Non-Invasive Delivery of Insulin for Breaching Hindrances against Diabetes.

Insulin is recognized as a crucial weapon in managing diabetes. Subcutaneous (s.c.) injections are the traditional approach for insulin administration, which usually have many limitations. Numerous alternative (non-invasive) slants through different routes have been explored by the researchers for making needle-free delivery of insulin for attaining its augmented absorption as well as bioavailability. The current review delineating numerous pros and cons of several novel approaches of non-invasive insulin delivery by overcoming many of their hurdles. Primary information on the topic was gathered by searching scholarly articles from PubMed added with extraction of data from auxiliary manuscripts. Many approaches (discussed in the article) are meant for the delivery of a safe, effective, stable, and patient friendly administration of insulin via buccal, oral, inhalational, transdermal, intranasal, ocular, vaginal and rectal routes. Few of them have proven their clinical efficacy for maintaining the glycemic levels, whereas others are under the investigational pipe line. The developed products are comprising of many advanced micro/nano composite technologies and few of them might be entering into the market in near future, thereby garnishing the hopes of millions of diabetics who are under the network of s.c. insulin injections.

Intravenous Hemin, a potential heme oxygenase-1 activator, does not protect from post-ERCP acute pancreatitis in humans: Results of a randomized multicentric multinational placebo-controlled trial.

OBJECTIVE: Hemin, a heme oxygenase 1 activator has shown efficacy in the prevention and treatment of acute pancreatitis in mouse models. We conducted a randomized controlled trial (RCT) to assess the protective effect of Hemin administration to prevent post-endoscopic retrograde cholangiopancreatography (ERCP) pancreatitis (PEP) in patients at risk. METHODS: In this multicenter, multinational, placebo-controlled, double-blind RCT, we assigned patients at risk for PEP to receive a single intravenous dose of Hemin (4 mg/kg) or placebo immediately after ERCP. Patients were considered to be at risk on the basis of validated patient- and/or procedure-related risk factors. Neither rectal NSAIDs nor pancreatic stent insertion were allowed in randomized patients. The primary outcome was the incidence of PEP. Secondary outcomes included lipase elevation, mortality, safety, and length of stay. RESULTS: A total of 282 of the 294 randomized patients had complete follow-up. Groups were similar in terms of clinical, laboratory, and technical risk factors for PEP. PEP occurred in 16 of 142 patients (11.3%) in the Hemin group and in 20 of 140 patients (14.3%) in the placebo group (p = 0.48). Incidence of severe PEP reached 0.7% and 4.3% in the Hemin and placebo groups, respectively (p = 0.07). Significant lipase elevation after ERCP did not differ between groups. Length of hospital stay, mortality and severe adverse events rates were similar between groups. CONCLUSION: We failed to detect large improvements in PEP rate among participants at risk for PEP who received IV hemin immediately after the procedure compared to placebo. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov number, NCT01855841).

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.

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.

Comparison of Berberine Bioavailability between Oral and Rectal Administrations in Rats.

The oral bioavailability of berberine is quite low due to extensive first-pass metabolism. To increase the bioavailability of berberine (BBR), the efficacy of rectal administration that can avoid intestinal and hepatic first-pass metabolism partly was evaluated using BBR sulfate in rats. BBR sulfate was administered intravenously (1 mg/kg as BBR), orally (10 mg/kg as BBR) and rectally (1, 3, or 10 mg/kg as BBR) using Witepsol® H15 suppository base to evaluate bioavailability in rats. Concentrations of BBR in plasma were determined by liquid chromatography-tandem mass spectrometry (LC-MS/MS). When BBR sulfate was administered orally, the average oral bioavailability was 0.26%. When BBR sulfate was administered rectally, the average bioavailabilities were 17.0% at 1 mg/kg, 24.3% at 3 mg/kg, and 12.3% at 10 mg/kg as BBR, respectively. Thus, rectal administration of BBR sulfate greatly increased the bioavailability of BBR as compared with oral administration, which would also increase the pharmacological activities of BBR in vivo.

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.

[Dynamic magnetic resonance imaging of the pelvic floor: Technical aspects]. / Dynamische Magnetresonanztomographie des Beckenbodens: Technische Aspekte.

BACKGROUND: Dynamic magnetic resonance imaging (MRI) of the pelvic floor plays a key role in imaging complex pelvic floor dysfunction. High-quality examination is crucial for diagnostic benefit but can be technically challenging. OBJECTIVES: The most important technical aspects (patient selection, patient preparation, MRI technology, MRI scan protocol, success control) for obtaining a state-of-the-art dynamic MRI of the pelvic floor are summarized. MATERIALS AND METHODS: Review of the scientific literature on dynamic pelvic MR imaging with special consideration of the joint recommendations provided by the expert panels of European Society of Urogenital Radiology/European Society of Gastrointestinal and Abdominal Radiology (ESUR/ESGAR) in 2016 and Society of Abdominal Radiology (SAR) in 2019. RESULTS: Examination with at least 1.5 T and a surface coil after rectal instillation of ultrasound gel is clinical standard. Dynamic MRI in a closed magnet with the patient in supine position is the most widespread technique. No clinically significant pathologies of the pelvic floor are missed compared to the sitting position in an open magnet. The minimum scan protocol should encompass static, high-resolution T2-imaging (i.e., T2-TSE) in three planes and dynamic sequences with high temporal resolution in sagittal (and possibly axial) plane (i.e., steady-state or balanced steady-state free precession) during squeezing, straining and evacuation. Detailed patient instruction and practicing prior to the scan improve patients' compliance and hence diagnostic quality. CONCLUSIONS: A technically flawless dynamic MRI of the pelvic floor according to these standards can provide information missed by other imaging modalities and hence alter therapeutic strategies.

Transanal total mesorectal excision (TaTME) in rectal cancer treatment within an expert center.

The objective of this study was to evaluate treatment outcomes in patients who underwent the TaTME procedure for cancer of the middle and low rectum in an expert center. Prospective analysis of the outcomes of all consecutive patients treated using the TaTME technique for cancer of the middle and distal rectum at the our medical center between March 1, 2015, and March 31, 2022. A total of 128 patients (34 women, 94 men; mean age 66.01 [38-85] years) with cancer of the middle and distal rectum qualified for TaTME. TaTME procedures were performed in 127/128 (99.22%) patients. Complications of surgery were observed in 22/127 (17.32%) patients. Negative proximal and distal margins were confirmed in all 127 patients. Complete (R0) resection of the mesorectum was confirmed in 125/127 (98.43%) and nearly complete (R1) resection was confirmed in 2/127 (1.57%) patients. The average follow-up period was 795 days (296-1522) days. Local recurrence was detected during the follow-up period in 2/127 (1.57%) patients. This study showed that the TaTME procedure is an effective and safe method for the minimally invasive treatment of middle and low rectal cancers, particularly within an expert center setting.

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.

In situ gel-forming oil as rectally delivering platform of hydrophobic therapeutics for ulcerative colitis therapy.

Because of their poor water-soluble properties and non-specific distribution, most hydrophobic therapeutics had limited benefit for patients with ulcerative colitis. Herein, an in-situ oil-based gel has been developed as a rectal delivery vehicle for these therapeutics. In situ gel-forming oil (BBLG) was composed of soybean phosphatidyl choline (40%, w/w), glyceryl dioleate (50%, w/w), and ethanol (10%, w/w). The hydrophobic laquinimod (LAQ) as a model drug was easily dissolved in gel-forming oil and its solubility was reaching to 7 ± 0.1 mg/mL. Importantly, upon contact with the colonic fluids, the gel-forming oil was quickly transited to a semi-solid gel, adhering to the inflamed colon mucosa and forming a protective barrier. Transmission Electron Microscopy showed that the gel network was arranged by the connected lipid spheres and LAQ was non-crystally encapsulated into the lipid spheres. Moreover, the universal adhesive test showed that the adhesive force and the adhesive energy of BBLG toward fresh colon tissues were 711 ± 12 mN and 25 ± 2 J/m2, which was 2.14-fold and 5-fold higher than that of the marketed Poloxamer 407 gel, respectively. Meanwhile, in vivo imaging confirmed that the retention time of BBLG in the colon lumen was more than 8 h after rectal administration. In vivo animal studies showed that BBLG also greatly enhanced the therapeutic impact of LAQ on TNBS-treated rats with ulcerative colitis, as evidenced by reduced disease activity index (DAI) scores and weight loss. Moreover, the colonic inflammation was significantly alleviated and the goblet cells were obliviously restored after treatment. Importantly, the gut mucosa barrier was largely repaired without any formation of fibrosis remodeling. Conclusively, in situ liquid gel may be a potential delivery system of hydrophobic medicines for ulcerative colitis.

Safety, Pharmacokinetics, and Pharmacodynamics of Midazolam Gel After Rectal Administration in Healthy Chinese Subjects.

BACKGROUND AND OBJECTIVES: Midazolam rectal gel is a novel rectal formulation that may be a promising and potential alternative to oral administration for pediatric sedation. The objective of this study was to evaluate the safety, pharmacokinetics, pharmacodynamics, and absolute bioavailability of midazolam rectal gel in healthy Chinese subjects. METHODS: An open-label, single-dose, randomized, two-period, two-treatment, crossover clinical study was conducted in 22 healthy subjects (16 males and six females), each receiving 2.5 mg intravenous midazolam in one period and 5 mg midazolam rectal gel in another period (the dosages here were calculated as active midazolam). Safety, pharmacokinetic, and pharmacodynamic assessments were conducted throughout the study. RESULTS: All of the subjects completed both treatment periods. The formulation of rectal gel was well tolerated, with no serious adverse events occurring. After a single rectal dose of 5 mg midazolam rectal gel, it was absorbed rapidly with a median value of time to peak concentration (Tmax) of 1.00 h, and mean values of the peak concentration (Cmax) and area under the concentration-time curve (AUC0-t) of 37.2 ng/mL and 137 h·ng/mL, respectively. The absolute bioavailability of rectal gel was 59.7%. The rectal gel exhibited a relatively delayed onset but a more stable sedative effect and a longer duration when compared with intravenous midazolam. CONCLUSION: Midazolam rectal gel may be a feasible alternative with a high level of acceptance in pediatric sedation and enhanced bioavailability compared to an oral formulation. The modeling results may help to disclose out the exposure-response relationship of midazolam rectal gel and support the design of an escalating-doses study and pediatric extrapolation study. CLINICAL TRIAL REGISTRATION: The study was registered at http://www.chinadrugtrials.org.cn (No. CTR20192350).

Continuous fluid infusion per rectum compared with intravenous fluid infusion in pigs.

BACKGROUND: Peripheral blood vessels in pigs are not easily accessible, making placement of intravenous catheters difficult. Alternative methods to intravenous administration of fluids, such as administering fluids via the rectum (proctoclysis), are warranted in pigs. HYPOTHESIS: Administration of polyionic crystalloid fluids via proctoclysis results in hemodilution changes similar to intravenous administration. The objectives of this study were to evaluate the tolerance for proctoclysis in pigs and compare analytes before and after intravenous or proctoclysis therapy. ANIMALS: Six healthy, growing, academic institution-owned pigs. METHODS: Randomized, cross-over design clinical trial, with 3 treatments (control, intravenous, and proctoclysis) with a 3-day washout period. The pigs were anesthetized and jugular catheters were placed. A polyionic fluid (Plasma-Lyte A 148) was administered at 4.4 mL/kg/h during the intravenous and proctoclysis treatments. Laboratory analytes, including PCV, plasma, and serum total solids, albumin, and electrolytes were measured over 12 h at T0 , T3 , T6 , T9 , and T12 . Effects of treatment and time on analytes were determined by analysis of variance. RESULTS: Proctoclysis was tolerated by pigs. Albumin concentrations decreased during the IV treatment between T0 and T6 (least square mean of 4.2 vs 3.9 g/dL; 95% CI of mean difference = -0.42, -0.06; P = .03). Proctoclysis did not significantly affect any laboratory analytes at any time points (P > .05). CONCLUSIONS AND CLINICAL IMPORTANCE: Proctoclysis did not demonstrate hemodilution similar to intravenous administration of polyionic fluids. Proctoclysis might not be an effective alternative to the intravenous administration of polyionic fluids in healthy euvolemic pigs.

Transition Zone Pull-through in Patients with Hirschsprung Disease: Is Redo Surgery Beneficial for the Long-term Outcomes?

INTRODUCTION: Transition zone pull-through (TZPT) is incomplete removal of the aganglionic bowel/transition zone (TZ) in patients with Hirschsprung disease (HD). Evidence on which treatment generates the best long-term outcomes is lacking. The aim of this study was to compare the long-term occurrence of Hirschsprung associated enterocolitis (HAEC), requirement of interventions, functional outcomes and quality of life between patients with TZPT treated conservatively to patients with TZPT treated with redo surgery to non-TZPT patients. METHODS: We retrospectively studied patients with TZPT operated between 2000 and 2021. TZPT patients were matched to two control patients with complete removal of the aganglionic/hypoganglionic bowel. Functional outcomes and quality of life was assessed using Hirschsprung/Anorectal Malformation Quality of Life questionnaire and items of Groningen Defecation & Continence together with occurrence of Hirschsprung associated enterocolitis (HAEC) and requirement of interventions. Scores between the groups were compared using One-Way ANOVA. The follow-up duration lasted from time at operation until follow-up. RESULTS: Fifteen TZPT-patients (six treated conservatively, nine receiving redo surgery) were matched with 30 control-patients. Median duration of follow-up was 76 months (range 12-260). No significant differences between groups were found in the occurrence of HAEC (p = 0.65), laxatives use (p = 0.33), rectal irrigation use (p = 0.11), botulinum toxin injections (p = 0.06), functional outcomes (p = 0.67) and quality of life (p = 0.63). CONCLUSION: Our findings suggest that there are no differences in the long-term occurrence of HAEC, requirement of interventions, functional outcomes and quality of life between patients with TZPT treated conservatively or with redo surgery and non-TZPT patients. Therefore, we suggest to consider conservative treatment in case of TZPT.

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 use of levetiracetam: best practice report for a stepwise approach for sustainable off-label decision making and treatment.

Off-label drug use is common practice in palliative care. It may pose a risk to the patient and benefit should outweigh harm. A decision and documentation aid for off-label use was developed to support practitioners in clinical practice off-label use. Using the example of the rectal administration of levetiracetam in three patient cases, the utilisation and benefits of the decision and documentation aid are presented and discussed. The rectal administration of levetiracetam clearly is an experimental treatment approach with little underlying evidence. To support and document the decision-making process for or against such an off-label use in clinical practice, it is helpful to have a structured approach in order to make this data comprehensible for a later point in time. Off-label use may be a permissible treatment alternative without underlying evidence, provided it takes place in a well-planned and well-monitored therapeutic setting and the benefits outweigh the potential risks.

WHO should accelerate, not stall, rectal artesunate deployment for pre-referral treatment of severe malaria.

The recent World Health Organization moratorium on rectal artesunate (RAS) for pre-referral treatment of severe childhood malaria is costing young lives. The decision was based on disappointing findings from a large observational study that provided RAS to community health workers with little training and supervision. This non-randomized, operational research has provided useful information to guide the implementation of RAS but is subject to bias and confounding and cannot be used to assess treatment effects. Parenteral artesunate reduces severe malaria mortality and a large body of evidence also shows RAS has lifesaving efficacy. There is now more than a decade of delay in conducting the necessary engagement and training required for successful deployment of RAS. Further delays will result in more preventable deaths.

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).

Rectal Administration of Celecoxib Liquid Suppositories with Enhanced Bioavailability and Safety in Rats.

BACKGROUND: Celecoxib is generally used for the treatment of rheumatoid arthritis, however its poor bioavailability and cytotoxicity in pure form have reduced its therapeutic efficacy. This study aims to develop celecoxib liquid suppositories with improved bioavailability and reduced toxicity. METHODS: The celecoxib liquid suppositories were prepared by thoroughly mixing celecoxib, poloxamer 188 and poloxamer 407, and tween-20, respectively used as drug, polymers and surfactant, in triple distilled water using cold technique. The developed liquid suppositories were characterized in terms of their gelation temperature, gelation time, and gel strength. Moreover, the muco-adhesive force was determined for the suppositories. The release behavior of the liquid suppositories was investigated in distilled water and compared with drug suspension. Furthermore, pharmacokinetics and morphological studies were carried out in rats after rectal administration of the celecoxib liquid suppository compared with drug suspension. RESULTS: Poloxamer 188 and Tween-20 concentrations have significantly reduced the gelation temperature and time; however, the gel strength and bio-adhesive force were significantly enhanced. The concentration of celecoxib has no significant effect on the properties of liquid suppositories. A significantly enhanced and potentially sustained drug release was observed from the celecoxib liquid suppositories as compared with the drug suspension. The optimized formulation was easy to administer rectally because it quickly forms gel upon insertion into the body due to a suitable gelation temperature of about 31.7 °C. After rectal administration in rats, the celecoxib liquid suppository gave a significantly increased pharmacokinetic profile including enhanced plasma concentration and 9.7 fold improved area under the curve (AUC) compared to the drug suspension. Additionally, the morphology study exhibited no toxicity to the rectal tissue, no signs of irritation, or injury after the application of suppository. However, severe rectal tissue toxicity and irritation was observed in the suspension treated rectum. CONCLUSION: It can be concluded that the liquid suppository system may significantly enhance the solubilization and bio-availability of sparingly water-soluble drugs as evident in the case of celecoxib with no toxicity at the site of application.

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.