The goal of this project was to utilize mechanistic simulation to demonstrate a methodology that could determine drug combination dose schedules and dose intensities that would be most effective in eliminating multidrug resistant cancer cells in early-stage colon cancer. An agent-based model of cell dynamics in human colon crypts was calibrated using measurements of human biopsy specimens. Mutant cancer cells were simulated as cells that were resistant to each of two drugs when the drugs were used separately. The drugs, 5-flurouracil and sulindac, have different mechanisms of action. An artificial neural network was used to generate nearly two hundred thousand two-drug dose schedules. A high-performance computer simulated each dose schedule as a in silico clinical trial and evaluated each dose schedule for its efficiency to cure (eliminate) multidrug resistant cancer cells and its toxicity to the host, as indicated by continued crypt function. Among the dose schedules that were generated, 2430 dose schedules were found to cure all multidrug resistant mutants in each of the 50 simulated trials and retained colon crypt function. One dose schedule was optimal; it eliminated multidrug resistant cancer cells with the minimum toxicity and had a time schedule that would be practical for implementation in the clinic. These results demonstrate a procedure to identify which combination drug dose schedules could be most effective in eliminating drug resistant cancer cells. This was accomplished using a calibrated agent-based model of a human tissue, and a high-performance computer simulation of clinical trials.

As acetylcholinesterase (AChE) plays a crucial role in advancing Alzheimer's disease (AD), its inhibition is a promising approach for treating AD. Sulindac is an NSAID of the aryl alkanoic acid class, consisting of a indene moiety, which showed neuroprotective behavior in recent studies. In this study, newer Indene analogs were synthesized and evaluated for their in vitro AChE inhibition. Additionally, compared with donepezil as the standard drug, these Indene analogs were accessed for their cell line-based toxicity study on SH-SY5Y cell line. The molecule SD-30, having hydrogen bond donor (HBD) at para-position, showed maximum AChE inhibition potential (IC50 13.86 ± 0.163 µM) in the indene series. Further, the SD-30 showed maximum BuChE inhibition potential (IC50 = 48.55 ± 0.136 µM) with a selectivity ratio of 3.50 and reasonable antioxidant properties compared to ascorbic acid (using DPPH assay). SD-30 (at a dose level: of 10 µM, 20 µM) effectively inhibited AChE-induced Aβ aggregation and showed no significant toxicity up to 30 mM against SH-SY5Y cell lines.

It is of interest to document the Molecular Dynamics Simulation and docking analysis of NF-κB target with sulindac sodium in combating COVID-19 for further consideration. Sulindac is a nonsteroidal anti-inflammatory drug (NSAID) of the arylalkanoic acid class that is marketed by Merck under the brand name Clinoril. We show the binding features of sulindac sodium with NF-κB that can be useful in drug repurposing in COVID-19 therapy.

The purpose of this study was to investigate the effect of incorporating chitosan (Ch) and chitosan oligosaccharides (ChO) into the commercially premixed antibiotic-loaded bone cement (ALBC). We compare antibiotic release profiles, antibacterial activity, and mechanical properties among different ALBC formulations. The hypothesis was that increasing the amount of Ch and ChO in the cement mixture would increase the antibiotics released and bacterial control. ALBC mixed with Ch or ChO may create a greater effect due to its superior dissolving property.

Malignant mesothelioma (MM) is an incurable cancer of the serosal lining that is often caused by exposure to asbestos. Therefore, novel agents for the prevention and treatment of this disease are urgently needed. Asbestos induces the release of pro-inflammatory cytokines such as IL-1β and IL-6, which play a role in MM development. IL-6 is a component of the JAK-STAT3 pathway that contributes to inflammation-associated tumorigenesis. Glycoprotein 130 (gp130), the signal transducer of this signaling axis, is an attractive drug target because of its role in promoting neoplasia via the activation of downstream STAT3 signaling. The anticancer drug, SC144, inhibits the interaction of gp130 with the IL-6 receptor (IL6R), effectively blunting signaling from this inflammatory axis. To test whether the inflammation-related release of IL-6 plays a role in the formation of MM, we evaluated the ability of SC144 to inhibit asbestos-induced carcinogenesis in a mouse model. The ability of sulindac and anakinra, an IL6R antagonist/positive control, to inhibit MM formation in this model were tested in parallel. Asbestos-exposed Nf2 +/-;Cdkn2a +/- mice treated with SC144, sulindac, or anakinra showed significantly prolonged survival compared to asbestos-exposed vehicle-treated mice. STAT3 activity was markedly decreased in MM specimens from SC144-treated mice. Furthermore, SC144 inhibited STAT3 activation by IL-6 in cultured normal mesothelial cells, and in vitro treatment of MM cells with SC144 markedly decreased the expression of STAT3 target genes. The emerging availability of newer, more potent SC144 analogs showing improved pharmacokinetic properties holds promise for future trials, benefitting individuals at high risk of this disease.

Sulindac is a medication used in a host of conditions. This activity reviews the indications, contraindications, activity, adverse events, and other key elements of therapy in the clinical setting related to the essential points needed by members of an interprofessional team.

A leading theory for ovarian carcinogenesis proposes that inflammation associated with incessant ovulation is a driver of oncogenesis. Consistent with this theory, nonsteroidal anti-inflammatory drugs (NSAIDs) exert promising chemopreventive activity for ovarian cancer. Unfortunately, toxicity is associated with long-term use of NSAIDs due to their cyclooxygenase (COX) inhibitory activity. Previous studies suggest the antineoplastic activity of NSAIDs is COX independent, and rather may be exerted through phosphodiesterase (PDE) inhibition. PDEs represent a unique chemopreventive target for ovarian cancer given that ovulation is regulated by cyclic nucleotide signaling. Here we evaluate PDE10A as a novel therapeutic target for ovarian cancer. Analysis of The Cancer Genome Atlas (TCGA) ovarian tumors revealed PDE10A overexpression was associated with significantly worse overall survival for patients. PDE10A expression also positively correlated with the upregulation of oncogenic and inflammatory signaling pathways. Using small molecule inhibitors, Pf-2545920 and a novel NSAID-derived PDE10A inhibitor, MCI-030, we show that PDE10A inhibition leads to decreased ovarian cancer cell growth and induces cell cycle arrest and apoptosis. We demonstrate these pro-apoptotic properties occur through PKA and PKG signaling by using specific inhibitors to block their activity. PDE10A genetic knockout in ovarian cancer cells through CRISP/Cas9 editing lead to decreased cell proliferation, colony formation, migration and invasion, and in vivo tumor growth. We also demonstrate that PDE10A inhibition leads to decreased Wnt-induced β-catenin nuclear translocation, as well as decreased EGF-mediated activation of RAS/MAPK and AKT pathways in ovarian cancer cells. These findings implicate PDE10A as novel target for ovarian cancer chemoprevention and treatment.

Bursera comprises ~100 tropical shrub and tree species, with the center of the species diversification in Mexico. The genomic resources developed for the genus are scarce, and this has limited the study of the gene flow, local adaptation, and hybridization dynamics. In this study, based on ~155 million Illumina paired-end reads per species, we performed a de novo genome assembly and annotation of three Bursera species of the Bullockia section: Bursera bipinnata, Bursera cuneata, and Bursera palmeri. The total lengths of the genome assemblies were 253, 237, and 229 Mb for B. cuneata, B. palmeri, and B. bipinnata, respectively. The assembly of B. palmeri retrieved the most complete and single-copy BUSCOs (87.3%) relative to B. cuneata (86.5%) and B. bipinnata (76.6%). The ab initio gene prediction recognized between 21,000 and 32,000 protein-coding genes. Other genomic features, such as simple sequence repeats (SSRs), were also detected. Using the de novo genome assemblies as a reference, we identified single-nucleotide polymorphisms (SNPs) for a set of 43 Bursera individuals. Moreover, we mapped the filtered reads of each Bursera species against the chloroplast genomes of five Burseraceae species, obtaining consensus sequences ranging from 156 to 160 kb in length. Our work contributes to the generation of genomic resources for an important but understudied genus of tropical-dry-forest species.

Colorectal carcinoma (CRC) is the most common of gastrointestinal cancers, the majority presenting with sporadic occurrence compared to the less frequently inherited syndromes. The increasing incidence, decreasing gender and age disparities, and the prevalent risk factors are concerning. The malignancy arising from benign precursor polyps transforms slowly over time. The adenoma variant polyps reported a marked upregulation of cyclooxygenases (COX), significantly COX-2 isoform, influenced by various determinants such as genetics, pathology, histology, and site of the carcinoma. These COX enzymes are responsible for prostaglandin synthesis and the consequent cascade of cell inflammation and proliferation. Therefore, COX inhibition by non-steroidal anti-inflammatory drugs (NSAIDs) targeted against both the isoforms COX-1 and COX-2 have been studied for decades in anticipation of preventing the occurrence of colorectal carcinoma in high-risk populations. This article has collated and highlighted the overexpression of COX enzymes by the adenomatous polyps and provides corroborating evidence from multiple studies in favor of COX inhibition by NSAIDs. Aspirin and Sulindac were two drugs to be initially proven to halt the progression and cause regression of the polyps. Celecoxib, a selective COX-2 inhibitor besides NSAIDs, was also used in experimental studies.

Mice bred in 2017 and entered into the C2017 cohort were tested for possible lifespan benefits of (R/S)-1,3-butanediol (BD), captopril (Capt), leucine (Leu), the Nrf2-activating botanical mixture PB125, sulindac, syringaresinol, or the combination of rapamycin and acarbose started at 9 or 16 months of age (RaAc9, RaAc16). In male mice, the combination of Rapa and Aca started at 9 months and led to a longer lifespan than in either of the two prior cohorts of mice treated with Rapa only, suggesting that this drug combination was more potent than either of its components used alone. In females, lifespan in mice receiving both drugs was neither higher nor lower than that seen previously in Rapa only, perhaps reflecting the limited survival benefits seen in prior cohorts of females receiving Aca alone. Capt led to a significant, though small (4% or 5%), increase in female lifespan. Capt also showed some possible benefits in male mice, but the interpretation was complicated by the unusually low survival of controls at one of the three test sites. BD seemed to produce a small (2%) increase in females, but only if the analysis included data from the site with unusually short-lived controls. None of the other 4 tested agents led to any lifespan benefit. The C2017 ITP dataset shows that combinations of anti-aging drugs may have effects that surpass the benefits produced by either drug used alone, and that additional studies of captopril, over a wider range of doses, are likely to be rewarding.

Cyclodextrins (CDs) as a pseudophase in pseudophase-to-pseudophase microextraction (P2ME) in capillary zone electrophoresis (CZE) are proposed. In this P2ME mode called CD to admicelle ME, a long plug of dilute analyte solution prepared in cetyltrimethylammonium bromide (CTAB) at the critical micellar concentration was injected into the capillary. This formed CTAB admicelles at the interface between the solution and the negatively charged capillary surface, where the analytes were trapped. The injection of CD solution released the admicelles and the analytes from the capillary surface due to the formation of stable CD/CTAB inclusion complexes. The analytes are concentrated at the CD front during injection and voltage separation. Various neutral CDs were found to be effective for CD to admicelle ME. To implement this in-line sample concentration technique in CZE, CD concentration, sample injection time, and sample:CD solution injection ratio were optimized. The optimized conditions for five model anionic analytes, namely, 4-bromophenol, sulindac, sulfamethizole, 4-vinylbenzoic acid, and succinylsulfathiazole, were 20 mM α-CD in 20 mM sodium tetraborate (pH 9.2) solution, sample injection time of 370 s, and CD:sample injection ratio of 1:2. The sensitivity enhancement factors (SEFs) were between 112 and 168. The SEFs of sulindac and sulfamethizole in particular were similar to previously published off-line microextraction techniques, which are typically time-consuming. The calculated values of LOQ, intra-/inter-day (n = 6/n = 10, 3 days) repeatability, and linearity (R2) of CD to admicelle ME were 0.0125-0.05 µg/mL, 1.5-4.6%, 1.8-4.8%, and ≥0.999, respectively. Finally, the potential of CD to admicelle ME to the analysis of artificial urine samples was demonstrated.

We present pseudophase-to-solvent microextraction (PSME) as a simple pressure-driven in-line sample concentration technique in capillary zone electrophoresis (CZE) for small organic anions. The developed technique is like solid-phase extraction; however, the chromatographic phase is a pseudophase, i.e., in-situ cetyltrimethylammonium bromide (CTAB) interfacial micelles. A large volume of sample (e.g., > 12 capillary volumes) prepared in [CTAB] ∼critical micelle concentration was injected into the capillary. The elution and enrichment of analytes trapped in the CTAB coating was facilitated by the high concentration of methanol in the background solution, which was introduced from the outlet end. Co-electroosmotic flow CZE was conducted after the concentrated analytes reached the tip of the inlet. Parameters such as sample loading time and elution time were optimised. Under optimised conditions, the SEFs of 187-573 achieved for the model anions (4-nitrophenol, 4-vinylbenzoic acid, mecoprop, indoprofen, sulfamethizole and sulindac) were comparable to previously reported off-line microextraction techniques. The calculated LOD (S/N = 3), LOQ (S/N = 10), intra-/inter- (n = 6/n = 9, 3 days) day repeatability and linearity (R2s) values in PSME-CZE were 4.2-20.1 ng/mL, 13.8-67.1 ng/mL, 5%, 10% and > 0.990, respectively. The PSME-CZE of fortified urine samples showed % recovery values of 93-108% with %RSDs (n = 3) of 4-10% for the model analytes.

Colorectal cancer (CRC) is the fourth most common cancer and third leading cause of cancer-related death worldwide. Use of chemopreventive agents (CPAs) to reduce the incidence of precursor colorectal adenomas could lower the future burden of CRC. Many classes of potential CPAs have been investigated. To identify the most effective CPAs, we conducted a systematic review and a network meta-analysis (NMA). An electronic search was performed through August 2020 to identify all randomized controlled trials (RCTs) assessing the efficacy of CPAs in reducing the incidence of colorectal adenomas at the time of surveillance colonoscopy among patients who had previously undergone polypectomy during an index colonoscopy. In total, 33 RCTs were included in the NMA, which was conducted under a Bayesian inference framework. Random effects models were used with adjustment for follow-up length and control group event rates to yield relative risks (RRs) and 95% credible intervals (CrIs). Our full network consisted of 13 interventions in addition to a placebo arm. Of 20,925 included patients, 7766 had an adenoma. Compared to placebo, the combination of difluoromethylornithine (DFMO) + Sulindac (RR 0.24, CrI 0.10-0.55) demonstrated a protective effect, while aspirin had a RR of 0.77 (CrI 0.60-1.00), celecoxib 800 mg had a RR of 0.56 (CrI 0.31-1.01) and metformin had a RR of 0.56 (CrI 0.22-1.39). Our results suggest that select CPAs may be efficacious in preventing the development of adenomas. Further studies are needed to identify those patients most likely to benefit and the minimum effective dosages of CPAs.

This study aimed to explore the mechanisms of action of a sulindac acetohydrazide derivative, N'-(4-dimethylaminobenzylidene)-2-1-(4-(methylsulfinyl) benzylidene)-5-fluoro-2-methyl-1H-inden-3-yl) acetohydrazide, against anticancer drug cisplatin induced organ damage. Using a rodent model, various markers of organ function and signaling pathways were examined and validated by molecular docking studies. The study involves five groups of animals: control, DMSO, CDDP, CDDP + DMFM, and DMFM. Biochemical enzyme activity, histopathology, tissue antioxidant, and oxidative stress markers were examined. RT-PCR and western blot analyses were conducted for the expression of inducible cyclooxygenase enzyme (COX-2), nuclear factor kappa beta (NF-κB), p65, IL-1, TNF-α, and inducible nitric oxide synthase (iNOS). Flow cytometry analysis of CD4 + TNF-α, CD4 + COX-2, and CD4 + STAT-3 cells in whole blood was performed. Structural and dynamic behavior of DMFM upon binding with receptor molecule molecular docking and dynamic simulations were performed using bioinformatics tools and software. Treatment with DMFM reversed cisplatin-induced malondialdehyde (MDA) and nitric oxide (NO) induction, whereas the activity of glutathione peroxidase (GPx), and superoxide dismutase (SOD) in the kidney, heart, liver, and brain tissues were increased. DMFM administration normalized plasma levels of biochemical enzymes. We observed a marked decline in CD4 + STAT3, TNF-α, and COX2 cell populations in whole blood after treatment with DMFM. DMFM downregulated the expression factors related to inflammation at the mRNA and protein levels, i.e., IL-1, TNF-α, iNOS, NF-κB, STAT-3, and COX-2. Dynamic simulations and in silico docking data supports the experimental findings. Our experimental and in silico results illustrated that DMFM may affect protective action against cisplatin-induced brain, heart, liver, and kidney damage via reduction of inflammation and ROS.

Colorectal cancer ranks as the third most lethal cancer worldwide, resulting in over 1 million cases and 900 000 deaths per year. According to population-based studies, administration of long-term non-steroidal anti-inflammatory drugs (NSAIDs) was proven to reduce the risk of a subject developing colorectal cancer. In the present study, the anti-cancer activity of two different NSAIDs, sulindac- (Pc-1) or diclofenac-substituted (Pc-2) asymmetric silicon phthalocyanine derivatives, was evaluated in four different colorectal cancer cell lines bearing various carcinogenic mutations. In this context, the IC50 values of each compound after 24 and 48 h were determined on HCT116, SW480, LoVo, and HT29 cell lines, and the effects of the compounds on programmed cell death pathways apoptosis and autophagy, their impact on cell cycle progression, and the effect of NSAID moieties they bear on COX-1 and COX-2 proteins were analyzed. In addition, the photophysical and photochemical properties of a synthesized Pc derivative bearing axial diclofenac and triethylene glycol groups (Pc-2) have been investigated, and the compound has been characterized by using different analytical techniques. Our results indicated that both compounds inhibit COX protein expression levels, activate apoptosis in all cell lines, and lead to cell cycle arrest in the G2/M phase, depending on the COX expression profiles of the cell lines, indicating that NSAIDs can be coupled with Pc's to achieve increased anti-cancer activity, especially on cancer cells known to have high COX activity.

The first aim of this study was to evaluate the usefulness of optimized human fecal material in simulating sulforeductase activity in the lower intestine by assessing bacterial degradation of sulindac and sulfinpyrazone, two sulforeductase substrates. The second aim was to evaluate the usefulness of drug degradation half-life generated in simulated colonic bacteria (SCoB) in informing PBPK models. Degradation experiments of sulfinpyrazone and of sulindac in SCoB were performed under anaerobic conditions using recently described methods. For sulfinpyrazone, the abundance of clinical data allowed for construction of a physiologically based pharmacokinetic (PBPK) model and evaluation of luminal degradation clearance determined from SCoB data. For sulindac, the availability of sulindac sulfide and sulindac sulfone standards allowed for evaluating the formation of the main metabolite, sulindac sulfide, during the experiments in SCoB. Both model compounds degraded substantially in SCoB. The PBPK model was able to adequately capture exposure of sulfinpyrazone and its sulfide metabolite in healthy subjects, in ileostomy and/or colectomy subjects, and in healthy subjects pretreated with metoclopramide by implementing degradation half-lives in SCoB to calculate intrinsic colon clearance. Degradation rates of sulindac and formation rates of sulindac sulfide in SCoB were almost identical, in line with in vivo data suggesting the sulindac sulfide is the primary metabolite in the lower intestine. Experiments in SCoB were useful in simulating sulforeductase related bacterial degradation activity in the lower intestine. Degradation half-life calculated from experiments in SCoB is proven useful for informing a predictive PBPK model for sulfinpyrazone.

Oxidative damage is believed to play a major role in the etiology of many age-related diseases and the normal aging process. We previously reported that sulindac, a cyclooxygenase (COX) inhibitor and FDA approved anti-inflammatory drug, has chemoprotective activity in cells and intact organs by initiating a pharmacological preconditioning response, similar to ischemic preconditioning (IPC). The mechanism is independent of its COX inhibitory activity as suggested by studies on the protection of the heart against oxidative damage from ischemia/reperfusion and retinal pigmented endothelial (RPE) cells against chemical oxidative and UV damage . Unfortunately, sulindac is not recommended for long-term use due to toxicities resulting from its COX inhibitory activity. To develop a safer and more efficacious derivative of sulindac, we screened a library of indenes and identified a lead compound, MCI-100, that lacked significant COX inhibitory activity but displayed greater potency than sulindac to protect RPE cells against oxidative damage. MCI-100 also protected the intact rat heart against ischemia/reperfusion damage following oral administration. The chemoprotective activity of MCI-100 involves a preconditioning response similar to sulindac, which is supported by RNA sequencing data showing common genes that are induced or repressed by sulindac or MCI-100 treatment. Both sulindac and MCI-100 protection against oxidative damage may involve modulation of Wnt/β-catenin signaling resulting in proliferation while inhibiting TGFb signaling leading to apoptosis. In summary MCI-100, is more active than sulindac in protecting cells against oxidative damage, but without significant NSAID activity, and could have therapeutic potential in treatment of diseases that involve oxidative damage. Significance Statement In this study, we describe a novel sulindac derivative, MCI-100, that lacks significant COX inhibitory activity, but is appreciably more potent than sulindac in protecting retinal pigmented epithelial (RPE) cells against oxidative damage. Oral administration of MCI-100 markedly protected the rat heart against ischemia/reperfusion damage. MCI-100 has potential therapeutic value as a drug candidate for age-related diseases by protecting cells against oxidative damage and preventing organ failure.

Obesity is associated with an increased risk of colon cancer. Our current study examines whether weight loss and/or treatment with the NSAID sulindac suppresses the protumor effects of obesity in a mouse model of colon cancer. Azoxymethane-treated male FVB/N mice were fed a low-fat diet (LFD) or high-fat diet (HFD) for 15 weeks, then HFD mice were randomized to remain on HFD (obese) or switch to LFD [formerly obese (FOb-LFD)]. Within the control (LFD), obese, and FOb-LFD groups, half the mice started sulindac treatment (140 ppm in the diet). All mice were euthanized 7 weeks later. FOb-LFD mice had intermediate body weight levels, lower than obese but higher than control (P < 0.05). Sulindac did not affect body weight. Obese mice had greater tumor multiplicity and burden than all other groups (P < 0.05). Transcriptomic profiling indicated that weight loss and sulindac each modulate the expression of tumor genes related to invasion and may promote a more antitumor immune landscape. Furthermore, the fecal microbes Coprobacillus, Prevotella, and Akkermansia muciniphila were positively correlated with tumor multiplicity and reduced by sulindac in obese mice. Coprobacillus abundance was also decreased in FOb-LFD mice. In sum, weight loss and sulindac treatment, alone and in combination, reversed the effects of chronic obesity on colon tumor multiplicity and burden. Our findings suggest that an investigation regarding the effects of NSAID treatment on colon cancer risk and/or progression in obese individuals is warranted, particularly for those unable to achieve moderate weight loss.

We report a retrospective case series of six Hispanic children with tumors treated with metronomic chemotherapy. The six cases comprised one rhabdoid tumor of the kidney, one ependymoma, two medulloblastomas, one neuroblastoma, and a type II neurocytoma of the spine. Treatment included oral cyclophosphamide daily for 21 days alternating with oral etoposide daily for 21 days in a backbone of daily valproic acid and celecoxib. In one case, celecoxib was substituted with sulindac. Of the six patients, three showed complete responses, and all patients showed some response to metronomic therapy with only minor hematologic toxicity. One patient had hemorrhagic gastritis likely associated with NSAIDs while off prophylactic antacids. These data add to a growing body of evidence suggesting that continuous doses of valproic acid and celecoxib coupled with alternating metronomic chemotherapy of agents such as etoposide and cyclophosphamide can produce responses in pediatric tumors relapsing to conventional dose chemotherapy.

Given the rapidly changing political rhetoric and policies concerning immigration, and the likely impact of this rhetoric on immigrants' adjustment, it is essential to understand the experiences of recently arrived immigrant individuals and families. This article describes methods to recruit and retain recently arrived Hispanic families in longitudinal research and clinical practice. Barriers to continued engagement with recent-immigrant families include residential mobility, wariness toward authority figures (including researchers and practitioners), and unpredictable work schedules. These barriers can lead to challenges related to recruitment/engagement, logistics, establishing trust, and retention. This article describes decisions made, experiences, and lessons learned in a longitudinal study of Hispanic families in two cities. We also provide implications for clinical practice.

Piperazine (PIP) is a pharmaceutically acceptable molecule and a good co-conformer in crystallographic engineering. Most of the non-steroidal anti-inflammatory drugs (NSAIDs) have poor aqueous solubility, which hinders their clinical application. The reports show that the solubility of many insoluble drugs can be significantly improved through salt formation with the PIP. In this work, we obtained a series of NSAIDs-PIP salts, such as ibuprofen-piperazine (IBU-0.5PIP) salt, indomethacin-piperazine (IND-0.5PIP) salt, sulindac-piperazine (SUL-0.5PIP) salt, phenylbutazone-piperazine (PBZ-0.5PIP) salt, ketoprofen-piperazine (KPF-0.5PIP) salt and flurbiprofen-piperazine (FLB-0.5PIP) salt. The spatial structure, arrangement, interaction and associations were expatiated by single crystal X-ray diffraction. Powder X-ray diffraction, Fourier transform infrared, differential scanning calorimetry, and thermogravimetric analysis were used to characterize the novel salts. The six new salts had more than 10 folds of solubility and a faster dissolution rate improved corresponding to the bulk drugs in pure water, and the significant improvement of solubility is closely related to the structure of salts.

Prospective short-term studies on effectiveness of non-steroidal anti-inflammatory drugs (NSAIDs) point towards a decrease in the number and size of polyps. Effectiveness and safety in the prevention of progression in familial polyposis with NSAIDs in long-term use, which is the prerequisite for therapeutic evaluation in prospective studies, is unknown. The total absolute observation period of 54 patients under sulindac was 399 patient years with a mean of 7.4 (2-19) years per patient. 36 patients (66.7%) showed a fast decrease of polyp burden, 8 (14.8%) were slow responders, and 9 (16.7%) had stable disease; one patient had a slow progression. Upper gastrointestinal (GI) polyp burden remained stable in 47% patients, increased in 31%, and improved in 22%. Advanced adenomas were found in 8 patients only within the first 5 years of chemoprevention, no patient developed desmoid disease, anamnestically evaluated on every follow-up. There were no life-threatening side-effects. Dosage and delivery pattern were essential for effectiveness. This study provides evidence that chemoprevention with sulindac is effective and safe and can, either alone or in combination with other drugs, become a long-term management option in cases of adenomatous polyposis. These results justify further long-term prospective chemoprevention studies to elaborate treatment protocols and guidelines.

Desmoid tumors are clonal fibroblastic neoplasms that arise in soft tissues. Patients with familial adenomatous polyposis (FAP) can develop intra-abdominal desmoid tumors. However, metachronous appearance of intra-abdominal desmoid tumor is rare, and its clinical course is not well known. Here, we report a case of spontaneous regression of metachronous intra-abdominal desmoid tumor in a 36-year-old man with FAP. The patient was diagnosed with FAP and underwent laparoscopic total colorectomy. Intra-abdominal desmoid tumor appeared 2 years later and progressed despite treatment with tamoxifen and sulindac. He received four cycles of combinatory therapy with dacarbazine and adriamycin, resulting in shrinkage and stabilization of the desmoid tumor even after cessation of chemotherapy. A new intra-abdominal desmoid tumor developed 2 years later at a different site from the first lesion and progressed from 65 mm to 70 mm in diameter within a month. The size of the first lesion, however, remained unchanged. We prepared for chemotherapy because the second lesion progressed, but follow-up computed tomography showed spontaneous shrinkage of the second lesion. The patient still has not needed additional therapy as of more than 4 years after the appearance of the second lesion. Immunohistochemical staining showed the presence of macrophages in the second lesion. Although metachronous intra-abdominal desmoid tumor is rare and management protocols have yet to be established, this case suggests that an active surveillance approach may be applicable under careful follow-up in asymptomatic patients.

Sulindac is a nonsteroidal anti-inflammatory prodrug that is converted to its pharmacologically active metabolite, sulindac sulfide, via a reduction reaction. It is widely accepted that the gut microbiota is responsible for sulindac activation; however, sulindac-induced gastrointestinal injury, which is caused by irritation of the gastrointestinal tract by its active metabolite, is uncommon. Therefore, it is surmised that sulindac is converted to its active metabolite in tissues after absorption. In this study, we sought to identify the enzyme(s) responsible for sulindac activation in tissues and to compare its/their contribution to the gut microbiota. Sulindac is enzymatically reduced in human intestinal, liver, and renal cytosols. Since sulindac is known to be reduced by methionine sulfoxide reductase (Msr) in Escherichia coli, we investigated whether the human ortholog MSRA catalyzes the sulindac reduction reaction. We found that recombinant human MSRA shows sulindac reductase activity with a similar Michaelis constant value as tissue cytosols. In addition, it was revealed that cytosolic factor(s) efficiently enhanced MSRA activity. By using the relative expression factor, the contribution of MSRA to the sulindac reductase activities in each tissue cytosol was calculated to be almost 100%. In mice, depletion of the gut microbiota by administration of antibiotics resulted in a 31% decrease in the area under the curve ratio of sulindac sulfide to sulindac, indicating that the contribution of tissue MsrA to sulindac activation is expected to be 69% in the body. In conclusion, we demonstrated that MSRA expressed in tissues is involved in sulindac activation, making a larger contribution than the gut microbiota. SIGNIFICANCE STATEMENT: Methionine sulfoxide reductase A is responsible for the activation of sulindac, a nonsteroidal anti-inflammatory prodrug, to sulindac sulfide, an active form, in human tissues. Methionine sulfoxide reductase A expressed in tissues activates sulindac with a higher contribution than gut microbiota in body.

Kolaviron is a mixture of bi-flavonoids from seed Garcinia kola seed, and has been previously shown to exhibit Nrf2 antioxidant-mediated inhibition of neuroinflammation in LPS-activated BV2 microglia. In this study, we investigated neuroprotective effects of kolaviron in LPS-induced memory impairment in rats. Wistar rats (225-250) g was used for this study. Memory impairment was induced with the systematic administration of 250 µg/mg lipopolysaccharide (LPS). The effect of kolaviron on the cognition and learning processes were assessed using the behavioral responses in the Morris water maze model. Effects of LPS injections on the physiological activities were assessed by biochemical assays before and after treatment. Peripheral administration of LPS showed reduction in the cognitive and locomotor process. It also led to reductions in the core body temperature, superoxide dismutase (SOD), and catalase levels, with an increase in Membrane lipid-peroxidation (MDA), intracellular glutathione (GSH) and nitric oxide (NO2). These pro-inflammatory mediators produced in response to LPS are hypothesized to affect cognition, and kolaviron was able to ameliorate the effect by significantly improving the cognitive and learning processes, revealed in the reduction of escape latency and path-length during the probe trial and increase in time spent within the quadrant during retrieval using Morris water maze. Similarly, LPS at 250 µg/kg induced a hypothermic effect in the treated animals. Kolaviron significantly was able to ameliorate the level of SOD and CAT by causing a significant increase while it caused a significant reduction in the level of NO2, GSH, and MDA. Kolaviron has considerable anti-inflammatory potentials, reducing lipopolysaccharide activation of macrophages. The memory-enhancing activity of kolaviron was comparable to Sulindac sulfide (a non-steroidal anti-inflammatory drug).