Synthetic Methods and Pharmacological Potentials of Triazolothiadiazines: A Review.

This review article examines the synthetic pathways for triazolothiadiazine derivatives, such as triazolo[3,4-b]thiadiazines, triazolo[5,1-b]thiadiazines, and triazolo[4,3-c]thiadiazines, originating from triazole derivatives, thiadiazine derivatives, or thiocarbohydrazide. The triazolothiadiazine derivatives exhibit several biological actions, including antibacterial, anticancer, antiviral, antiproliferative, analgesic, anti-inflammatory, and antioxidant properties. The review article aims to assist researchers in creating new biologically active compounds for designing target-oriented triazolothiadiazine-based medicines to treat multifunctional disorders.

Developmental exposure to pesticides that disrupt retinoic acid signaling causes persistent retinoid and behavioral dysfunction in zebrafish.

Early developmental exposure to environmental toxicants may play a role in the risk for developing autism. A variety of pesticides have direct effects on retinoic acid (RA) signaling and as RA signaling has important roles in neurodevelopment, such compounds may cause developmental neurotoxicity through an overlapping adverse outcome pathway. It is hypothesized that a pesticide's embryonic effects on retinoid function may correspond with neurobehavioral disruption later in development. In the current studies, we determined the effects of RA-acting pesticides on neurobehavioral development in zebrafish. Buprofezin and imazalil caused generalized hypoactivity in the larval motility test, whereas chlorothalonil and endosulfan I led to selective hypoactivity and hyperactivity, respectively. With buprofezin, chlorothalonil, and imazalil, hypoactivity and/or novel anxiety-like behaviors persisted in adulthood and buprofezin additionally decreased social attraction responses in adulthood. Endosulfan I did not produce significant adult behavioral effects. Using qPCR analyses of adult brain tissue, we observed treatment-induced alterations in RA synthesis or catabolic genes, indicating persistent changes in RA homeostasis. These changes were compound-specific, with respect to expression directionality, and potential patterns of homeostatic disruption. Results suggest the likely persistence of disruptions in RA signaling well into adulthood and may represent compensatory mechanisms following early life stage exposures. This study demonstrates that early developmental exposure to environmental toxicants that interfere with RA signaling causes short as well as long-term behavioral disruption in a well-established zebrafish behavioral model and expand upon the meaning of the RA adverse outcome pathway, indicating that observed effects likely correspond with the nature of underlying homeostatic effects.

Discovery of novel 6-p-tolyl-3-(3,4,5-trimethoxybenzyl)-7H-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazine derivative as a potent tubulin inhibitor with promising in vivo antitumor activity.

Building on our prior research, a novel series of trimethoxyphenoxymethyl- and trimethoxybenzyl-substituted triazolothiadiazine compounds has been designed and achieved successfully via a direct ring-closing strategy. Initial biological evaluation illustrated that the most active derivative B5 exhibited significant cell growth inhibitory activity toward HeLa, HT-29, and A549 giving the IC50 values of 0.046, 0.57, and 0.96 µM, respectively, which are greater or similar with CA-4. The mechanism study revealed that B5 caused the G2/M phase arrest, induced cell apoptosis in HeLa cells in a concentration-dependent manner, and also showed potent tubulin polymerization inhibitory effect. Meanwhile, B5 exerted significant antivascular activity in the wound-healing and tube formation assays. Most importantly, B5 remarkably inhibited tumor growth without obvious signs of toxicity in A549-xenograft mice model. These observations indicate that 6-p-tolyl-3-(3,4,5-trimethoxybenzyl)-7H-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazine might be considered as the potential lead compound to develop highly efficient anticancer agents with potent selectivity over normal human cells.

Synthesis and biological evaluation of novel 5-substituted/unsubstituted triazolothiadiazines as tubulin depolymerizing and vascular disrupting agents with promising antitumor activity.

A novel series of 5-substituted/unsubstituted [1,2,4]triazolo[3,4-b][1,3,4] thiadiazine compounds has been achieved successfully through chemoselective reduction of the C = N bond, based on our prior work. Initial biological evaluation illustrated that the most active derivative 7j exhibited significant cell growth inhibitory activity toward MCF-7, A549, HCT116, and A2780 with the IC50 values of 0.75, 0.94, 2.90, and 4.15 µM, respectively. Most importantly, all the representative analogs did not demonstrate obvious cytotoxic activity against the non-tumoural cell line HEK-293 (IC50 > 100 µM). The mechanism study revealed that 7j caused the G2 /M phase arrest, induced cell apoptosis in HeLa cells in a concentration-dependent manner, and also showed potent tubulin polymerization inhibitory effect. Meanwhile, 7j exerted significant antivascular activity in the wound-healing and tube formation assays. These observations indicate that 5-unsubstituted 6,7-dihydro-5H-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazine scaffold might be considered as a potential lead for antitubulin inhibitors to develop highly efficient anticancer agents with potent selectivity over normal human cells.

Taurolidine lock in the treatment of colonization and infection of totally implanted venous access devices in cancer patients.

BACKGROUND: Taurolidine lock is known to be effective in preventing catheter-related infections in a variety of venous access devices, including long term venous access devices for chemotherapy. Though, literature about the use of taurolidine for treating catheter colonization or catheter-related blood stream infection is scarce. METHOD: We have retrospectively reviewed the safety and efficacy of 2% taurolidine lock for treatment of catheter-colonization and of catheter-related bloodstream infection in cancer patients with totally implanted venous access devices. Diagnosis of colonization or catheter-related infection was based on paired peripheral and central blood cultures, according to the method of Delayed Time to Positivity. RESULTS: We recorded 24 cases of catheter-related infection and two cases of colonization. Taurolidine lock-associated with systemic antibiotic therapy-was successful in treating all cases of catheter-related infection, with disappearance of clinical symptoms, normalization of laboratory values, and eventually negative blood cultures. Taurolidine lock was also safe and effective in treating device colonization. No adverse effect was reported. CONCLUSION: In our retrospective analysis, 2% taurolidine lock was completely safe and highly effective in the treatment of both catheter-colonization and catheter-related bloodstream infection in cancer patients with totally implanted venous access devices.

Thiadiazine-thione derivatives ameliorate STZ-induced diabetic neuropathy by regulating insulin and neuroinflammatory signaling.

Diabetes Mellitus is accompanied by chronic hyperglycemia, inflammation, and related molecular processes, which leads to diabetic neuropathy. In this work, we tested Thiadiazine-thione (TDT) synthetic derivatives TDT1 and TDT2 against streptozotocin (STZ)-induced diabetic neuropathy. Sprague Dawley's rats, SH-SY5Y neuronal and BV2 microglial cells were employed in this work, followed by behavioral, biochemical, and morphological studies utilizing RT-qPCR, ELISA, Immunoblotting, immunohistochemistry, Immunofluorescence, and in silico analyses. TDT1 and TDT2 abolished STZ-induced allodynia and hyperalgesia. Next, we examined IRS1/PI3K/AKT signaling to assess TDT1 and TDT2's impact on diabetic neuropathy. STZ downregulated IRS1, PI3K, AKT mRNA and protein expression in rat spinal cord and SH-SY5Y neuronal cells. TDT1 and TDT2 improved IRS1, PI3k, and AKT mRNA and protein expression. STZ elevated GSK3ß mRNA and protein expression in vivo and in vitro, whereas TDT1 and TDT2 mitigated it. STZ increased the expression of inflammatory mediators such as p-NF-κB, TNF-α, and COX-2 in rat spinal cord lysates. TDT1 and TDT2 co-treatment with STZ decreased inflammatory cytokine expression by ameliorating astrocytosis (revealed by increased GFAP) and microgliosis (indicated by increased Iba1). TDT1 and TDT2 reduced STZ-induced JNK, Iba1, and COX-2 upregulation in BV2 microglial cells validating our in vivo findings. In silico molecular docking and MD simulations analyses suggested that TDT1 and TDT2 have IRS binding affinity, however, both compounds had an identical binding affinity, but distinct interaction pattern with IRS protein residues. Overall, these findings demonstrate that TDT derivatives mitigated STZ-induced neuropathy through modulating the insulin and inflammatory signaling pathways.

The Antiseptic and Antineoplastic Agent Taurolidine Modulates Key Leukocyte Functions.

BACKGROUND/AIM: Although taurolidine is known to exert a wide spectrum of biological actions, its effects on immune cells have not been characterized in detail. In this study, we investigated the ex vivo effects of taurolidine on relevant innate and adaptive immune cell functions. MATERIALS AND METHODS: Leukocyte functions in whole blood were assessed following treatment with various taurolidine concentrations. Viability of peripheral blood mononuclear cells (PBMCs) and granulocytes was measured using the WST-1 assay. PBMC function was assessed by measuring TNFα and IFNγ production after stimulation with lipopolysaccharide (LPS) or Candida, respectively. Reactive oxygen species (ROS) production by granulocytes was measured in whole blood using luminol-enhanced chemiluminescence. Granulocyte degranulation and activation were evaluated by membrane expression of degranulation (CD63, CD66B) and adhesion markers (CD62L, CD11b) using immunofluorescent staining followed by flow-cytometric analysis. RESULTS: Taurolidine decreased viability of PBMCs and granulocytes: after 2 h, IC50 concentrations were 500 and 520 µg/ml, respectively. Following prolonged exposure (≥24 h) of PBMCs, the IC50 concentrations declined to 40 µg/ml. PBMC cytokine production significantly decreased at taurolidine concentrations below the cytotoxic threshold, whereas no changes in ROS production were observed. The expression of all granulocyte adhesion and degranulation markers increased at concentrations higher than 500 µg/ml (the cytotoxic level of taurolidine). CONCLUSION: Taurolidine exhibits a dose- and time-dependent cytotoxicity toward PBMCs and granulocytes. The effects on PBMCs, as exemplified by a decrease in cytokine production, occurred below the toxic threshold, whereas granulocyte function (ROS production) remained unchanged at these taurolidine concentrations. Granulocyte activation and degranulation markers only increased at cytotoxic taurolidine concentrations.

[Determination of dazomet and its metabolite methyl isothiocyanate residues in plant-derived foods by gas chromatography-triple quadrupole mass spectrometry].

Dazomet is a kind of crystal solid that is stable at room temperature and acts as a fumigant. It is commonly used to control soil fungi, as an insecticide, and in sterilization and weeding. It can effectively kill root-knot nematodes, soil pests, weeds, and many soil-borne disease-causing organisms, to provide clean and healthy soil. Dazomet slowly decomposes and releases methyl isothiocyanate, methylamine, carbon disulfide, and hydrogen sulfide in acidic soil, and diffuses upward through the spaces in the soil to kill contact organisms. When agricultural crops are planted in soil treated with cotton wool, the residues in the grown crop can cause harm to human body when consumed. To ensure the quality and safety of food crops, it is important to develop a detection method for dazomet and its metabolites in plant-derived foods. Hence, in this study, a rapid and simultaneous determination method was developed for dazomet and its metabolite methyl isothiocyanate residues in plant-derived foods by gas chromatography-triple quadrupole mass spectrometry (GC-MS/MS). The sample pretreatment and chromatographic conditions were optimized in the experiment. Subsequently, dazomet and its metabolite methyl isothiocyanate residues in vegetables, fruits, grains, nuts, tea, and spices were extracted with ethyl acetate, and purified using graphitized carbon, a primary-secondary amine, stearyl-bonded silica gel, and anhydrous magnesium sulfate as dispersive solid-phase extraction sorbents. After centrifugation and filtration, the target compounds were analyzed in the multiple reaction monitoring (MRM) mode by GC-MS/MS, and quantified by matrix matching external standard method. The matrix effects of the samples were also evaluated. The matrix effect was found to be in the range of 2.5% to 13.6% for methyl isothiocyanate in 16 matrices. As this matrix effect was weak, there was no need for compensatory measures. In contrast, the matrix effect of dazomet in 16 matrices was in the range of 240.3% to 331.2%. This matrix effect was strong and required compensation. Finally, a matrix matching calibration method was used to compensate the matrix effects. The relative matrix effects of other tested substrates were analyzed using lettuce as the representative substrate; it was found that all showed weak matrix effects. Therefore, the use of lettuce as a representative matrix to prepare a matrix standard curve can effectively correct the matrix effects of dazomet and methyl isothiocyanate in other substrates. Under the optimal conditions, the calibration curves were linear in the range of 0.005-1 mg/L with correlation coefficients higher than 0.99. Recovery tests were conducted by adding mixed standards to blank samples at four levels. The recoveries were in the range of 74.2%-117.2% with relative standard deviations (RSDs, n=6) of 2.8%-9.0%. The limits of quantification (LOQs) of dazomet and methyl isothiocyanate were 0.01 mg/kg. The accuracy and precision of this method met the requirements of pesticide residue determination. The established method was used to detect dazomet and its metabolite methyl isothiocyanate residues in six samples of Chinese cabbage, Chinese chives, cowpea, lettuce, eggplant, ginger, celery, potato, orange, kiwifruit, tomato, chili, rice, tea, almond, and Cuminum cyminum L. in the laboratory, and nothing was detected. The method is simple, rapid, and sensitive; overcomes the shortcomings of existing methods that require two pretreatment steps and two sets of equipment; and meets the requirements for the detection of dazomet and its metabolite methyl isothiocyanate residues in plant-derived foods.

Exploring the potential of taurolidine in inducing mobilization and detachment of colon cancer cells: a preliminary in-vitro study.

BACKGROUND: Recently, taurolidine has been intensively studied on a variety of in-vitro cancer cell-lines and first data exhibit encouraging antitumoral effects. While the clinical use of taurolidine is considered, some studies with in-vivo experiments contradict this beneficial effect and even indicate advanced cancer growth. The aim of this study is to further investigate this paradox in-vivo effect by taurolidine and closely analyze the interaction of cancer cells with the surrounding environment following taurolidine exposure. METHODS: HT-29 (ATCC® HTB-38™) cells were treated with taurolidine at different concentrations and oxaliplatin using an in-vitro model. Morphological changes with respect to increasing taurolidine dosage were visualized and monitored using electron microscopy. Cytotoxicity of the agents as well as extent of cellular detachment by mechanical stress was measured for each substance using a colorimetric MTS assay. RESULTS: Both taurolidine and oxaliplatin exhibit cell toxicity on colon cancer cells. Taurolidine reshapes colon cancer cells from round into spheric cells and further induces cluster formation. When exposed to mechanical stress, taurolidine significantly enhances detachment of adherent colon carcinoma cells compared to the control (p < 0.05) and the oxaliplatin group (p < 0.05). This effect is dose dependent. CONCLUSIONS: Beside its cytotoxic effects, taurolidine could also change mechanical interactions of cancer cells with their environment. Local cancer cell conglomerates could be mechanically mobilized and may cause metastatic growth further downstream. The significance of changes in cellular morphology caused by taurolidine as well as its interaction with the microenvironment must be further addressed in clinical cancer therapies. Further clinical studies are needed to evaluate both the safety and efficacy of taurolidine for the treatment of peritoneal surface malignancies.

Vision on Synthetic and Medicinal Facets of 1,2,4-Triazolo[3,4-b][1,3,4]thiadiazine Scaffold.

The present review article strives to compile the latest synthetic approaches for the synthesis of triazolothiadiazine and its derivatives, along with their diverse pharmacological activities, viz. anticancer, antimicrobial, analgesic and anti-inflammatory, antioxidant, antiviral, enzyme inhibitors (carbonic anhydrase inhibitors, cholinesterase inhibitors, alkaline phosphatase inhibitors, anti-lipase activity, and aromatase inhibitors) and antitubercular agents. The review focuses particularly on the structure-activity relationship of biologically important 1,2,4-triazolo[3,4-b][1,3,4]thiadiazines, which have profound importance in drug design, discovery and development. In silico pharmacokinetic and molecular modeling studies have also been summarized. It is hoped that this review article will be of help to researchers engaged in the development of new biologically active entities for the rational design and development of new target-oriented 1,2,4-triazolo[3,4-b][1,3,4]thiadiazine-based drugs for the treatment of multifunctional diseases.

Preventative treatment with Fluorothiazinon suppressed Acinetobacter baumannii-associated septicemia in mice.

The high prevalence of multidrug-resistant Acinetobacter baumannii has emerged as a serious problem in the treatment of nosocomial infections in the past three decades. Recently, we developed a new small-molecule inhibitor belonging to a class of 2,4-disubstituted-4H-[1,3,4]-thiadiazine-5-ones, Fluorothiazinon (FT, previously called CL-55). FT effectively suppressed the T3SS of Chlamydia spp., Pseudomonas aeruginosa, and Salmonella sp. without affecting bacterial growth in vitro. In this study, we describe that prophylactic use of FT for 4 days prior to challenge with resistant clinical isolates of A. baumannii (ABT-897-17 and 52TS19) suppressed septic infection in mice, resulting in improved survival, limited bacteraemia and decreased bacterial load in the organs of the mice. We show that FT had an inhibitory effect on A. baumannii biofilm formation in vitro and, to a greater extent, on biofilm maturation. In addition, FT inhibited Acinetobacter isolate-induced death of HeLa cells, which morphologically manifested as apoptosis. The mechanism of FT action on A. baumannii is currently being studied. FT may be a promising candidate for the development of a broad-spectrum anti-virulence drug to use in the prevention of nosocomial infections.

Discovery of ( ±)-3-(1H-pyrazol-1-yl)-6,7-dihydro-5H-[1,2,4]triazolo[3,4-b][1,3,4] thiadiazine derivatives with promising in vitro anticoronavirus and antitumoral activity.

A new series of ( ±)-(3-(3,5-dimethyl-1H-pyrazol-1-yl)-6-phenyl-6,7-dihydro-5H-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazin-7-yl)(phenyl)methanones were efficiently synthesized starting from 4-amino-5-hydrazinyl-4H-1,2,4-triazole-3-thiol 1, acetyl acetone 2, various aromatic and heterocyclic aldehydes 3 and phenacyl bromides 4. All the newly synthesized compounds were tested for their antiviral and antitumoral activity. It was shown that subtle structural variations on the phenyl moiety allowed to tune biological properties toward antiviral or antitumoral activity. Mode-of-action studies revealed that the antitumoral activity was due to inhibition of tubulin polymerization.

The efficacy of taurolidine containing lock solutions for the prevention of central-venous-catheter-related bloodstream infections: a systematic review and meta-analysis.

The incidence of central venous catheter (CVC)-related bloodstream infections is high in patients requiring a long-term CVC. Therefore, infection prevention is of the utmost importance. The aim of this study was to provide an updated overview of randomized controlled trials (RCTs) comparing the efficacy of taurolidine containing lock solutions (TL) to other lock solutions for the prevention of CVC-related bloodstream infections in all patient populations. On 15th February 2021, PubMed, Embase and The Cochrane Library were searched for RCTs comparing the efficacy of TLs for the prevention of CVC-related bloodstream infections with other lock solutions. Exclusion criteria were non-RCTs, studies describing <10 patients and studies using TLs as treatment. Risk of bias was evaluated using the Cochrane Risk of Bias 2 tool. A random effects model was used to pool individual study incidence rate ratios (IRRs). Subgroup analyses were performed based on the following factors: CVC indication, comparator lock and bacterial isolates cultured. A total of 14 articles were included in the qualitative synthesis describing 1219 haemodialysis, total parenteral nutrition and oncology patients. The pooled IRR estimated for all patient groups together (nine studies; 918 patients) was 0.30 (95% confidence interval 0.19-0.46), favouring the TLs. Adverse events (10 studies; 867 patients) were mild and scarce. The quality of the evidence was limited due to a high risk of bias and indirectness of evidence. The use of TLs might be promising for the prevention of CVC-related bloodstream infections. Large-scale RCTs are needed to draw firm conclusions on the efficacy of TLs.

Selectivity of herbicides applied to Brazilian tree species at post-emergence

The presence of weeds in silvicultural systems has been considered one of the main obstacles to the success of projects designed to recover degraded areas. The aim of this study was to evaluate the selectivity of herbicides applied at post-emergence in the initial growth of seedlings of capixingui (Croton floribundus), açoita-cavalo (Luehea divaricata), and guaritá (Astronium graveolens), in the municipalities of Jaboticabal and Junqueirópolis, state of São Paulo. The experimental design was completely randomized, with four replications, and the treatments consisted of herbicides (g a.i.·ha-1) clethodim + phenoxaprop-p-ethyl (50 + 50), sethoxydim (184), quizalofop-p-ethyl (75), nicosulfuron (50), fluazifop-p-butyl (125), fomesafen (225), haloxyfop-methyl (48), bentazon (720), chlorimuron-ethyl (15), in addition to control without herbicide. The characteristics analyzed were: plant height increase and visual phytointoxication at 7, 14, 21, 28, 35, and 42 days after herbicide application. At the end of the experiment, the shoots of the plants were removed to assess shoot dry matter. The herbicides clethodim + fenoxaprop-p-ethyl, fluazifop-p-butyl, and quizalofop-p-ethyl showed selective potential for the species capixingui, açoita-cavalo, and guaritá. The herbicide chlorimuron-ethyl caused mild intoxication symptoms when applied to seedlings of capixingui and açoita-cavalo; also, it was not selective for the guaritá species grown in Jaboticabal. All species showed selectivity to the herbicides sethoxydim, fomesafen, haloxyfop-methyl, and nicosulfuron, as their growth and initial development were not influenced. The herbicide bentazon caused high percentages of injury to açoita-cavalo plants in both cultivation places, but it did not influence the growth and development of the species.

Synthesis and Evaluation of Novel 1,2,6-Thiadiazinone Kinase Inhibitors as Potent Inhibitors of Solid Tumors.

A focused series of substituted 4H-1,2,6-thiadiazin-4-ones was designed and synthesized to probe the anti-cancer properties of this scaffold. Insights from previous kinase inhibitor programs were used to carefully select several different substitution patterns. Compounds were tested on bladder, prostate, pancreatic, breast, chordoma, and lung cancer cell lines with an additional skin fibroblast cell line as a toxicity control. This resulted in the identification of several low single digit micro molar compounds with promising therapeutic windows, particularly for bladder and prostate cancer. A number of key structural features of the 4H-1,2,6-thiadiazin-4-one scaffold are discussed that show promising scope for future improvement.

Preparation and Size Control of Efficient and Safe Nanopesticides by Anodic Aluminum Oxide Templates-Assisted Method.

Efficient and safe nanopesticides play an important role in pest control due to enhancing target efficiency and reducing undesirable side effects, which has become a hot spot in pesticide formulation research. However, the preparation methods of nanopesticides are facing critical challenges including low productivity, uneven particle size and batch differences. Here, we successfully developed a novel, versatile and tunable strategy for preparing buprofezin nanoparticles with tunable size via anodic aluminum oxide (AAO) template-assisted method, which exhibited better reproducibility and homogeneity comparing with the traditional method. The storage stability of nanoparticles at different temperatures was evaluated, and the release properties were also determined to evaluate the performance of nanoparticles. Moreover, the present method is further demonstrated to be easily applicable for insoluble drugs and be extended for the study of the physicochemical properties of drug particles with different sizes.

Synthesis and evaluation of multi-target-directed ligands with BACE-1 inhibitory and Nrf2 agonist activities as potential agents against Alzheimer's disease.

Cumulative evidence suggests that ß-amyloid and oxidative stress are closely related with each other and play key roles in the process of Alzheimer's disease (AD). Multitarget regulation of both pathways might represent a promising therapeutic strategy. Here, a series of selenium-containing compounds based on ebselen and verubecestat were designed and synthesized. Biological evaluation showed that 13f exhibited good BACE-1 inhibitory activity (IC50 = 1.06 µΜ) and potent GPx-like activity (ν0 = 183.0 µM min-1). Aß production experiment indicated that 13f could reduce the secretion of Aß1-40 in HEK APPswe 293T cells. Moreover, 13f exerted a cytoprotective effect against the H2O2 or 6-OHDA caused cell damage via alleviation of intracellular ROS, mitochondrial dysfunction, Ca2+ overload and cell apoptosis. The mechanism studies indicated that 13f exhibited cytoprotective effect by activating the Keap1-Nrf2-ARE pathway and stimulating downstream anti-oxidant protein including HO-1, NQO1, TrxR1, GCLC, and GCLM. In addition, 13f significantly reduced the production of NO and IL-6 induced by LPS in BV2 cells, which confirmed its anti-inflammatory activity as a Nrf2 activator. The BBB permeation assay predicted that 13f was able to cross the BBB. In summary, 13f might be a promising multi-target-directed ligand for the treatment of AD.

Cost-effectiveness of taurolidine locks to prevent recurrent catheter-related blood stream infections in adult patients receiving home parenteral nutrition: a 2-year mirror-image study.

BACKGROUND & AIMS: The use of long-term taurolidine locks (LTTL) seems to be effective in preventing catheter-related blood stream infections (CRBSI), especially in patients on home parenteral nutrition (HPN). This work targets the cost-effectiveness of LTTL in a cohort of adult HPN patients. METHODS: A monocentric mirror-image design study was conducted in our referral centre among long-term HPN patients experiencing recurrent CRBSI. From 7th January 2011, LTTL were started after the third CRBSI episode within 12 months. CRBSI data was prospectively collected until 7th January 2013, in the same way as it had retrospectively been done before initiating LTTL. A cost-effective analysis was conducted to estimate the incremental costs and effects on CRBSI with LTTL. The efficacy of LTTL on CRBSI rate was assessed over 1000 days of catheter use. RESULTS: A total of 31,100 catheter days were analysed in 37 patients (median [interquartile range (IQR)]) aged 58 [42-68] years. The mean ± SD proven CRBSI rate was 3.18 ± 3.51 per 1000 catheter days before the introduction of LTTL and 0.39 ± 1.50 per 1000 catheter days after its introduction (p < 0.0001). Considering both proven and probable CRBSI requiring hospital management, LTTL reduced by (mean [bootstrap CI 95%]) -2.63 [-3.26 to -2.06] infections per patient (from 2.89 [2.31 to 3.49] before to 0.26 [0.13 to 0.41] after) as well as incremental costs by -7 258 [-10 450 to -4 016] € (from 11 176 [8 004 to 14 968] € before to 3 918 [2 390 to 5 445] € after). CONCLUSION: Implementing LTTL to prevent recurrent CRBSI is cost-effective by dramatically decreasing their incidence.

Taurolidina para prevenir infecciones asociadas a catéter venoso central en niños con insuficiencia intestinal: experiencia preliminar en un hospital terciario chileno / Taurolidine for the prevention of catheter-related infections in children with intestinal insufficiency: preliminary experience in a Chilean tertiary hospital

INTRODUCCIÓN: Taurolidina es una molécula con propiedades anti-endotóxicas, antimicrobianas y anti-inflamatorias, que inhibe la adhesión bacteriana, lo que ha permitido usarla como terapia de sellado en catéter venoso central de larga duración (CVC) para prevenir infecciones del torrente sanguíneo asociadas a CVC (ITS-CVC). OBJETIVO: Dar a conocer una experiencia preliminar, la primera en Chile, con taurolidina como terapia de sellado para prevenir ITS-CVC y reportar su eficacia. MÉTODO: Se instiló una solución en base a taurolidina en el CVC de tres niños con insuficiencia intestinal, dependientes de alimentación parenteral, atendidos en un hospital terciario de la Región de Valparaíso, y se comparó la tasa de ITS-CVC antes y después de su uso mediante un análisis retrospectivo. RESULTADOS: en los dos pacientes que iniciaron terapia de sellado inmediatamente después de instalado el CVC, la tasa de ITS-CVC se logró llevar a cero, mientras que, en el tercero, portador de un CVC instalado 9 meses antes, con ITS-CVC recurrentes, un nuevo episodio de ITS-CVC obligó a suspender la profilaxis. CONCLUSIONES: La terapia de sellado con solución en base a taurolidina previno las ITS-CVC cuando ésta se inició al momento de instalarse el CVC, no así en un CVC antiguo con ITS-CVC recurrentes.

BACKGROUND: Taurolidine is a molecule with anti-endotoxic, anti-microbial and anti-inflammatory properties that inhibits bacterial adhesion, allowing for its use as lock therapy for the prevention of catheter-related bloodstream infections (CRBSI) in long-term central venous catheters (CVC). AIM: To report a preliminary experience, the first one in Chile, using lock therapy with taurolidine for the prevention of CRBSI and to report its efficacy. METHOD: A taurolidine-based solution was instilled in the CVC of three children with intestinal insufficiency dependent on parenteral nutrition, attended in a Chilean tertiary hospital, and the rate of CRBSI before and after its use was compared in retrospect. RESULTS: In the two patients who started lock therapy immediately after the installation of their CVC, the rate of CRBSI was brought to zero, whereas in the third patient, who had a 9 months-old CVC with a recurrent CRBSI history, an intercurrent CRBSI forced discontinuation of the prophylaxis. CONCLUSIONS: Lock therapy with a taurolidine-based solution prevented CRBSIs when it was begun immediately after installing the CVC, in contrast with an old CVC with a history of recurrent CRBSIs.