popular technique; however, post-ERCP pancreatitis (PEP) remains a major adverse event. The administration of rectal nonsteroidal anti-inflammatory drugs (NSAIDs) is reportedly effective in preventing PEP. However, the recommended dose varies and the efficacy of low-dose rectal NSAIDs remains unclear. Therefore, we decided to investigate the effectiveness of low-dose rectal diclofenac on PEP prevention, using propensity score matching. METHODS: This single-center retrospective study included 401 patients who underwent ERCP between July 2015 and March 2020. After December 2016, we administered rectal diclofenac within 30 min before the ERCP procedure as widely as possible. Patients were divided into those who did (diclofenac group) and did not (control group) receive rectal diclofenac. Patients weighing ≥ 50 kg were administered a 50 mg dose, while those weighing < 50 kg were administered a 25 mg dose. The incidence and severity of PEP in the two groups were assessed by propensity score matching analysis. RESULTS: Among 401 patients undergoing ERCP, 367 fulfilled the inclusion criteria. Overall, 187 patients received rectal diclofenac (diclofenac group) and 180 did not (control group). After propensity score matching, 105 pairs were selected for evaluation. Overall, seven (6.7%) patients in the diclofenac group and 10 (9.5%) in the control group developed PEP (P = 0.45). Moderate or severe PEP occurred in four (3.8%) patients in the diclofenac group and six (5.7%) in the control group (P = 0.52). CONCLUSIONS: The administration of low-dose rectal diclofenac could not reduce the incidence and severity of PEP.