Thiadiazole/Thiadiazine Derivatives as Insecticidal Agent: Design, Synthesis, and Biological Assessment of 1,3,4-(Thiadiazine/Thiadiazole)-Benzenesulfonamide Derivatives as IGRs Analogues against Spodoptera littoralis.

In keeping with our investigation, a simple and practical synthesis of novel heterocyclic compounds with a sulfamoyl moiety that can be employed as insecticidal agents was reported. The compound 2-hydrazinyl-N-(4-sulfamoylphenyl)-2-thioxoacetamide 1 was coupled smoothly with triethylorthoformate or a variety of halo compounds, namely phenacyl chloride, chloroacetyl chloride, chloroacetaldehyde, chloroacetone, 1,3-dichloropropane, 1,2-dichloroethane, ethyl chloroformate, 2,3-dichloro-1,4-naphthoquinone, and chloroanil respectively, which afforded the 1,3,4-thiadiazole and 1,3,4-thiadiazine derivatives. The new products structure was determined using elemental and spectral analysis. Under laboratory conditions, the biological and toxicological effects of the synthetic compounds were also evaluated as insecticides against Spodoptera littoralis (Boisd.). Compounds 3 and 5 had LC50 values of 6.42 and 6.90 mg/L, respectively. The investigated compounds (from 2 to 11) had been undergoing molecular docking investigation for prediction of the optimal arrangement and strength of binding between the ligand (herein, the investigated compounds (from 2 to 11)) and a receptor (herein, the 2CH5) molecule. The binding affinity within docking score (S, kcal/mol) ranged between -8.23 (for compound 5), -8.12 (for compound 3) and -8.03 (for compound 9) to -6.01 (for compound 8). These compounds were shown to have a variety of binding interactions within the 2CH5 active site, as evidenced by protein-ligand docking configurations. This study gives evidence that those compounds have 2CH5-inhibitory capabilities and hence may be used for 2CH5-targeting development. Furthermore, the three top-ranked compounds (5, 3, and 9) and the standard buprofezin were subjected to density functional theory (DFT) analysis. The highest occupied molecular orbital-lowest unoccupied molecular orbital (HOMO-LUMO) energy difference (ΔE) of compounds 5, 3, and 9 was found to be comparable to that of buprofezin. These findings highlighted the potential and relevance of charge transfer at the molecular level.

Cost-effectiveness of taurolidine-citrate in a cohort of patients with intestinal failure receiving home parenteral nutrition.

BACKGROUND: Catheter-related bloodstream infections (CRBSIs) in patients receiving home parenteral nutrition (HPN) for chronic intestinal failure (CIF) are associated with significant morbidity and financial costs. Taurolidine is associated with a reduction in bloodstream infections, with limited information on the cost-effectiveness as the primary prevention. This study aimed to determine the cost-effectiveness of using taurolidine-citrate for the primary prevention of CRBSIs within a quaternary hospital. METHODS: All patients with CIF receiving HPN were identified between January 2015 and November 2022. Data were retrospectively collected regarding patient demographics, HPN use, CRBSI diagnosis, and use of taurolidine-citrate. The direct costs associated with CRBSI-associated admissions and taurolidine-citrate use were obtained from the coding department using a bottom-up approach. An incremental cost-effective analysis was performed, with a time horizon of 4 years, to compare the costs associated with primary and secondary prevention against the outcome of cost per infection avoided. RESULTS: Forty-four patients received HPN within this period. The CRBSI rates were 3.25 infections per 1000 catheter days before the use of taurolidine-citrate and 0.35 infections per 1000 catheter days after taurolidine-citrate use. The incremental cost-effectiveness ratio indicates primary prevention is the weakly dominant intervention, with the base case value of $27.04 per CRBSI avoided. This held with one-way sensitivity analysis. CONCLUSION: Taurolidine-citrate in the primary prevention of CRBSIs in patients with CIF receiving HPN is associated with reduced hospital costs and infection rates.

Inheritance and fitness cost of buprofezin resistance in a near-isogenic, field-derived strain and insecticide resistance monitoring of Laodelphax striatellus in China.

BACKGROUND: Laodelphax striatellus is one of the most destructive pests of rice and other cereal crops. Chemical control is still the most efficient way to control this pest, but insecticide resistance always threatens this approach. RESULTS: Monitoring data (2003-2020) showed that Chinese field populations of L. striatellus developed high-level buprofezin resistance within the first four years. This high-level resistance to buprofezin was stable for about ten years and persisted even when buprofezin selection pressure was absent. An established near-isogenic strain (YN-NIS) with 90.8-fold resistance to buprofezin had resistance inheritance of autosomal and incomplete dominance, and the resistance was controlled by multiple genes with no obvious fitness costs (relative fitness of 0.8707). Furthermore, the susceptibility of 29 field populations to another seven insecticides (2014-2020) showed that: (i) low-level resistance to pymetrozine, dinotefuran, sulfoxaflor and thiamethoxam was first detected in 2014 (eight years after introduction), 2016 (three years after), 2017 (four years after) and 2019 (19 years after), respectively, (ii) moderate resistance levels to chlorpyrifos were found for all populations across multiple years, and (iii) no resistance was detected for nitenpyram and triflumezopyrim. CONCLUSION: The fast buprofezin resistance development in L. striatellus would be caused by incomplete dominant resistance with almost no fitness cost in the resistant strain. Nitenpyram and triflumezopyrim showed no resistance and can be used as the main insecticide for the control of L. striatellus. These findings provide key fundamental information for controlling L. striatellus.

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.

Synthesis and Anti-Proliferative Assessment of Triazolo-Thiadiazepine and Triazolo-Thiadiazine Scaffolds.

A series of triazolo-thiadiazepines 4a-k were synthesized with excellent yields using dehydrated PTSA as a catalyst in toluene. Two triazolo-thiadiazines were obtained; 8a was formed directly by reflux in ethanol, whereas, PTSA promoted the formation of 8b. The molecular structure of the formed triazolo-thiadiazepines is identical to the imine-form 4a-k and not the enamine-tautomer 6a-k. The structures of the newly synthesized triazolo-thiadiazepines 4a-k and triazolo-thiadiazines 8a-b were elucidated using NMR (1H, and 13C), 2D NMR, HRMS, and X-ray single crystal. Furthermore, 4a was deduced using X-ray single crystal diffraction analysis. These new thiadiazepine hits represent an optimized series of previously synthesized indole-triazole derivatives for the inhibition of EGFR. The cytotoxicity activity against two cancer cell lines including human liver cancer (HEPG-2) and breast cancer (MCF-7) was promising, with IC50 between 12.9 to 44.6 µg/mL and 14.7 to 48.7 µg/mL for the tested cancer cell lines respectively, compared to doxorubicin (IC50 4.0 µg/mL). Docking studies revealed that the thiadiazepine scaffold presented a suitable anchor, allowing good interaction of the various binding groups with the enzyme binding regions and sub-pockets.

Buprofezin dissipation and safety assessment in open field cabbage and cauliflower using GC/ITMS employing an analyte protectant.

An analytical method for the determination of buprofezin residues in cabbage and cauliflower was developed and validated using gas chromatography with ion trap mass spectrometry. The analyte protectant d-sorbitol was used at a concentration level of 0.5 mg mL-1 in acetonitrile instead of in matrix for constructing the calibration curves of the buprofezin standard. The average recoveries ranged from 91.3 to 96.8%, with an RSD of ≤2.7%. The limits of detection and quantitation of the method in cabbage and cauliflower were 1.3, 1.7 and 4.3, 6.2 µg kg-1 , respectively. The residual levels and dissipation kinetics of buprofezin 25% wettabe powder in cabbage and cauliflower cultivated under open field conditions was investigated at the single (T1) and double (T2) recommended rates of application. Half-life periods were found to be 1.73 and 2.1 days in cabbage, whereas in cauliflower, these values were 1.85 and 2.36 days at T1 and T2, respectively. Based on the dissipation study, and the maximum residue limit value of 0.05 mg kg-1 , the proposed pre-harvest interval of buprofezin in cabbage was 3-6 days and that in cauliflower was 4-10 days. The results showed that buprofezin is safe for application at both recommended application rates.

Clinical and economic impact of the taurolidine lock on home parenteral nutrition.

INTRODUCTION: catheter-related bloodstream infections (CRBSI) are one of the most serious concerns in patients on home parenteral nutrition (HPN) which involve high morbidity and cost for the healthcare system. In the last years, taurolidine lock has proven to be beneficial in the prevention of CRBSI; however, the evidence of its efficiency is limited. OBJECTIVE: to determine if taurolidine lock is a cost-effective intervention in patients on HPN. MATERIALS AND METHODS: retrospective study in patients on HPN with taurolidine lock. We compared the CRBSI rate and cost of its complications before and during taurolidine lock. RESULTS: thirteen patients, six (46%) males and seven (54%) females, with a mean age of 61.08 (SD = 14.18) years received taurolidine lock. The total days of catheterization pre and per-taurolidine were 12,186 and 5,293, respectively. The underlying disease was benign in five patients (38.5%) and malignant in eight (61.5%). The CRBSI rate pre vs per-taurolidine was 3.12 vs 0.76 episodes per 1,000 catheter days (p = 0.0058). When the indication was a high CRBSI rate, this was 9.72 vs 0.39 (p < 0.001) in pre and per-taurolidine period respectively. No differences have been observed in the occlusion rates. None of the patients reported any adverse effects. The total cost of CRBSI in the pre-taurolidine period was 151,264.14 euros vs 24,331.19 euros in the per-taurolidine period. CONCLUSIONS: our study shows that taurolidine lock is a cost-effective intervention in patients on HPN with high risk of CRBSI.

Randomised clinical trial: 2% taurolidine versus 0.9% saline locking in patients on home parenteral nutrition.

BACKGROUND: The catheter lock solutions 2% taurolidine and 0.9% saline are both used to prevent catheter-related bloodstream infections (CRBSIs) in home parenteral nutrition patients. AIMS: To compare the effectiveness and safety of taurolidine and saline. METHODS: This multicentre double-blinded trial randomly assigned home parenteral nutrition patients to use either 2% taurolidine or 0.9% saline for 1 year. Patients were stratified in a new catheter group and a pre-existing catheter group. Primary outcome was the rate of CRBSIs/1000 catheter days in the new catheter group and pre-existing catheter group, separately. RESULTS: We randomised 105 patients, of which 102 were analysed as modified intention-to-treat population. In the new catheter group, rates of CRBSIs/1000 catheter days were 0.29 and 1.49 in the taurolidine and saline arm respectively (relative risk, 0.20; 95% CI, 0.04-0.71; P = 0.009). In the pre-existing catheter group, rates of CRBSIs/1000 catheter days were 0.39 and 1.32 in the taurolidine and saline arm respectively (relative risk, 0.30; 95% CI, 0.03-1.82; P = 0.25). Excluding one outlier patient in the taurolidine arm, mean costs per patient were $1865 for taurolidine and $4454 for saline (P = 0.03). Drug-related adverse events were rare and generally mild. CONCLUSIONS: In the new catheter group, taurolidine showed a clear decrease in CRBSI rate. In the pre-existing catheter group, no superiority of taurolidine could be demonstrated, most likely due to underpowering. Overall, taurolidine reduced the risk for CRBSIs by more than four times. Given its favourable safety and cost profile, taurolidine locking should be considered as an additional strategy to prevent CRBSIs. TRIAL REGISTRATION: Clinicaltrials.gov, identifier: NCT01826526.

Taurolidine-based catheter lock regimen significantly reduces overall costs, infection, and dysfunction rates of tunneled hemodialysis catheters.

Catheter-related infections and dysfunction are the main catheter complications causing morbidity and mortality in hemodialysis patients. However, there are no consistent data for the choice of catheter lock solutions for tunneled hemodialysis lines. In this prospective, multicenter, randomized, controlled trial, two lock regimens using three commercial catheter lock solutions were compared in 106 hemodialysis patients with a newly inserted tunneled central catheter. In the taurolidine group, TauroLock™-Hep500 was used twice per week and TauroLock™-U25,000 once a week. In the citrate group, a four percent citrate solution was used after each dialysis. Both groups were compared regarding catheter-related infections, catheter dysfunction, and costs. Over a period of 15,690 catheter days, six catheter-related infections occurred in six of 52 patients in the taurolidine group, but 18 occurred in 13 of 54 patients in the citrate group, corresponding to 0.67 and 2.7 episodes of catheter-related infections per 1000 catheter days, respectively (Incidence Rate Ratio 0.25, 95% confidence interval, 0.09 to 0.63). Catheter dysfunction rates were significantly lower in the taurolidine group (18.7 vs. 44.3/1000 catheter days) and alteplase rescue significantly more frequent in the citrate group (9.8 vs. 3.8/1000 catheter days). These differences provided significant catheter-related cost savings of 43% in the taurolidine group vs. citrate group when overall expenses per patient and year were compared. Thus, use of taurolidine-based catheter lock solutions containing heparin and urokinase significantly reduced complications related to tunneled hemodialysis catheters when compared to four percent citrate solution and was overall more cost-efficient.

Taurolidine-citrate-heparin lock reduces catheter-related bloodstream infections in intestinal failure patients dependent on home parenteral support: a randomized, placebo-controlled trial.

Background: In patients with intestinal failure who are receiving home parenteral support (HPS), catheter-related bloodstream infections (CRBSIs) inflict health impairment and high costs.Objective: This study investigates the efficacy and safety of the antimicrobial catheter lock solution, taurolidine-citrate-heparin, compared with heparin 100 IE/mL on CRBSI occurrence.Design: Forty-one high-risk patients receiving HPS followed in a tertiary HPS unit were randomly assigned in a double-blinded, placebo-controlled trial. External, stratified randomization was performed according to age, sex, and prior CRBSI incidence. The prior CRBSI incidence in the study population was 2.4 episodes/1000 central venous catheter (CVC) days [95% Poisson confidence limits (CLs): 2.12, 2.71 episodes/1000 CVC days]. The maximum treatment period was 2 y or until occurrence of a CRBSI or right-censoring because of CVC removal. The exact permutation tests were used to calculate P values for the log-rank tests.Results: Twenty patients received the taurolidine-citrate-heparin lock and 21 received the heparin lock, with 9622 and 6956 treatment days, respectively. In the taurolidine-citrate-heparin arm, no CRBSIs occurred, whereas 7 CRBSIs occurred in the heparin arm, with an incidence of 1.0/1000 CVC days (95% Poisson CLs: 0.4, 2.07/1000 CVC days; P = 0.005). The CVC removal rates were 0.52/1000 CVC days (95% Poisson CLs: 0.17, 1.21/1000 CVC days) and 1.72/1000 CVC days (95% Poisson CLs: 0.89, 3.0/1000 CVC days) in the taurolidine-citrate-heparin and heparin arm, respectively, tending to prolong CVC survival in the taurolidine arm (P = 0.06). Costs per treatment year were lower in the taurolidine arm (€2348) than in the heparin arm (€6744) owing to fewer admission days related to treating CVC-related complications (P = 0.02).Conclusions: In patients with intestinal failure who are life dependent on HPS, the taurolidine-citrate-heparin catheter lock demonstrates a clinically substantial and cost-beneficial reduction of CRBSI occurrence in a high-risk population compared with heparin. This trial was registered at clinicaltrials.gov as NCT01948245.

In Vitro Assessment of the Antimicrobial Efficacy of Optimized Nitroglycerin-Citrate-Ethanol as a Nonantibiotic, Antimicrobial Catheter Lock Solution for Prevention of Central Line-Associated Bloodstream Infections.

The rapid, broad-spectrum, biofilm-eradicating activity of the combination of 0.01% nitroglycerin, 7% citrate, and 20% ethanol and its potential as a nonantibiotic, antimicrobial catheter lock solution (ACLS) were previously reported. Here, a nitroglycerin-citrate-ethanol (NiCE) ACLS optimized for clinical assessment was developed by reducing the nitroglycerin and citrate concentrations and increasing the ethanol concentration. Biofilm-eradicating activity was sustained when the ethanol concentration was increased from 20 to 22% which fully compensated for reducing the citrate concentration from 7% to 4% as well as the nitroglycerin concentration from 0.01% to 0.0015% or 0.003%. The optimized formulations demonstrated complete and rapid (2 h) eradication of methicillin-resistant Staphylococcus aureus (MRSA), vancomycin-intermediate Staphylococcus aureus (VISA), methicillin-resistant Staphylococcus epidermidis (MRSE), vancomycin-resistant enterococci (VRE), multidrug-resistant (MDR) Pseudomonas aeruginosa, MDR Klebsiella pneumoniae, MDR Enterobacter cloacae, MDR Acinetobacter baumannii, MDR Escherichia coli, MDR Stenotrophomonas maltophilia, Candida albicans, and Candida glabrata biofilms. The optimized NiCE lock solutions demonstrated anticoagulant activities comparable to those of heparin lock solutions. NiCE lock solution was significantly more effective than taurolidine-citrate-heparin lock solution in eradicating biofilms of Staphylococcus aureus and Candida glabrata The optimized, nonantibiotic, heparin-free NiCE lock solution demonstrates rapid broad-spectrum biofilm eradication as well as effective anticoagulant activity, making NiCE a high-quality ACLS candidate for clinical assessment.

Residual determination and risk assessment of buprofezin in plum (Prunus domestica) grown in open-field conditions following the application of three different formulations.

This study was conducted to characterize the residual level and perform a risk assessment on buprofezin formulated as an emulsifiable concentrate, wettable powder, and suspension concentrate over various treatment schedules in plum (Prunus domestica). The samples were extracted with an AOAC quick, easy, cheap, effective, rugged, and safe, 'QuEChERS', method after major modifications. As intrinsic interferences were observed in blank plum samples following dispersive-solid phase extraction (consisting of primary secondary amine and C18 sorbents), amino cartridges were used for solid-phase extraction. Analysis was carried out using liquid chromatography with diode array detection and confirmed by liquid chromatography-tandem mass spectrometry. The method showed excellent linearity with determination coefficient (R2 = 1) and satisfactory recoveries (at two spiking levels, 0.5 and 2.5 mg/kg) between 90.98 and 94.74% with relative standard deviation (RSD) ≤8%. The limit of quantification (0.05 mg/kg) was considerably lower than the maximum residue limit (2 mg/kg) set by the Codex Alimentarius. Absolute residue levels for emulsifiable concentrates were highest, perhaps owing to the dilution rate and adjuvant. Notably, all formulation residues were lower than the maximum residue limit, and safety data proved that the fruits are safe for consumers. Copyright © 2016 John Wiley & Sons, Ltd.

A new haemodialysis catheter-locking agent reduces infections in haemodialysis patients.

BACKGROUND: Intravenous catheters for haemodialysis increase the risk of sepsis. This study investigates the use of a taurolidine/citrate catheter-locking agent for patients receiving hospital-based haemodialysis, auditing the number and cost of infections before and after its introduction. METHODS: The incidence and cost of treatment of catheter sepsis occurring in all patients receiving haemodialysis via a line were investigated over 6-month periods before and after introducing the taurolidine/citrate line-locking agent. RESULTS: A reduction of 4.62 infections per 1000 catheter days, or 88.5%, was shown after the introduction of the new line-locking agent. The total costs of line infections in the first 6 months were 52,500 euros, (41,000 pounds); after the introduction of the taurolidine/citrate locks, these reduced to 33,300 euros, (26, 000 pounds), a reduction of 19,200 euros (15,000 pounds). CONCLUSIONS: The use of a taurolidine/citrate haemodialysis catheter-locking agent in our haemodialysis population has significantly reduced the line sepsis rate, with a positive impact on morbidity, mortality and cost.

Oxygen wastage of stunned myocardium in vivo is due to an increased oxygen cost of contractility and a decreased myofibrillar efficiency.

OBJECTIVE: We investigated whether an increased oxygen cost of contractility and/or a decreased myofibrillar efficiency contribute to oxygen wastage of stunned myocardium. Because Ca(2+)-sensitizers may increase myofibrillar Ca(2+)-sensitivity without increasing cross-bridge cycling, we also investigated whether EMD 60263 restores myofibrillar efficiency and/or the oxygen cost of contractility. METHODS: Regional fiber stress and strain were calculated from mesomyocardially implanted ultrasound crystals and left ventricular pressure in anesthetized pigs (n=18). Regional myocardial oxygen consumption (MVO(2)) was measured before contractility (end-systolic elastance, E(es)) and total myofibrillar work (stress-strain area, SSA) were determined from stress-strain relationships. Atrial pacing at three heart rates and two doses of dobutamine were used to vary SSA and E(es), respectively. After stunning (two times 10-min ischemia followed by 30-min reperfusion), measurements were repeated following infusion of saline (n=8) or EMD 60263 (1.5 mg.kg(-1) i.v., n=10). Linear regression was performed using: MVO(2)=alpha.SSA+beta.E(es)+gamma.HR(-1) (alpha(-1), myofibrillar efficiency; beta, oxygen cost of contractility; and gamma, basal metabolism/min). RESULTS: Stunning decreased SSA by 57% and E(es) by 64%, without affecting MVO(2), while increasing alpha by 71% and beta by 134%, without affecting gamma. From the wasted oxygen, 72% was used for myofibrillar work and 18% for excitation-contraction coupling. EMD 60263 restored both alpha and beta. CONCLUSIONS: Oxygen wastage in stunning is predominantly caused by a decreased myofibrillar efficiency and to a lesser extent by an increased oxygen cost of contractility. Considering that EMD 60263 reversed both causes of oxygen wastage, it is most likely that this drug increases myofibrillar Ca(2+)-sensitivity without increasing myofibrillar cross-bridge cycling.

Economy of contraction of cardiomyocytes as influenced by different positive inotropic interventions.

In the present study the effects of the novel cardiotonic agent EMD-57033 on contraction and energetic demand of isolated, electrically stimulated cardiomyocytes were investigated and compared with the effects of enhancement of extracellular calcium and of the beta-mimetic isoproterenol. In a specially designed setup [H. Rose, K.H. Strotmann, S. Pöpping, Y. Fischer, D. Kulsch, and H. Kammermeier. Am. J. Physiol. 261 (Heart Circ. Physiol. 30): H1329-H1334, 1991] parameters of contractile behavior and metabolic demand (O2 consumption) of isolated cardiac myocytes were measured. For a given enhancement of contractile performance (cell shortening) the increase in energetic demand (VO2) after application of EMD-57033 were markedly lower than on treatment with elevated extracellular Ca2+ concentration or with isoproterenol. This economization of positive inotropic effects was proposed to be due to two factors. First, stimulation-related ion cycling was only slightly enhanced with marked increase in contraction amplitude after application of EMD-57033. Second, calcium sensitization reflected in a leftward shift of the calcium concentration needed for half-maximum force development could be interpreted to be mediated by modulation of the cross-bridge dynamics of the myofilaments, where reduction of the switch-off rate of the cross bridges and prolongation of their force-generating states were presumed to be involved. Lowered pH (7.0) decreased economy of contraction. EMD-57033 restored contraction amplitude and economy of contraction at lowered pH.

The calcium sensitizer EMD 53998 antagonizes phosphate-induced increases in energy cost of isometric tension in cardiac skinned fibres.

We have investigated whether a Ca(2+)-sensitizing substance, the thiadiazinone derivative EMD 53998, can alter the ratio of ATPase activity to force, i.e. the tension cost in skinned fibres of swine cardiac trabecula in which the tension cost was increased by inorganic phosphate. In the presence of 10 mM inorganic phosphate (Pi) and thapsigargin 20 microM, EMD 53998 reduced the energy cost of isometric tension over the entire range of activating Ca2+ concentrations, resulting in a consistent change in slope (approximately 20% decrease) of the ATPase/force relation. We confirmed that in the absence of added phosphate and at maximal Ca2+ activation EMD 53998 had little if any effect on tension cost. We had previously reported that the effects of EMD 53998 and Pi on calcium sensitivity and maximum isometric tension are mutually antagonistic and our new energy data now support the proposal that EMD 53998 functionally antagonizes the effects of Pi on crossbridges. The decrease in the slope of the relation between ATPase and force caused by EMD 53998 may be interpreted to reflect either a decrease in the rate of 'detachment' (g(app)) of crossbridges or an increase in average force per crossbridge, as predicted by classical crossbridge models. Since the Pi release step of the crossbridge cycle is associated with the rate of 'attachment' (f(app)) rather than g(app), we conclude that the decrease in tension cost with EMD 53998 most likely reflects an increased force per crossbridge.(ABSTRACT TRUNCATED AT 250 WORDS)

A new cardiotonic drug reduces the energy cost of active tension in cardiac muscle.

The novel thiadiazinone EMD 57033 (EMD) increases the calcium responsiveness of the contractile proteins in cardiac muscle. In skinned ventricular trabeculae isolated from guinea-pig heart, application of 10 microM EMD shifted the curve relating isometric tension to the applied calcium concentration to the left and increased maximal tension by 15%. In intact trabeculae, the rate of heat production, an indicator of the rate of ATP hydrolysis in the steady state, and isometric tension were measured at 37 degrees C. Both the thiadiazinone (EMD; 2.5, 5, and 10 microM) and the cardiac glycoside dihydro-ouabain (DHO; 5, 10, and 20 microM) produced a concentration-dependent increase in contraction-related heart production (Hc) and in the tension time integral of isometric contractions (Tti). In the presence of EMD the energy cost of active tension (Hc/Tti) was substantially decreased as compared to control conditions. The energy cost of the positive inotropic effect of EMD (43.8 mW N-1 cm-1) was only about half as large as the energy cost of the positive inotropic effect of DHO (88.4 mW N-1 cm-1). It is concluded that EMD causes a change in cross-bridge kinetics that increases the contractility of cardiac muscle and improves the economy of chemo-mechanical energy transduction. Our results suggest that EMD 57033 represents a prototype of a new class of cardiotonic agents that might be potentially useful in the therapy of congestive heart failure.