Oral Tolerability Research Articles

Keverprazan, a novel potassium-competitive acid blocker: Multiple oral doses safety, tolerability, pharmacokinetics, and pharmacodynamics in healthy subjects.

Keverprazan, a novel potassium-competitive acid blocker, was approved for treating acid-related diseases. This study aimed to analyze the safety, pharmacokinetics (PKs) and pharmacodynamics (PDs) of multiple doses of keverprazan. This was a randomized, positive-/placebo-controlled, phase Ic trial. Twenty-six healthy adults were randomized to receive 20 mg/day keverprazan (n = 8), 40 mg/day keverprazan (n = 8), placebo (n = 6), or 20 mg/day vonoprazan (n = 4) for 7 days. Safety, PK and PD assessments were conducted. In the keverprazan, vonoprazan, and placebo groups, adverse events (AEs) were reported in nine (56.25%), two (50.00%), and three (50.00%) subjects, respectively. AEs were mild except a moderate abdominal pain leading to withdraw. No serious AEs occurred. The plasma concentration-time profiles of keverprazan showed rapid absorption (median time to maximum plasma concentration of 1.25-3.0 h). The terminal half-life was 6.23 and 7.01 h for keverprazan 20 and 40 mg groups on day 7. The maximum plasma concentration was 43.1 and 93.2 ng/mL, respectively. There was no apparent accumulation of keverprazan and the major metabolite after 7-day administration. The intragastric pH greater than 5 holding time ratios (HTRs) over 24 h postdose increased from 79.1%, 84.4%, and 84.5% on day 1 to 99.0%, 97.4%, and 100.0% on day 7 in the vonoprazan 20 mg and keverprazan 20 and 40 mg groups, respectively. The intragastric pH greater than 5 HTR of keverprazan reached a plateau at 20 mg. Keverprazan is well-tolerable. A steady-state in exposure was generally reached after 7 days of treatment. A dose of 20 mg/day keverprazan can elicit a significant, stable, and long-lasting gastric acid inhibition effect.

Mechanisms of Azole Resistance in CandidaA Narrative Review

Candida species, opportunistic fungal pathogens, pose a significant threat to human health, and the emergence of drug-resistant Candida strains has become a major concern in clinical settings, limiting the efficacy of antifungal therapies. Azoles are a class of antifungal agents that play a crucial role in the management of fungal infections. They have several advantages which contributes to their widespread use, like their broad-spectrum activity, availability in systemic and topical formulations, good oral bioavailability, tolerability, target specificity, established efficacy, and low toxicity for long-term prophylaxis. Azole resistance in Candida species poses a significant therapeutic challenge in the management of fungal infections, particularly in immunocompromised individuals. One common mechanism of resistance involves alterations in the target enzyme, cytochrome P450 14-alpha-demethylase (CYP51), which is essential for ergosterol biosynthesis, a crucial component of fungal cell membranes. Mutations in the CYP51 gene can lead to structural changes in the enzyme, reducing its affinity for azoles and thus decreasing their inhibitory effect. Another mechanism involves overexpression of efflux pumps, such as ATP-binding cassette (ABC) transporters and major facilitator superfamily (MFS) transporters. These pumps actively remove azoles from fungal cells, preventing them from reaching effective concentrations and thereby reducing their antifungal activity. A better understanding of the mechanisms underlying drug resistance is crucial for developing effective strategies to overcome this growing problem. This review describes and summarises the mechanisms associated with azole resistance in Candida, exploring the genetic, biochemical, and cellular factors contributing to this phenomenon. Additionally, potential approaches to combat azole resistance are discussed, aiming to pave the way for the development of novel therapeutic interventions.

Mechanisms of Azole Resistance in CandidaA Narrative Review

Candida species, opportunistic fungal pathogens, pose a significant threat to human health, and the emergence of drug-resistant Candida strains has become a major concern in clinical settings, limiting the efficacy of antifungal therapies. Azoles are a class of antifungal agents that play a crucial role in the management of fungal infections. They have several advantages which contributes to their widespread use, like their broad-spectrum activity, availability in systemic and topical formulations, good oral bioavailability, tolerability, target specificity, established efficacy, and low toxicity for long-term prophylaxis. Azole resistance in Candida species poses a significant therapeutic challenge in the management of fungal infections, particularly in immunocompromised individuals. One common mechanism of resistance involves alterations in the target enzyme, cytochrome P450 14-alpha-demethylase (CYP51), which is essential for ergosterol biosynthesis, a crucial component of fungal cell membranes. Mutations in the CYP51 gene can lead to structural changes in the enzyme, reducing its affinity for azoles and thus decreasing their inhibitory effect. Another mechanism involves overexpression of efflux pumps, such as ATP-binding cassette (ABC) transporters and major facilitator superfamily (MFS) transporters. These pumps actively remove azoles from fungal cells, preventing them from reaching effective concentrations and thereby reducing their antifungal activity. A better understanding of the mechanisms underlying drug resistance is crucial for developing effective strategies to overcome this growing problem. This review describes and summarises the mechanisms associated with azole resistance in Candida, exploring the genetic, biochemical, and cellular factors contributing to this phenomenon. Additionally, potential approaches to combat azole resistance are discussed, aiming to pave the way for the development of novel therapeutic interventions

The effect of cladribine on immunoglobulin levels compared to B cell targeting therapies in multiple sclerosis.

Cladribine is a useful therapeutic option in RRMS with moderate to high disease activity. Its oral formulation and tolerability make it a useful alternative to infusion therapies. Cladribine is known to deplete CD19+ B lymphocytes, but its effect on immunoglobulin subsets is unclear. To identify whether cladribine therapy in pwMS reduces immunoglobulin subset levels as a surrogate marker of infection risk. A 'real-world' retrospective analysis of 341 pwMS presenting to a single tertiary centre between March 2017 and July 2021. Differences in immunoglobulin levels between cladribine, other disease-modifying therapies and no active treatment were assessed using a univariate ANOVA. Three hundred and forty-one patients had immunoglobulin levels assessed, with 29 patients treated with cladribine. The mean IgG, IgM and IgA levels on cladribine therapy were 10.44 ± 0.40, 0.99 ± 0.09 and 2.04 ± 0.18 g/L respectively. These were not significantly different from patients not on active treatment. There was a statistically significant reduction in IgG and IgM levels for patients treated with ocrelizumab (9.37 ± 0.19 and 0.68 ± 0.04 g/L) and natalizumab (8.72 ± 0.53 and 0.69 ± 0.12 g/L) compared to patients not on treatment. Cladribine therapy for RRMS was not associated with immunoglobulin subset deficiencies. This is contrasted to ocrelizumab and natalizumab which demonstrate significant reductions in both IgG and IgM levels.

Development, characterization and In-vitro evaluation of guar gum based new polymeric matrices for controlled delivery using metformin HCl as model drug.

Currently, hydrogels are considered as ideal biomaterials due to their unique structure and characteristics that facilitates considerable hydrophilicity, swelling, drug loading and release. In this study, we report pH-responsive GG-MAA-AMPS hydrogel delivery system prepared via free radical polymerization technique. Hydrogels were loaded with Metformin HCl as a model drug. Hydrogels were characterized through Fourier transform infrared spectroscopy (FTIR), thermogravimetric analysis (TGA), differential scanning calorimetry (DSC), X-ray diffraction (XRD) and scanning electron microscopy (SEM). FTIR confirmed the successful crosslinking of reactants, hydrogel network formation and drug loading. TGA and DSC proved the higher thermal stability of reactants after crosslinking and drug loading. XRD analysis showed decrease in crystallinity of drug after loading into the hydrogels. SEM revealed smooth and glassy appearance of both loaded and unloaded hydrogels. Gel content was increased with increase in concentration of reactants. Drug entrapment was decreased by increasing concentration of GG and AMPS while MAA acted inversely. Hydrogels displayed pH-dependent swelling and drug release behavior being high at pH 6.8 and 7.4 while low at acidic pH (1.2). Oral tolerability in rabbits showed that hydrogels were safe without causing any hematological or histopathological changes in healthy rabbits. Based on the obtained results, GG-MAA-AMPS can be considered as potential carrier for metformin HCl as well as other hydrophilic drugs.

A comparative pharmacokinetics study of Ashwagandha (Withania somnifera) Root Extract sustained-release capsules: an open-label, randomized, two treatment, two-sequence, two period, single-dose crossover clinical study

Background: In this open-label, randomized, balanced, two-treatment, two-sequence, two-period, crossover, single-dose oral comparative pharmacokinetics study, the pharmacokinetics, safety, and tolerability of test product ‘ashwagandha (Withania somnifera)’ root extract sustained release capsule 300 mg (Prolanza™), each containing 15 mg withanolides (administered dose: 2×15 mg) was compared with that of a reference product (organic KSM-66 ashwagandha extract [vegan] capsule, each containing 15 mg withanolides [administered dose: 2×15 mg]).Methods: Total 14 healthy men were randomized to receive either the test or the reference product as a single dose of 2 capsules in sequence, administered under fasting conditions. Plasma concentrations of total withanolides, withanolide A and 12-deoxywithastramonolide were measured using validated liquid chromatography–mass spectroscopy/mass spectroscopy.Results: The test product had higher relative absorption, better relative bioavailability, and longer elimination half-life indicating a sustained-release profile compared to reference. Specifically, the relative bioavailability of the test formulation was 12, 44, and 11 times higher for total withanolides, withanolide A and 12-deoxywithastramonolide, respectively. No adverse events were reported during the study.Conclusions: The sustained-release profile of the test product, compared to reference product, will provide more long-lasting therapeutic effects from a single daily dose (Retrospectively applied on Clinical Trials Registry - India [CTRI]. Application reference number: REF/2020/03/032408). The study reports the unique sustained release formulation of Withania somnifera (Ashwagandha) root extract. The pharmacokinetic study also reports for first time, the successful plasma estimation of withanolide A and 12-deoxywithastraamonolide, the major phytoactives of ashwagandha.

Oral magnesium supplements for cancer treatment-induced hypomagnesemia: Results from a pilot randomized trial.

Background and AimsOptimal management of cancer treatment‐induced hypomagnesemia (hMg) is not known. We assessed the feasibility of using a novel pragmatic clinical trials model to compare two commonly used oral Mg replacement strategies.MethodsPatients with grade 1 to 3 hMg while receiving either platinum‐based chemotherapy or epidermal growth factor receptor inhibitors (EGFRI) were randomized to oral magnesium oxide (MgOx) or oral magnesium citrate (MgCit). The trial methodology utilized the integrated consent model. Feasibility would be successful if; accrual rate was ≥5 patients a month and if measures of patient and physician engagement, were > 50%. Secondary endpoints included; comparison of Mg levels, cardiac arrhythmias, and rates of treatment delay/hospitalizations.ResultsFrom July 2016 to December 2017, an average of 1 patient a month was accrued. All 15 eligible and approached patients consented to participate in the study (100% engagement) and 7/15 were randomized to MgOx and 8/15 to MgCit. The percentage of physicians who approached patients for the study was 4 of 6 (66.6% engagement). The mean slope of change in Mg (mmol/L/day) was 0.0022 (95% CI: −0.0001 to 0.0044) for MgOx and 0.0006 (95% CI, −0.0012 to 0.0024) for MgCit (P = .2123). Three patients (20%) required IV magnesium while on the study (2 MgCit and 1 MgOx). Grade 1 diarrhea occurred in 3 patients in the MgCit arm.ConclusionDespite oral magnesium tolerability and meeting most of its feasibility endpoints, this study did not meet its target accrual rate. Alternative designs would be necessary for a definitive efficacy study.

Safety and tolerability of a natural supplement containing glucosinolates, phytosterols and citrus flavonoids in adult women: a randomized phase I, placebo-controlled, multi-arm, double-blinded clinical trial

Objective To evaluate the safety and tolerability of an oral herbal supplement containing glucosinolates, phytosterols, and citrus flavonoids (Warmi®, Lima Perú;) in otherwise healthy adult women. Methods This was a phase-I, randomized parallel three arms, double-blinded, and a placebo-controlled clinical trial. A total of 55 participants aged 18-40 were randomly assigned to one of three groups to receive for three months: (1) an oral herbal supplement of 1650 mg/day; (2) an oral herbal supplement of 3300 mg/day; or (3) an oral placebo 3300 mg/day. The primary endpoints were oral safety and tolerability of the supplement. The secondary endpoint was its effect on vital functions, anthropometrics, and laboratory tests. We used an exploratory approach by covariance analysis (ANCOVA) adjusted for the variables’ baseline value for the secondary outcomes. Results All women completed three months of follow-up, reporting no side effects. Our exploratory analysis revealed that treatment with the herbal supplement of 1650 mg/day was associated with increased glucose and uric acid levels. In comparison, the herbal supplement 3300 mg/day was associated with reduced breathing rate, increased basal temperature, and systolic blood pressure, both compared to the placebo group. However, despite significant differences, none of these was clinically significant. Conclusion The oral herbal supplement had a favorable safety and tolerability profile in studied women. There is a need to study its potential as an option to treat menopausal symptoms.

Effects of odevixibat on pruritus and bile acids in children with cholestatic liver disease: Phase 2 study

PurposeIleal bile acid transporter inhibition is a novel therapeutic concept for cholestatic pruritus and cholestatic liver disease progression. Odevixibat, a potent, selective, reversible ileal bile acid transporter inhibitor, decreases enteric bile acid reuptake with minimal systemic exposure. Oral odevixibat safety, tolerability, and efficacy in pediatric patients with cholestatic liver disease and pruritus were evaluated. Patients and methodsIn this phase 2, open-label, multicenter study, children received 10‒200 μg/kg oral odevixibat daily for 4 weeks. Changes in serum bile acid levels (primary efficacy endpoint), pruritus, and sleep disturbance were explored. ResultsTwenty patients were enrolled (8 females; 1‒17 years; 4 re-entered at a different dose). Diagnoses included progressive familial intrahepatic cholestasis (n = 13; 3 re-entries), Alagille syndrome (n = 6), biliary atresia (n = 3), and other intrahepatic cholestasis causes (n = 2; 1 re-entry). Mean baseline serum bile acid levels were high (235 µmol/L; range, 26‒564) and were reduced in the majority (−123.1 μmol/L; range, −394 to 14.5, reflecting reductions of up to 98%). Patient-reported diary data documented improved pruritus (3 scales) and sleep. With 100 μg/kg, mean (SEM) decrease was 2.8 (1.1) points for pruritus (visual analogue itch scale 0−10) and 2.9 (0.9) points for sleep disturbance (Patient-Oriented Scoring Atopic Dermatitis scale 0−10). Reduced pruritus correlated significantly with reduced serum bile acids (P ≤ 0.007). Significant correlations were also observed between autotaxin levels and pruritus. All patients completed the study. No serious adverse events were treatment related; most adverse events, including increased transaminases, were transient. ConclusionsOrally administered odevixibat was well tolerated, reduced serum bile acids, and improved pruritus and sleep disturbance in children with cholestatic diseases.

Gelatin/carboxymethyl cellulose based stimuli-responsive hydrogels for controlled delivery of 5-fluorouracil, development, in vitro characterization, in vivo safety and bioavailability evaluation

Current work focuses on the synthesis and characterization of novel pH-sensitive biocompatible gelatin/carboxymethyl cellulose based hydrogels by free radical polymerization technique cross-linked with glutaraldehyde. Effect of pH, polymer ratio and variable crosslinking concentrations on dynamic swelling, equilibrium swelling, porosity, sol-gel analysis and in vitro release pattern was investigated. Hydrogel structure was confirmed by FTIR, XRD, and DSC. Moreover scanning electron microscopy confirmed the porous structure of gel network. Various structure property relationships like average molecular weight between crosslinks (Mc), solvent interaction parameters, volume fraction of polymer (V2,s) and diffusion coefficient (D) that affect the release behaviour were determined. Results showed that maximum swelling and highest release of drug occurred at pH 1.2. Porosity and gel fraction increased by increasing polymer load. The invivo absorption and pharmacokinetics evaluation in rabbit’s models revealed the controlled nature of hydrogels. MTT assay confirmed the biocompatible nature of blank hydrogels against Vero cell lines and cytotoxic potential against HeLa cell lines. The preliminary safety evaluation and oral tolerability revealed that the hydrogel solution is safe up to 4000 mg/kg body weight without causing any hematological or histopathological changes in rabbits.

β-Cyclodextrin-based (IA-co-AMPS) Semi-IPNs as smart biomaterials for oral delivery of hydrophilic drugs: Synthesis, characterization, in-Vitro and in-Vivo evaluation

Currently, the synthesis of multi-polymer based hydrogels called interpenetrating networks (IPNs) is more in practice due to enhanced tunability and effective drug release features in comparison to single components. IPNs are synthesized by crosslinking two or more polymeric networks where one of the networks is synthesized in the presence of the other network. In comparison to conventional hydrogels, the IPN systems exhibit enhanced mechanical features with good swelling, drug entrapment and release profile. The objective of this study was to prepare β-CD-based pH-responsive semi-IPN hydrogels utilizing the strong ionizable functionalities of itaconic acid (IA) and 2 acrylamido-2methylpropane sulfonic acids AMPS. The semi-IPNs were prepared through free radical polymerization technique using N, N′-methylene bisacrylamide (MBA) as a crosslinking agent and ammonium persulfate (APS) as reaction imitator. Loxoprofen sodium was chosen as a model drug. The network formation and drug loading were confirmed through Fourier transform infrared spectroscopy (FTIR) while thermal behavior was evaluated through thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC). X-ray diffraction (XRD) and scanning electron microscopy (SEM) were used to check the change in the crystallinity and morphology of the prepared semi-IPNs. The behavior, efficiency, safety and oral tolerability of the semi-IPNs were tested through various in-vitro and in-vivo studies. FTIR results confirmed the successful crosslinking and drug loading in the semi-IPNs while TGA and DSC proved their thermal stability. XRD showed a decrease in crystallinity while SEM confirmed the uneven and rough surface with some cracks. The semi-IPNs exhibited high swelling and drug release at pH 5.5 and 7.4 than the acidic pH 1.2. Drug release followed first-order kinetic while release phenomena was diffusion-based following non-Fickian mechanism. Oral tolerability suggested that the hydrogel dispersion was well tolerable up to 3200 mg/kg without causing any histopathological or hematological changes. The obtained results suggested that β-CD-IA-AMPS semi-IPNs could be a safe and efficient carrier for oral delivery of hydrophilic drugs.

Pharmacokinetic Profile of Oxaliplatin-Loaded pH-Responsive Hydrogels in Rabbits.

Oxaliplatin (OXP), a 3rd generation platinum compound, which causes severe side effects due to; impulse high concentration in the bloodstream thereby exposing healthy cells at a high ratio, nonspecific delivery at the target site and non-compliance is administered intravenously. The project was aimed at the development, characterization, and in-vitro and in-vivo evaluation of pHresponsive hydrogels for oral administration of OXP. Hydrogel formulations were synthesized through a free radical polymerization technique followed by brief characterization using various techniques. The hydrogels were investigated for various in-vitro studies such as sol-gel, drug loading, swelling, drug release, and MTT-assay. While in-vivo studies such as oral tolerability, histopathology, and hematology studies were performed on rabbits. A simple and sensitive HPLC-UV method was optimized and the comparative pharmacokinetic study was performed in rabbits using OXP-oral solution and OXP-loaded hydrogels. In-vitro characterization confirmed that the reactant was successfully crosslinked to form thermally stable hydrogels with decreased crystallinity and rough surface. Swelling and drug release showed that hydrogels were more responsive to basic pH (6.8 and 7.4) in comparison with pH 1.2. The blank hydrogels were cytocompatible as more than 95% of the cells were viable while free OXP and OXP-loaded hydrogels displayed dosedependent cytotoxic effect. In-vivo studies confirmed that chitosan and gelatin hydrogel suspension was well tolerable up to 3800 mg/kg and 4000 mg/kg of body weight, respectively. Hematology and serum chemistry reports were well within the range suggesting normal liver and kidney functions. Similarly, histopathology slides of rabbit vital organs were also found normal without causing any histopathological change. HPLC-UV method was successfully optimized for OXP detection in oral solution and hydrogels administered to rabbits. A significant difference was found among various pharmacokinetic parameters by comparing the two groups including half-life (t1/2), tmax, Cmax, AUCtot MRT, Vz, and Lz.

Abstract 1956: In vitro and in vivo characterization of novel MAT2A allosteric inhibitors

Abstract Background: MAT2A (Methionine adenosyltransferase 2A) catalyzes the formation of S-adenosylmethionine (SAM) from methionine and ATP. PRMT5, a highly conserved protein arginine methyltransferase that is required for cell proliferation, uses SAM as its methyl donor. PRMT5 activity is inhibited by increased MTA levels in methylthioadenosine phosphorylase (MTAP)-deleted tumor cells. MTAP-deleted tumor cells are thus more vulnerable to MAT2A inhibition compared to MTAP-WT cells. This synthetic lethality between MTAP and MAT2A suggests that MAT2A inhibitors may be useful as anti-tumor agents in the MTAP-deleted cancers, which occurs in ~ 15% of all cancers. Results: We have designed, synthesized and evaluated a novel series of small-molecule MAT2A inhibitors that are very potent in biochemical assays. Co-crystal structures of inhibitor-MAT2A complexes were solved and shed light on binding mode and key interactions. Biochemical mechanistic studies suggested that these compounds are allosteric inhibitors of MAT2A and are non-competitive inhibitors of MAT2A with respect to both ATP and methionine. These compounds displayed potent cellular anti-proliferation activity as well as cellular SAM modulation along with desired DMPK properties. Optimized compounds, upon oral dosing, demonstrated significant PD marker modulation and tumor growth inhibition in HCT116 MTAP-null and several endogenous MTAP-null xenograft mouse models. These agents demonstrated an acceptable safety profile in 7-day oral repeat dose tolerability studies in the rat. Citation Format: Zhonghua Pei, Muzaffar Alam, Neil Bhola, Leah Cleary, Jake Drummond, Marcus Fisher, Melissa Fleury, Candy Garcia, Atieh Givmanesh, Xin Linghu, Ethan McSpadden, Zineb Mounir, Claire Neilan, Zach Newby, Senthil Perumal, Richard Steel, James Sutton, Kedar Vaidya, Marie-Claire Wagle, Jianhong Wang, Bing Yao, Mark Lackner, Michael P. Dillon. In vitro and in vivo characterization of novel MAT2A allosteric inhibitors [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 1956.

Tolerability of Highly Protein Bound Targeted Oral Oncolytic Drugs in Patients With Hypoalbuminemia: A Retrospective Analysis.

Hypoalbuminemia is commonly observed in cancer patients. Given the pharmacokinetic interactions between serum proteins and protein bound medications, administration of highly protein bound targeted oral oncolytic drugs may result in elevated unbound drug levels and decreased tolerability in those with hypoalbuminemia. To describe the impact of hypoalbuminemia on oral oncolytic drug tolerability. A retrospective study was conducted of adult patients receiving treatment with targeted oral oncolytic drugs with ≥95% protein binding. The primary end point of this study was to compare time to discontinuation resulting from documented toxicity in those with and without hypoalbuminemia. The study included 143 patients receiving 16 targeted oral oncolytic drugs (42% with hypoalbuminemia, 58% without hypoalbuminemia). Adverse events were common, with similar incidence among patients with and without hypoalbuminemia (73% vs 76%, respectively; P = 0.727). Median time to therapy discontinuation resulting from documented toxicity was significantly shorter in those with hypoalbuminemia (22 months vs not reached; P = 0.003). Cox regression demonstrated that hypoalbuminemia was the only significant risk factor for shorter time to discontinuation resulting from documented adverse effects (hazard ratio = 3.0; 95% CI = 1.15-8.0; P = 0.025). This represents the first report of the impact of hypoalbuminemia on tolerability of highly protein bound oral oncolytic drugs, demonstrating that patients with hypoalbuminemia may be at increased risk for early discontinuation resulting from toxicity. Given the importance of maintaining dose intensity in patients receiving oncolytic therapy, albumin levels should be monitored throughout treatment and supportive care maximized in those developing hypoalbuminemia.

Short-term Postoperative Outcomes Before and After the Establishment of the Siriraj Upper Gastrointestinal Cancer Center: A Propensity Score Matched Analysis

Objective To evaluate short-term postoperative outcomes compared between before and 1 year after the establishment of the Siriraj Upper Gastrointestinal Cancer Center (UGICC). Materials and Methods Medical records of 211 patients who underwent radical gastrectomy at Siriraj Hospital during January 2012-September 2018 were reviewed (before UGICC; B-UGICC). Data of 40 patients operated upon during October 2018-September 2019 were prospectively collected after the establishment of UGICC (A-UGICC). Propensity score (PPS) matched analysis was conducted, and short-term outcomes were compared. Enhanced Recovery After Surgery (ERAS) protocol was applied to some patients in A-UGICC. Results of conventional care (CC) were compared with ERAS protocol. Results PPS matched 78 patients in B-UGICC, and 40 patients in A-UGICC. Median postoperative length of stay (POS) was significantly shorter in A-UGICC than in B-UGICC; however, complications and time to oral diet tolerability were not significantly different between groups. In A-UGICC, median POS and time to toleration of oral diet were significantly shorter among 15 ERAS patients than among 25 CC patients. Intestinal recovery and time to ambulation trended to be earlier in ERAS. 103 CC and 15 ERAS patients were matched to 36 non-ERAS and 13 ERAS patients. Median time to toleration of oral diet was significantly shorter in ERAS than in CC (P<0.001). Median POS was significantly shorter in ERAS (P<0.001). Postoperative complications were non-significantly different between ERAS and CC. There was no mortality in this study. Conclusion UGICC with multidisciplinary team approach contributed to improvement of postoperative short-term outcomes.

Health care utilization and patient-related outcomes in patients with malignant bowel obstruction admitted to a United States safety net hospital.

50 Background: Malignant bowel obstruction (MBO) and gastric outlet obstruction (GOO) can be a late complication of intra-abdominal malignancy with a poor prognosis. Most studies about its outcomes have focused on survival. There is paucity of studies assessing health care utilization and end of life care decisions. Methods: We retrospectively collected data from the electronic medical record of patients admitted with MBO or GOO at a safety-net hospital in Chicago, US between January 2013 and December 2017. The charts were analyzed for outcomes related to end of life care and health care utilization. The outcomes were compared by across three broad treatment arms: those that received surgical intervention, those that received venting gastrostomy (VG) and those that were treated medically alone. Results: Forty-six patients were identified of which 31 were admitted with MBO. 25 (54%) of them were due to stage IV cancers. Mean age of study population was 61 years. Surgical management, VG and medical management were done in 17, 8 and 21 patients respectively. There was no difference in ICU admission rate, length of stay of index admission, 90 day-readmission rate or mean visits to the ER between the groups. Patients receiving venting gastrostomy tube had highest rate of oral solid food tolerability. Twenty-eight patients died or were enrolled in hospice within a median of 115 days. Conclusions: All modalities of treatment had similar health utilization measures in patients with MBO and GOO. Surgical management, if feasible, has the longest time to hospice enrollment or death and should be offered to patients who are suitable. [Table: see text]

Synthesis, Characterization and Safety Profiling of Eudragit-Based pHResponsive Hydrogels: A Promising Platform for Colonic Delivery of Losartan Potassium.

The aim of the present study was to design an efficient delivery system with an anticipated swelling and drug release properties for a prolonged drug release as well as to target colon for various hydrophilic drugs. For this purpose, the pH-responsive hydrogel comprising a combination of Eudragit and acrylic acid was formed. The hydrogels were characterized for spectral (FTIR), thermal (TGA/DSC), structural (XRD), and morphological (SEM) investigations. Oral tolerability was assessed in rabbits for biocompatibility and oral use of the prepared hydrogels. The results showed that an increased incorporation of Eudragit and cross-linking agent retorted the swelling, drug loading, and drug release properties at both acid (pH 1.2) and basic pH (pH 6.8 and 7.4) , while acrylic acid presented the inverse results. The oral tolerability and toxicity studies depicted that the developed hydrogels were safe up to 3800 mg/kg body weight and caused no hematological or histopathological changes when compared with the control group. Therefore, the newly developed formulations presented adequate swelling, drug loading, release behavior, and biocompatibility properties and thus can be used as a promising tool for the colonic delivery of various hydrophilic drugs.

An evaluation of enasidenib for the treatment of acute myeloid leukemia

ABSTRACTIntroduction: Despite recent progress, the prognosis of acute myeloid leukemia remains poor, mainly in older and in relapsed/refractory patients. Recently, a large number of novel agents have been developed thanks to a better understanding of its pathogenesis. Among these, the potent inhibitor of the isocitrate dehydrogenase-2 (IDH2) mutant protein, enasidenib (formerly AG-221), has demonstrated promising antileukemic activity by targeting IDH2 mutations.Area covered: This review describes the mechanisms of action, the pharmacodynamic and pharmacokinetic properties, the safety, and efficacy of enasidenib. Phase I/II/III clinical trials are also reported and discussed.Expert opinion: Enasidenib is a novel agent able to differentiate leukemic blasts in functional, maturating cells. This drug is characterized by oral bioavailability and good tolerability. As a monotherapy, it demonstrates clinical and laboratorial improvement, in 19.6% and 38.8% of cases respectively. Differentiation syndrome is the most relevant, potentially life-threatening side effect, which physicians must be aware of. The authors believe that the way forwards now is to explore the role of enasidenib as a chemoresistance revertant when associated with chemotherapy, as a ‘bridge to transplant’ or when associated other novel agents if we wish to maximize its use.

Pectin-based (LA-co-MAA) semi-IPNS as a potential biomaterial for colonic delivery of oxaliplatin.

This study describes the fabrication of chemically crosslinked pectin-based LA-co-MAA hydrogels through free radical polymerization technique for the colonic delivery of oxaliplatin. Methylene bisacrylamide was used as a crosslinking agent and ammonium persulfate as an initiator. The successful fabrication and drug loading were confirmed through Fourier transform infrared spectroscopy (FTIR). The thermal investigations through differential scanning calorimetry (DSC) and thermogravimetric analysis (TGA) suggested the higher thermal stability of the unloaded and OXP-loaded formulations as compared to the raw materials. X-ray diffraction (XRD) analysis showed a decrease in crystallinity after crosslinking. The swelling, drug loading, and drug release were increased with an increase in the concentration of pectin and lactic acid (LA) while methacrylic acid (MAA) displayed an inverse behavior. The in-vitro biodegradability was evaluated against lysozyme and collagenase. The results showed that the hydrogels were stable against blank PBS as compared to lysozyme and collagenase. MTT-assay proved that the blank hydrogels were cytocompatible while free OXP and OXP-loaded hydrogels displayed dose-dependent effect against Vero, MCF-7, and HCT-116 cell lines. The oral tolerability study in rabbits confirmed that the hydrogel dispersion was well-tolerable up to 3650 mg/kg of body weight without causing any histopathological or hematological changes when compared with the control group.

Gelatin-based hydrogels as potential biomaterials for colonic delivery of oxaliplatin

In present investigation, gelatin-based (AA-co-AMPS) hydrogels were prepared using N, N’-Methylenebisacrylamide (MBA) as a cross-linker and ammonium per sulfate (APS) as an initiator. The successful crosslinking and network formation was confirmed by Fourier transform infrared spectroscopy (FT IR). Differential scanning calorimetry (DSC) and thermogravimetric analysis (TGA) investigations proved the higher thermal stability and successful entrapment of oxaliplatin (OXP) in the polymeric network. X-ray diffraction (XRD) confirmed the loss in crystallinity of the drug after loading in the hydrogel. Scanning electron microscopy (SEM) revealed the porous surface of the hydrogel. The newly formed hydrogels were responsive to change in pH. The swelling, drug loading and drug release was increased with increase in concentration of acrylic acid (AA) while gelatin and 2-acrylamido 2-methylpronesulfonic acid (AMPS) were found to act inversely. The in-vitro enzymatic degradation study showed that the blank hydrogels were more stable against the blank PBS than the collagenase and lysozyme. MTT-assay proved that the blank hydrogels were cyto-compatible while free OXP as well as OXP-loaded hydrogels showed dose dependent controlled cytotoxicity against Vero, MCF-7 and HCT-116 cell lines. The preliminary safety evaluation and oral tolerability showed that the hydrogel suspension was biocompatible and well tolerable upto 4000 mg/kg of body weight without causing any hematological or histopathological changes in rabbits.