Efficacy and safety of tyrosine kinase inhibitors alone or in combination with radiation therapy for metastatic renal cell carcinoma: A protocol for evidence-based systematic review and Bayesian network meta-analysis.

BACKGROUND: Given the lack of evidence for survival benefit in patients with metastatic renal cell carcinoma from the addition of radiation therapy to tyrosine kinase inhibitor therapy, this Bayesian network meta-analysis aimed to evaluate survival outcomes in patients receiving radiation therapy plus tyrosine kinase inhibitor therapy. METHODS: The preferred reporting items for systematic reviews and meta-analyses reporting guidelines were followed to conduct this study. The electronic databases of PubMed, Cochrane Library, EMBASE, and Web of Science were searched from the inception to August 2021. All phase III clinical trials that reported the outcomes of tyrosine kinase inhibitor with radiation therapy compared with those of tyrosine kinase inhibitor or radiation therapy alone for patients with metastatic renal cell carcinoma were considered eligible for inclusion in this meta-analysis. Overall survival as the primary outcome of interest, and adverse events as secondary outcome of interest were recorded for meta-analysis. RESULTS: A Bayesian network meta-analysis is an appropriate statistical method to compare all treatment options by statistically simulating the estimated results of a comprehensive trial, and to compare treatments by common and associated comparators. In addition, Bayesian network meta-analysis can produce ranking probabilities of treatments, which may contribute to clinicians' clinical decision-making.

Determination of azoxystrobin, topramezone, acetamiprid, fluometuron and folpet in their commercially available pesticide formulations by liquid chromatography.

A rapid, simple, precise and accurate high performance liquid chromatographic (HPLC) analytical method was developed and validated for the determination of the active substances (a.s.) azoxystrobin, topramezone, acetamiprid, fluometuron and folpet in their respective commercially available formulations. The method was used for the analysis of samples under the frame of the national quality control program of plant protection products in the Greek market. Chromatographic separation of the active substances from additives and co-formulants is achieved using isocratic elution with acetonitrile and 0.1% phosphoric acid solution (60:40 v/v) at a flow rate of 0.4 mL min-1 on a C18 monolithic column (Chromolith Performance-RP18e 100 × 4.6 mm) and UV detection at 230 nm. Validation parameters of the method fulfilled acceptability criteria. Recovery of all individual compounds was in the range 97.8-100.9%. Precision expressed as relative standard deviation was lower than the theoretical values of the modified Horwitz equation. Correlation coefficients of linearity of response were better than 0.999. The benefits of the proposed method are significant reduction in analysis time and total cost since all analytes were determined with the same extraction procedures and chromatographic system. Analysis of real samples for all active ingredients confirmed fitness for purpose of the suggested method.

Real-world 2-year outcome of atrial fibrillation treatment with dabigatran, apixaban, and rivaroxaban in patients with and without chronic kidney disease.

Patients with non-valvular atrial fibrillation (NVAF) and chronic kidney disease (CKD) are at increased risk of stroke and bleeding. Although direct oral anticoagulant (DOAC) trials excluded patients with severe CKD, a growing portion of CKD patients have been starting DOACs and limited data from real-world outcome in this high-risk setting are available. The INSigHT registry included 632 consecutive NVAF patients that started apixaban (256 patients, 41%), dabigatran (245, 39%) and rivaroxaban (131, 20%) between 2012 and 2015. Based on creatinine clearance, two sub-cohorts were defined: (1) non-CKD group (CrCl 60-89 mL/min, 413 patients) and (2) CKD group (15-59 ml/min, 219). Compared to non-CKD patients, those with CKD, were at higher ischemic (CHA2DS2-VASc 4.5 vs 2.9, p < 0.001) and hemorrhagic risk (HAS-BLED 2.4 vs 1.8, p < 0.001). At 2-year follow-up, the overall ISTH-major bleeding and thromboembolic event rates were 5.2% and 2.3% and no significant difference between non-CKD and CKD patients for both efficacy and safety endpoints were observed. In non-CKD patients, the 2-year ISTH-major bleeding rates were higher in rivaroxaban group (HR 2.9, 95% CI 1.1-7.3; p = 0.047) while dabigatran showed non-significant excess in thromboembolic events (HR 4.3, 95% CI 0.9-20.8; p = 0.068). In CKD patients, a significantly higher rate of thromboembolic events was observed in rivaroxaban (HR 6.3, 95% CI 1.1-38.1; p = 0.044). This real-world, non-insurance database registry shows remarkable 2-year safety and efficacy profile of DOACs even in patients with moderate to severe CKD. Head to head differences between DOACs are exploratory, hypothesis generating and warrant further investigation in larger studies.

A Review on the New and Old Anticoagulants.

Anticoagulants serve as the primary strategy for the prevention and treatment of both arterial and venous thromboembolism. Anticoagulants disrupt coagulation by interfering at various points in the coagulation cascade. This class of medications does not lyse clots that already exist; rather, it prevents thrombus formation and prevents or slows the extension of an existing clot. For decades, the standard therapy for patients requiring oral anticoagulation was warfarin. However, due to some of the shortcomings of warfarin, including the need for continuous routine monitoring, longtime onset and offset of anticoagulation effect, major food and drug interactions, and high incidence of bleeding, newer agents, termed direct oral anticoagulants, or DOACs were developed. This article will provide a review of clinically important information regarding the most commonly used anticoagulants and their reversal agents.

Hydroxy-fipronil is a new urinary biomarker of exposure to fipronil.

Occupational medical surveillance is highly desirable in manufacturing facilities where exposure to chemicals is significant. The insecticide fipronil is generally considered safe for humans but with increasing use, exposure to fipronil is of concern. Identification of urinary metabolites of fipronil may allow development of affordable, cheap and rapid procedures for human exposure evaluation. In this study we developed a fast and easy approach for synthesis of hydroxy-fipronil, a potential urinary metabolite of fipronil. This standard was used to develop a sensitive analytical LC-MS/MS method with a limit of quantification (LOQ) of 0.4ng/mL. Fipronil sulfone, a known metabolite, and hydroxy-fipronil were quantified in urine samples from rats treated with a fipronil containing diet. Fipronil sulfone concentration centered around 20ng/mL, while the concentration of hydroxy-fipronil was dose-dependent ranging in 10-10,000ng/mL and thus being a more sensitive marker of fipronil exposure. A fipronil immunoassay with cross-reactivity to hydroxy-fipronil showed a good correlation in signal intensity with LC-MS data. It was also used to demonstrate the applicability of the method for sample screening in the evaluation of exposure levels.

Passage of fiproles and imidacloprid from urban pest control uses through wastewater treatment plants in northern California, USA.

Urban pest control insecticides-specifically fipronil and its 4 major degradates (fipronil sulfone, sulfide, desulfinyl, and amide), as well as imidacloprid-were monitored during drought conditions in 8 San Francisco Bay (San Francisco, CA, USA) wastewater treatment plants (WWTPs). In influent and effluent, ubiquitous detections were obtained in units of ng/L for fipronil (13-88 ng/L), fipronil sulfone (1-28 ng/L), fipronil sulfide (1-5 ng/L), and imidacloprid (58-306 ng/L). Partitioning was also investigated; in influent, 100% of imidacloprid and 62 ± 9% of total fiproles (fipronil and degradates) were present in the dissolved state, with the balance being bound to filter-removable particulates. Targeted insecticides persisted during wastewater treatment, regardless of treatment technology utilized (imidacloprid: 93 ± 17%; total fiproles: 65 ± 11% remaining), with partitioning into sludge (3.7-151.1 µg/kg dry wt as fipronil) accounting for minor losses of total fiproles entering WWTPs. The load of total fiproles was fairly consistent across the facilities but fiprole speciation varied. This first regional study on fiprole and imidacloprid occurrences in raw and treated California sewage revealed ubiquity and marked persistence to conventional treatment of both phenylpyrazole and neonicotinoid compounds. Flea and tick control agents for pets are identified as potential sources of pesticides in sewage meriting further investigation and inclusion in chemical-specific risk assessments. Environ Toxicol Chem 2017;36:1473-1482. © 2016 SETAC.

Determination of riociguat and its major human metabolite M-1 in human plasma by stable-isotope dilution LCMS/MS.

BACKGROUND: Riociguat (BAY 63-2521) is an oral NO-independent as well as NO-synergistic stimulator of soluble guanylate cyclase (sGC) for the treatment of pulmonary hypertension. BAY 60-4552 (M-1) is its pharmacologically active major metabolite. An isotope dilution LC-ESI-MS/MS method has been developed and validated for the simultaneous determination of riociguat and M-1 in lithium heparinized human plasma. RESULTS: The validated concentration range covers 0.500 µg/l (LLOQ) to 100 µg/l (ULOQ) for both analytes. Interassay accuracy and precision (%CV) for both analytes ranged from 92.7 to 111% and from 2.61 to 9.89%, respectively. CONCLUSION: The method proved to be selective, specific, sufficiently sensitive, highly reproducible and robust for the analysis of large numbers of samples.

Isotopic fingerprinting for the authenticity control of crop protection active compounds using the representative insecticide Fipronil.

Isotopic fingerprinting was evaluated for its potential to generate characteristic fingerprints of crop protection products in an extensive survey, using the insecticide Fipronil. One hundred and twenty batches of Fipronil from the BASF production site in France were analyzed for the isotope ratios of δ(13)C, δ(15)N, and δ(34)S. Samples spanned a production time of four years and were analyzed by elemental analysis, coupled to isotope ratio mass spectrometry (EA/IRMS). A number of Fipronil samples from other sources were analyzed in the same manner and were compared to the samples from BASF by means of multivariate data analysis. The isotopic fingerprint was sufficiently specific to differentiate between Fipronil from BASF production and Fipronil from other producers. This suggests that isotopic fingerprinting is suitable for the authenticity control of active compounds in crop protection products. It is anticipated that this technique will deliver great benefit in the defense against counterfeits and illegal parallel imports.

Safety and efficacy of high-dose fomepizole compared with ethanol as therapy for ethylene glycol intoxication in cats.

OBJECTIVE: To determine the safety and efficacy of high-dose fomepizole compared with ethanol (EtOH) in cats with ethylene glycol (EG) toxicosis. DESIGN: Prospective study. SETTING: University veterinary research laboratory. ANIMALS: Thirteen cats. INTERVENTIONS: Two cats received injections of high-dose fomepizole (Study 1). Three cats received lethal doses of EG and fomepizole treatment was initiated 1, 2, or 3 hours later (Study 2). Eight cats received a lethal dose of EG and were treated with fomepizole or EtOH (Study 3). Cats treated with fomepizole received 125 mg/kg IV initially, then 31.25 mg/kg at 12, 24, and 36 hours. Cats treated with EtOH received 5 mL of 20% EtOH/kg IV initially, then every 6 hours for 5 treatments, then every 8 hours for 4 treatments. Cats also received fluids and supportive therapy as needed. MEASUREMENTS AND MAIN RESULTS: Clinical signs were monitored and serial blood analyses performed. Cats receiving fomepizole experienced mild sedation but no biochemical evidence of toxicity. Cats receiving fomepizole for EG intoxication survived if therapy was initiated within 3 hours of EG ingestion. One of the 6 developed acute renal failure (ARF) but survived. Only 1 of the 3 cats treated with EtOH 3 hours following EG ingestion survived; 2 developed ARF and were euthanized. Cats treated 4 hours following EG ingestion developed ARF, whether treated with EtOH or fomepizole. CONCLUSIONS: Fomepizole is safe when administered to cats in high doses, prevents EG-induced fatal ARF when therapy is instituted within 3 hours of EG ingestion, and is more effective than treatment with EtOH.

Celecoxib to prevent restenosis--results from the COREA-TAXUS trial.

Celecoxib inhibits Akt, which is stimulated during restenosis. Cell and animal studies showed that celecoxib inhibited Akt stimulation and restenosis. Recently, the COREA-TAXUS (Effect of Celecoxib on Restenosis after Coronary Angioplasty with Taxus stent) trial was performed in subjects with angina or a positive-stress test receiving paclitaxel-eluting stents. The primary end point at 6 months was the in-stent, late luminal loss, which was 0.49 mm in the celecoxib-treated group; less than the 0.75 mm in the group not treated with celecoxib. The rate of revascularisation of the target lesion was lower in celecoxib-treated subjects (5%) than in the untreated subjects (15%). In conclusion, this is an excellent demonstration of translating a mechanism of action of a drug into a clinical use.

Determination of celecoxib in human plasma and breast milk by high-performance liquid chromatographic assay.

A rapid and simple HPLC assay was developed for the determination of celecoxib in human plasma and breast milk. After proteins were precipitated with acetonitrile, celecoxib was resolved on a C18 column and detected by UV detection at 254 nm. Standard curves were linear over the concentration range 10-2000 microg/L (r(2)>0.99). Bias was

[An experimental tool essential for the evaluation of insecticides: the testing huts]. / Un outil expérimental indispensable à l'évaluation des insecticides: les cases-pièges.

The following study analyses the potentialities of the experimental huts built in M'be Valley (Côte d'Ivoire) where the evaluations of the insecticide products have been carried out for many years in line with the WHOPES protocol on the methodology of stage 2 assays. Starting a testing station first requires a good knowledge of the sensitivity of Anopheles gambiae to the main insecticide families. Then thanks to the experimental huts the efficacy of the various means of treatment can be compared with the one in untreated huts; this study focuses on house spraying using 100 mg a.i./m2 and bednets impregnated with lambda-cyhalothrin at a dose of 15 mg a.i./m2. The fipronil used in house spraying doesn't show any repellent effect, however it does have an irritating effect that increases the natural exophily of An. gambiae females entering the testing huts. The blood-feeding rate recorded in the treated huts was reduced to 24% and to 38% mortality rate consisting mainly of a 24 hours delayed mortality. The bednets treated with lambda-cyhalothrin have greatly reduced the contact between man and vector since the entry rate of An. gambiae females was cut down by 68% compared to the control. The exophily of this anopheles was twofold greater with the impregnated bednets and the blood-feeding rate reduced to 47%. Finally the global mortality rate, two thirds of immediate mortality, one third of delayed mortality, reached 35%. The experimental huts in the M'be Valley therefore provide essential information regarding the selection of the most efficacious insecticides against An. gambiae. This experimental method must be extended to other sites in order to finalize ever more selective and appropriate means of control against nuisance and disease-vector mosquitoes.

[Sanitary standardization of 1-carbamoyl-3(5)-methylpyrazole, N-hydroxymethyl-3(5)-methylpyrazole and 4-amino-1,2,4-triazole in the water of reservoirs]. / Gigienicheskoe normirovanie 1-karbamoil-3(5)-metilpirazola, N-gidroksimetil-3(5)-metilpirazola i 4-amino-1,2,4-triazola v vode vodoemov.

Since there is a problem in the sanitary protection of water reservoirs, nitrification inhibitors (NI), such as CMP, HMMP, ATG, were tested for their effects on the organoleptic properties and sanitary regimen of model water basins. The threshold concentrations of the inhibitors were found to be 0.49, 230, and 229 mg/l, respectively. The agents were classified as highly stable. They failed to affect on self-clearance. In chronic intoxication, the inactive doses were 0.128 mg/kg for CMP, 0.165 mg/kg for HMMP, and 1.36 mg/kg for ATG (1/1000 of LD50). The maximum allowable water concentrations were 0.01, 0.01, and 0.1 mg/l, respectively (in the context of complex sanitary standardization). The limiting hazard index was sanitarily toxicological (Hazard Class 3).

Evaluation of efficacy of selamectin and fipronil against Ctenocephalides felis in cats.

OBJECTIVE: To evaluate efficacy of monthly administration of selamectin and fipronil against Ctenocephalides felis in cats. DESIGN: Randomized controlled trial. ANIMALS: 36 healthy cats. PROCEDURE: Cats known to be free of fleas were infested with 100 unfed adult fleas on days -28 and -21. On days 0, 30, 60, 90, and 120, sixteen cats (8 pairs/treatment group) were treated by topical administration of selamectin (6 mg/kg [2.7 mg/lb] of body weight) or fipronil (7.5 mg/kg [3.4 mg/lb]). Four control cats (2 pairs) were not treated. On day -6 and every 2 weeks after initial treatment, comb counts were performed to detect fleas. Flea counts were recorded, and fleas (< or =50) that had been removed were replaced onto the cat. On day 89, fleas were not replaced. On day 91 and every 7 days until the end of the study (day 150), cats were challenged with 20 adult fleas. Flea counts were compared between and within treatments. RESULTS: 14 days after treatment, geometric mean flea counts were reduced by 71.2% by fipronil treatment and 35.3% by selamectin treatment. Both treatments resulted in 97 to 98% reduction in flea counts on day 29 and 99.8 to 100% reduction from day 44 to the end of the study. CONCLUSIONS AND CLINICAL RELEVANCE: Selamectin is as effective as fipronil in treating infestation in cats housed for 3 months in a flea-infested environment under conditions known to support the flea life cycle and in protecting against subsequent weekly challenges with C felis for an additional 2 months.

Evaluation of efficacy of selamectin, fipronil, and imidacloprid against Ctenocephalides felis in dogs.

OBJECTIVE: To evaluate efficacy of monthly administration of selamectin, fipronil, and imidacloprid against Ctenocephalides felis in dogs. DESIGN: Randomized controlled trial. ANIMALS: 44 healthy dogs. PROCEDURE: Dogs known to be free of fleas were infested with 100 unfed adult fleas on days -28 and -21. On days 0, 30, 60, 90, and 120, dogs (12/group) were treated by topical administration of selamectin (6 mg/kg [2.7 mg/lb] of body weight), fipronil (7.5 mg/kg [3.4 mg/lb]), or imidacloprid (10 mg/kg [4.5 mg/lb]); 8 untreated dogs were used as controls. On day -6 and every 2 weeks after initial treatment, comb counts of viable adult fleas were made, and fleas (< or =50/dog) were replaced onto the dog from which they were removed. On day 89, fleas were not replaced. On day 91 and every 7 days until the end of the study, dogs were challenged with 20 adult fleas. RESULTS: 14 days after initial treatment, geometric mean flea counts were reduced by 97.5 to 99.1 % for all treatments, compared with pretreatment counts on day -6. Selamectin, fipronil, and imidacloprid reduced geometric mean flea counts by 99.7 to 100% from day 29 to the end of the study. CONCLUSIONS AND CLINICAL RELEVANCE: Selamectin is as effective as fipronil and imidacloprid in reducing C felis infestation in dogs housed for 3 months in a flea-infested environment under conditions known to support the flea life cycle, and in protecting against subsequent weekly challenges with C felis for an additional 2 months.