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An Old Drug for a New Application: Carbazochrome-Sodium-Sulfonate in HHT
... Considering the first sensitivity analysis, Table 5 In the second sensitivity analysis, after excluding patients with head injuries (n = 66), 72 patients remained: 22 and 50 in the CSS + TXA and TXA groups, respectively. ...
... CSS is one of the oldest drugs that has been used for various indications, such as in surgical settings, 7,8,10,19,20 gastrointestinal bleeding, 4,5 trauma, 6 pulmonary hemorrhage, 9 refractory chronic prostatitis 21 , hereditary hemorrhagic telangiectasia, 22 or dengue vascular permeability. 23,24 Accordingly, CSS has applications other than as a hemostatic agent. ...
... 23,24 Accordingly, CSS has applications other than as a hemostatic agent. [21][22][23][24] It can be safely used by patients with certain medical conditions. Additionally, CSS is economically beneficial 4 ; 100 mg of CSS costs 88 Japanese Yen, which is <1 USD. 25 Accordingly, the use of this low-cost drug could reduce the requirement for blood transfusion, making it an attractive option. ...
Aim
Reducing the blood transfusion volume is important in severe trauma. We hypothesized that carbazochrome sodium sulfonate (CSS) combined with tranexamic acid (TXA) would reduce blood transfusions in severe trauma.
Methods
From April 2017 to March 2023, data were collected from patients (aged ≥16 years) admitted to our hospital for trauma and administered packed red blood cells (pRBC) and plasma transfusions within 12 h postinjury. Patients infused with CSS and TXA (CSS + TXA group) were compared with those infused with TXA alone (TXA group). The outcomes were blood product transfusion volumes within and after 24 h, the number of patients receiving >6 units of pRBC transfusion after 24 h, duration of intensive care unit and in‐hospital stays, and 28‐day in‐hospital mortality.
Results
In total, 138 patients were included in the study. In the univariate analyses, the CSS + TXA group (n = 62) showed a significant reduction in the total pRBC transfusion volume, in‐hospital days, and number of patients receiving >6 units of pRBCs in the delayed phase. Based on the multivariate logistics regression analysis, only the CSS + TXA group had a significantly lower adjusted odds ratio for receiving >6 units of pRBC transfusion after 24 h. During the in‐hospital days, the CSS + TXA group did not experience an increased incidence of major complications when compared with the TXA group.
Conclusion
In patients with trauma, treatment with CSS with TXA may reduce the requirement for blood transfusion after 24 h. Moreover, this treatment can improve admission outcomes without increasing complications.
... There exist medicinal substances based on NAH (Figure 1), such as nitrofurazone (broad-spectrum topical antibacterial agent) [24]; nitrofurantoin (oral antibacterial agent for treating gastrointestinal tract infections) [25]; nifuroxazide (antibacterial agent of use with gastrointestinal infections); carbazochrome (hemostatic agent, tested with good results against hereditary hemorrhagic telangiectasia) [26,27]; dantrolene and azumolene (approved for the treatment of malign hyperthermia) [28,29]; aldoxorubicin (a hydrazone derivative of doxorubicin, specifically a maleinimidoalkanoyl hydrazone), which functions as an albumin-binding prodrug of doxorubicin and reached phase III clinical trials for treating metastatic soft tissue sarcoma with deep localization-it releases doxorubicin at the target site with fewer systemic adverse effects, including lack of cardiotoxicity [30]; LASSBio-294 ((2-thienylidene)-3,4-methylenedioxybenzoylhydrazine) (under preclinical testing for the treatment of heart failure) [31,32]; and PAC-1 ((4-benzylpiperazino)acetic acid-(3-allyl-2-hydroxybenzylidene)hydrazide) (procaspase activator that reached clinical studies testing stage in 2015). In terms of the correlation between structure and activity, the segment of PAC-1 denoted orto-hydroxy-N-acyl hydrazone plays a crucial role in binding zinc and triggering the activation of procaspase 3 [33,34]. ...
... There exist medicinal substances based on NAH (Figure 1), such as nitrofurazone (broad-spectrum topical antibacterial agent) [24]; nitrofurantoin (oral antibacterial agent for treating gastrointestinal tract infections) [25]; nifuroxazide (antibacterial agent of use with gastrointestinal infections); carbazochrome (hemostatic agent, tested with good results against hereditary hemorrhagic telangiectasia) [26,27]; dantrolene and azumolene (approved for the treatment of malign hyperthermia) [28,29]; aldoxorubicin (a hydrazone derivative of doxorubicin, specifically a maleinimidoalkanoyl hydrazone), which functions as an albumin-binding prodrug of doxorubicin and reached phase III clinical trials for treating metastatic soft tissue sarcoma with deep localization-it releases doxorubicin at the target site with fewer systemic adverse effects, including lack of cardiotoxicity [30]; LASSBio-294 ((2-thienylidene)-3,4-methylenedioxybenzoylhydrazine) (under preclinical testing for the treatment of heart failure) [31,32]; and PAC-1 ((4-benzylpiperazino)acetic acid-(3-allyl-2-hydroxybenzylidene)hydrazide) (procaspase activator that reached clinical studies testing stage in 2015). In terms of the correlation between structure and activity, the segment of PAC-1 denoted orto-hydroxy-N-acyl hydrazone plays a crucial role in binding zinc and triggering the activation of procaspase 3 [33,34] When examining compounds containing the NAH fragment, it is essential to assess their stability. ...
N-acyl hydrazone (NAH) is recognized as a promising framework in drug design due to its versatility, straightforward synthesis, and attractive range of biological activities, including antimicrobial, antitumoral, analgesic, and anti-inflammatory properties. In the global context of increasing resistance of pathogenic bacteria to antibiotics, NAHs represent potential solutions for developing improved treatment alternatives. Therefore, this research introduces six novel derivatives of (EZ)-N’-benzylidene-2-(6-chloro-9H-carbazol-2-yl)propanehydrazide, synthesized using a microwave-assisted method. In more detail, we joined two pharmacophore fragments in a single molecule, represented by an NSAID-type carprofen structure and a hydrazone-type structure, obtaining a new series of NSAID-N-acyl hydrazone derivatives that were further characterized spectrally using FT-IR, NMR, and HRMS investigations. Additionally, the substances were assessed for their tuberculostatic activity by examining their impact on four strains of M. tuberculosis, including two susceptible to rifampicin (RIF) and isoniazid (INH), one susceptible to RIF and resistant to INH, and one resistant to both RIF and INH. The results of our research highlight the potential of the prepared compounds in fighting against antibiotic-resistant M. tuberculosis strains.
... There exist medicinal substances based on NAH (Figure 1), counting nitrofurazone (broad spectrum topical antibacterial agent) [26], nitrofurantoin (oral antibacterial agent for treating gastrointestinal tract infections) [27], nifuroxazide (antibacterial agent of use in gastrointestinal infections), carbazochrome (hemostatic agent, tested with good results against hereditary hemorrhagic telangiectasia) [28,29], dantrolene and azumolene (approved for the treatment of malign hyperthermia) [30,31], aldoxorubicin (a hydrazone derivative of doxorubicin, specifically a maleinimidoalkanoyl hydrazone), which functions as an albumin-binding prodrug of doxorubicin that reached phase III clinical trials for treating metastatic soft tissue sarcoma with deep localization; it releases doxorubicin at the target site with less systemic adverse effects, including lack of cardiotoxicity [32], LASSBio-294 ((2-thienylidene)-3,4-methylenedioxybenzoylhydrazine) (under preclinical testing for the treatment of heart failure) [33,34], and PAC-1 ((4-benzylpiperazino)acetic acid-(3-allyl-2-hydroxybenzylidene)hydrazide) (procaspase activator that reached clinical studies testing stage in 2015). In terms of the correlation between structure and activity, the segment of PAC-1, denoted by ortho-hydroxy-N-acyl hydrazone, plays a crucial role in binding Zinc and triggering the activation of procaspase 3 [35,36] When examining compounds containing the NAH fragment, it becomes essential to assess their stability. ...
N-acyl hydrazone (NAH) has been remarked as a promising scaffold in drug design, given its versatility, ease of synthesis, and appealing biological activities (i.e., antimicrobial, antitumoral, analgesic, and anti-inflammatory properties). In the global context of increasing resistance of pathogenic bacteria to antibiotics, NAHs represent potential solutions for developing improved treatment alternatives. Thus, this study presents 6 new derivatives of (EZ)-N'-benzylidene-(2RS)-2-(6-chloro-9H-carbazol-2-yl)propanohydrazide that were obtained through a microwave-assisted synthesis method. In more detail, we have joined two pharmacophore fragments in a single molecule, represented by an NSAID-type carprofen structure and a hydrazone-type structure, obtaining a new series of NSAID-N-acyl hydrazone derivatives that were further characterized spectrally using FT-IR, NMR, and HRMS investigations. Moreover, the compounds have been evaluated for their tuberculostatic activity, testing their effects on four M. tuberculosis strains (two of them susceptible to rifampicin (RIF) and isoniazid (INH), one susceptible to RIF and resistant to INH and one resistant to both RIF and INH). The results of our research highlight the potential of the prepared compounds in fighting against antibiotic-resistant M. tuberculosis strains.
... Tranexamic acid stabilized the coagulative and fibrinolytic parameters and relieved the bleeding tendency in a patient suffering from aortic dissection with an acute exacerbation of chronic DIC [7]. In addition, carbazochrome has a beneficial effect in treating capillary fragility induced by hereditary hemorrhagic telangiectasia by modulating fibrinolysis through the alteration of the endothelial cell function [8]. Furthermore, furosemide, spironolactone, thiamine, phytonadione, tranexamic acid, and carbazochrome all have anti-inflammatory effects [9][10][11][12][13]. ...
A 48-year-old Mongolian man developed bilateral leg edema after suffering from a fever for three months. He lost his appetite, and the edema gradually spread from the legs, becoming systemic. In addition, he had difficulty in moving. He had a history of being diagnosed with numerous venous malformations and Kasabach-Merritt syndrome when he was a child. On arrival, he had numerous venous malformations over pale skin, edema at each extremity, and anemic conjunctiva. Chest roentgen showed bilateral pleural effusion, and cardiac echography findings showed a left ventricular ejection fraction of 30% with diffuse hypokinesis. The results of a blood analysis showed coagulopathy, which was compatible with disseminated intravascular coagulation and pancytopenia. He was diagnosed with blue rubber bleb nevus syndrome with Kasabach-Merritt syndrome and heart failure. Use of diuretics, thiamine, iron, phytonadione, carbazochrome, and tranexamic acid, in addition to intermittent transfusion resulted in the improvement of his Kasabach-Merritt syndrome. Radical management of blue rubber bleb nevus syndrome was deemed impossible by dermatologists due to the large amount of venous malformations. We encountered an extremely rare case of blue rubber bleb nevus syndrome with Kasabach-Merritt and heart failure. Multimodal therapy might help manage Kasabach-Merritt syndrome following improvement in coagulopathy and pancytopenia.
... [11] Carbazochrome is a hemostatic agent and is indicated for capillary and parenchymal hemorrhage. [11][12][13][14] In addition, the application of N-acylhydrazones has been addressed for the detection of metal ions [15][16][17][18][19][20][21] and anions [19,22] in biological and environmental samples. ...
We describe a fast, simple, and effective synthesis of N‐acylhydrazones via a solid‐state melt reaction under catalyst‐ and solvent‐free conditions. The reactions of 2‐furoic hydrazide, 2‐thiophenecarboxylic acid hydrazide and substituted alkyl/aryl‐acylhydrazides with aromatic aldehydes proceeded well at 120 °C in only 30 min to give the corresponding products in good to excellent isolated yields (74–100%) without purification using column chromatography. Gram scale experiments also worked well. This method could be considered as a green procedure, which has a high atom economy (94.69–94.90%), high reaction mass efficiency (84.27–87.33%), low E‐factor (0.15–0.19 g/g), and low process mass intensity (13.21–14.30 g/g).
... CSS has been used to treat bleeding of the gastrointestinal and respiratory tracts. The hemostatic effect of CSS has been shown in instances of hereditary hemorrhagic telangiectasia and total knee arthroplasty; however, CSS has not demonstrated hemostatic effects in instances of colonic diverticular bleeding [7][8][9]. Therefore, research regarding the hemostatic effects of CSS is currently controversial, especially in cases of gastrointestinal bleeding. ...
Background
Carbazochrome sodium sulfonate (CSS) is conventionally administered to prevent post-endoscopic submucosal dissection (ESD) bleeding in many institutions, but research on its preventive efficacy is lacking. Therefore, we investigated the risk of post-ESD bleeding and the preventive efficacy of CSS administration.
Methods
We retrospectively reviewed 304 lesions in 259 patients with gastric neoplasms who underwent ESD at Asahikawa Medical University Hospital from 2014 to 2021. In the CSS group, CSS 100 mg/day was intravenously infused with maintenance fluid replacement on postoperative days 0–2. The risk factors of post-ESD bleeding, including CSS administration, were investigated.
Results
The overall rate of post-ESD bleeding was 4.6% (14/304). The univariate analysis showed that atrial fibrillation (Af), warfarin intake, heparin replacement, and tumor location in the lower third were significant risk factors for increasing the likelihood of postoperative bleeding. In the multivariate analysis, Af (odds ratio [OR] 3.83, 95% CI 1.02–14.30; p < 0.05), heparin replacement (OR 4.60, 95% CI 1.02–20.70; p < 0.05), and tumor location in the lower third of the stomach (OR 6.67, 95% CI 1.43–31.00; p < 0.05) were independent factors for post-ESD bleeding. Post-ESD bleeding was observed in 5.2% (9/174) of the CSS group and 3.8% (5/130) of the non-CSS group, with no significant difference between the two groups ( p = 0.783). Additionally, CSS was not shown to have preventive effects in groups with higher-risk factors, such as Af diagnosis, warfarin use, heparin replacement, and tumor location in the lower third of the stomach.
Conclusion
CSS administration was not effective for the prevention of the post-ESD bleeding in the overall patient population as well as in higher-risk patients. This suggests that the administration of CSS for post-ESD bleeding prevention may need to be reconsidered.
... 14,15 Furthermore, CSS is also used in urology, otolaryngology, etc., and studies have shown that CSS can improve symptoms of nose bleeding as well as pain and post-urination symptoms in patients with refractory chronic prostatitis. 16,17 Furthermore, one study showed that TXA combined with CSS had significantly reduced blood loss after total knee arthroplasty without increasing the risk of thromboembolism complications. 18 Therefore, we speculated that the use of CSS combined with TXA during and following THA could reduce perioperative blood loss, transfusion rate, and inflammatory reaction, and accelerate postoperative recovery without the occurrence of thromboembolic complications. ...
Aims
The purpose of this study was to examine the efficacy and safety of carbazochrome sodium sulfonate (CSS) combined with tranexamic acid (TXA) on blood loss and inflammatory responses after primary total hip arthroplasty (THA), and to investigate the influence of different administration methods of CSS on perioperative blood loss during THA.
Methods
This study is a randomized controlled trial involving 200 patients undergoing primary unilateral THA. A total of 200 patients treated with intravenous TXA were randomly assigned to group A (combined intravenous and topical CSS), group B (topical CSS), group C (intravenous CSS), or group D (placebo).
Results
Mean total blood loss (TBL) in groups A (605.0 ml (SD 235.9)), B (790.9 ml (SD 280.7)), and C (844.8 ml (SD 248.1)) were lower than in group D (1,064.9 ml (SD 318.3), p < 0.001). We also found that compared with group D, biomarker level of inflammation, transfusion rate, pain score, and hip range of motion at discharge in groups A, B, and C were significantly improved. There were no differences among the four groups in terms of intraoperative blood loss (IBL), intramuscular venous thrombosis (IMVT), and length of hospital stay (LOS).
Conclusion
The combined application of CSS and TXA is more effective than TXA alone in reducing perioperative blood loss and transfusion rates, inflammatory response, and postoperative hip pain, results in better early hip flexion following THA, and did not increase the associated venous thromboembolism (VTE) events. Intravenous combined with topical injection of CSS was superior to intravenous or topical injection of CSS alone in reducing perioperative blood loss. Cite this article: Bone Joint Res 2021;10(6):354–362.
... Recently, it has been recommended with vitamin C, vitamin E, and lysozyme for the treatment of chronic periodontitis after root planing [23]. Also, CZ shows a potential helpful action in treating hereditary hemorrhagic telangiectasia [24]. However, the analytical literature of CZ suffers from some limitations and shortcomings. ...
The design of a cheap, simple, and handy sensing system for rapid quantitation of pharmaceuticals is very mandatory to ease drug development procedures, quality control, health care, etc. This work describes a simple, innovative, and easily manufactured paper-based device using a correction pen as a plotter for hydrophobic/lipophobic barriers and the graphene quantum dots for recognition and quantification of the hemostatic drug, carbazochrome, via fluorescence turn-off mechanism mediated by the inner filter effect. A smartphone-based all-in-one device fitted with an inexpensive 365 nm flashlight as a UV light source and a free image processing software was developed for rapid and reliable interpretation of the fluorescence change from the paper-based device upon introduction of the drug. The simple and convenient steps permit the analysis of many samples in a very short time. The smartphone-based all-in-one device featured excellent sensitivity for carbazochrome with a limit of detection equals to 12 ng/detection zone and good %recovery (100.0 ± 0.4). The reliability of the device was ascertained by favorable statistical comparison with the analogous optimized conventional fluorimetry method and a reference HPLC method. The device has been successfully applied for versatile quantitation of carbazochrome in tablets and on manufacturing equipment surfaces with excellent recoveries. The device offers many green aspects that definitely assist the implementation of the sustainability concept to analytical laboratories. The cost-efficiency, reliability, and ease of fabrication as well as the greenness and user friendship qualify the device for wide application in low-income communities.
... For example, dantrolene and azumolene (Additional file 1: Fig. S1B) are effective against malignant hyperthermia, presenting with a fast heart rate and muscle rigidity [1,2]. In addition, nifroxiazide (Additional file 1: Fig. S1C) and carbazochrome (Additional file 1: Fig. S1D) are used to treat diarrhea and hereditary hemorrhagic telangiectasia, respectively [3,4]. Nitrofurantoin (Additional file 1: Fig. S1E) and nitrofurazone (Additional file 1: Fig. S1F) display anti-bacterial activities [5]. ...
There is accumulating evidence that compounds containing N -acylhydrazone or 4-chromenone moieties can be active against multiple cancer cell types, yet the combined effect of these chemical groups is unclear. This study aimed to develop more effective anti-cancer compounds by combining 4-chromenone and N -acylhydrazone. Thirteen derivatives were designed, synthesized, and characterized, and their structures were identified using nuclear magnetic resonance spectroscopy and high-resolution mass spectrometry. Most of the derivatives exhibited moderate to high efficacy in inhibiting the clonogenicity of HCT116 colon cancer cells. In particular, derivative 12 , ( E )- N '-((6-methoxy-4-oxo-4 H -chromen-3-yl)methylene)isonicotinohydrazide, strongly inhibited clonogenicity (GI 50 = 34.8 μM) of HCT116 cells and aurora kinase A (aurA) activity in vitro (IC 50 = 1.4 μM). In silico docking experiment predicted that derivative 12 interacts with aurA based on computational docking and calculations of binding free energy. When derivative 12 was exposed to HCT116 cells, the phosphorylation of aurA at Thr288 was dose-dependently decreased within 60 min. Further analysis showed that derivative 12 destroyed the mitotic spindle in HCT116 cells. These results suggest that derivatives of 4-chromenone combined with N -acylhydrazone are feasible in the development of selective aurA inhibitor and could be considered potential chemotherapeutic agents.
... A recent randomized controlled trial by Luo et al. showed that CSS reduced perioperative blood loss in patients undergoing total knee arthroplasty, without thromboembolic com-plications (7). One small observational case-only study reported that CSS may have improved bleeding symptoms in patients with hereditary hemorrhagic telangiectasia (9). However, to our knowledge, no study has examined the effect of CSS in gastrointestinal bleeding. ...
Objective Carbazochrome sodium sulfonate (CSS) has been routinely used to treat bleeding; however, no study has examined the effect of CSS for gastrointestinal bleeding. Therefore, we aimed to investigate the effect of CSS for colonic diverticular bleeding.
Methods We performed a nationwide observational study using the Japanese Diagnosis Procedure Combination inpatient database. We identified patients who were admitted for diverticular bleeding from July 2010 to March 2018. Patients who received CSS on the day of admission were defined as the CSS group, and those not receiving CSS were defined as the control group. The primary outcome was in-hospital mortality. Secondary outcomes were length of stay, total costs, and blood transfusion within 7 days of admission. Propensity score matching analyses were performed to compare outcomes between the two groups.
Results A total of 59,965 patients met our eligibility criteria. Of these, 14,437 (24%) patients received CSS on the day of admission. One-to-one propensity score matching created 14,379 matched pairs. There was no significant difference in the in-hospital mortality between the CSS and control groups (0.6% vs. 0.5%, respectively; odds ratio: 0.96; 95% confidence interval: 0.72-1.29). The length of stay was longer in the CSS group than in the control group (11.4 vs. 11.0 days, respectively; difference: 0.44; 95% confidence interval: 0.14-0.73). There were no significant differences in the total costs or the proportion of patients receiving blood transfusion between the groups.
Conclusions CSS may not reduce in-hospital mortality, length of stay, total costs, or the need for blood transfusion in patients with colonic diverticular bleeding.
... In addition to its use in orthopedics, CSS is also used in other disciplines [16e21]. For example, the study by Passali et al [16] found that CSS can improve the bleeding symptoms of hereditary hemorrhagic telangiectasia. Studies by Oh-oka et al [17] have shown that CSS can effectively improve pain and postmicturition symptoms in patients with refractory chronic prostatitis. ...
Background:
Postoperative recovery after total knee arthroplasty (TKA) is associated with postoperative anemia, allogeneic transfusion, and stress immune responses to surgery. Carbazochrome sodium sulfonate (CSS) reduces bleeding through several mechanisms. We assessed the effect of CSS combined with tranexamic acid (TXA) on postoperative anemia, blood transfusion, and inflammatory responses.
Methods:
This study was designed as a randomized, placebo-controlled trial of 200 patients undergoing unilateral primary TKA. Patients were divided into 4 groups: group A received TXA plus topical and intravenous CSS; group B received TXA plus topical CSS only; group C received TXA plus intravenous CSS only; group D received TXA only.
Results:
Total blood loss in groups A (609.92 ± 221.24 mL), B (753.16 ± 247.67 mL), and C (829.23 ± 297.45 mL) was lower than in group D (1158.26 ± 334.13 mL, P < .05). There was no difference in total blood loss between groups B and C. We also found that compared with group D, the postoperative swelling rate, biomarker level of inflammation, visual analog scale pain score, and range of motion at discharge in groups A, B, and C were significantly improved (P < .05). No thromboembolic complications occurred. There were no differences in transfusion rate, intraoperative blood loss, platelet count, or average length of stay among the 4 groups (P > .05).
Conclusion:
CSS combined with TXA was more effective than TXA alone in reducing perioperative blood loss and inflammatory response and did not increase the incidence of thromboembolism complications.
... This treatment was shown to be beneficial for the management of HHT. 40 In Canada, the drug testosterone 17-enanthate 3-benzilic acid hydrazone (4) in combination with estradiol benzoate and estradiol dienanthate has been approved as an intramuscular formulation under the brand name of Climacteron®. Climacteron® injections were discontinued in 2005 due to safety concerns based on supraphysiological serum testosterone levels in premenopausal women that can be associated with hirsutism, virilization, and aggression. ...
Over the last two decades, N-acylhydrazone (NAH) has been proven to be a very versatile and promising motif in drug design and medicinal chemistry. Herein, we discuss the current and future challenges in the emergence of bioactive NAH-based scaffolds and to developing strategies to overcome the failures in drug discovery. The NAH-related approved drugs nitrofurazone, nitrofurantoin, carbazochrome, testosterone 17-enanthate 3-benzilic acid hydrazine, nifuroxazide, dantrolene, and azumolene are already used as therapeutics in various countries. PAC-1 is an NAH-based therapeutic agent that entered clinical trials in 2015. Another NAH-derived scaffold, LASSBio-294, is in preclinical trials. This review highlights the detailed comprehensive assessment and therapeutic landscape of bioactive NAH motif scaffolds in preclinical and clinical studies published to date and their promise and associated challenges in current and future drug discovery of NAH-based drugs that will progress to clinical use.
Purpose
A drug known as carbazochrome sodium sulfonate (CSS) can reduce blood loss. But, it is not known how it can prevent the development of hemostatic and inflammatory conditions in patients who undergo bilateral simultaneous total hip arthroplasty (SBTHA). This study will analyze the safety and effectiveness of combining this drug with SBTHA.
Methods
The study was conducted on 100 patients who underwent SBTHA with simultaneous total hip replacement. They were split into two groups: group B received TXA with CSS, group A received TXA with no CSS. The main observation of the study was the total blood loss, which is the most common indication of blood loss. Other secondary indicators of the study included hidden blood loss, postoperative blood transfusion rate, level of inflammatory reactants, hip function, pain score, venous thromboembolism (VTE) and the incidence of adverse events.
Results
Group B had significantly lower TBL and HBL compared to Group A. Group B showed significant improvement in inflammatory biomarker levels, blood transfusion rate when compared to Group A ( p < .05). No thromboembolic complications occurred in either group. There were no significant differences between the two groups in terms of postoperative swelling rate, intraoperative blood loss, visual analog scale pain score, platelet count, discharge motion and average length of stay.
Conclusions
As a hemostatic agent, CSS combined with TXA can reduce postoperative blood loss in patients undergoing SBTHA, and is more effective than TXA alone in terms of blood loss and inflammation, and does not increase the incidence of thromboembolic complications.
Due to its important biological and pharmacological properties, in the field of medicinal chemistry and drug discovery, the N-acylhydrazone motif has shown to be extremely adaptable and promising. This scaffold has become a crucial component in the synthesis of numerous bioactive agents. N-Acylhydrazones are also interesting biological and synthetic tools due to their easy and straightforward synthesis. The current review provides a summary of the analgesic and anti-inflammatory activities of N-acylhydrazone derivatives over the past ten years. A brief discussion of structure-activity relationships is also provided which may guide researchers in medicinal chemistry to develop derivatives based on N-acylhydrazone scaffold as potent anti-inflammatory candidates.
The N-acylhydrazone motif has been shown to be particularly adaptable and promising in the area of medicinal chemistry and drug development, due to its significant biological and pharmacological characteristics. Moreover, N-acylhydrazones are appealing synthetic and biological tools because of their simple and straightforward synthesis. This scaffold has emerged as a fundamental building block for the synthesis of bioactive compounds. Particularly, the N-acylhydrazone scaffold served as a base for the synthesis of a number of potent anticancer agents acting via different mechanisms. An updated summary of the anticancer activity of N-acylhydrazone derivatives described in the literature (from 2017 to 2022) is provided in the current review. It discusses the structure-activity relationship (SAR) of N-acylhydrazone derivatives exhibiting anticancer potential, which could be helpful in designing and developing new derivatives as effective antiproliferative candidates in the future.
Background: The hemostatic effect of tranexamic acid (TXA) combined with carbazochrome sodium sulfonate (CSS) in total hip arthroplasty (THA) has not been determined. Therefore we performed a randomized study aiming to evaluate the effects of CSS combined with TXA on perioperative blood loss and inflammatory response of THA.
Hypothesis: CSS combined with TXA can effectively reduce perioperative blood loss and immune response compared to TXA.
Material and methods: This randomized placebo-controlled trial assigned 150 patients undergoing unilateral primary total hip arthroplasty who underwent direct anterior approach surgery to 3 groups: group A received TXA plus topical CSS; group B received TXA only; and group C received placebo. The main outcome was total blood loss. Secondary outcomes included reduction in hemoglobin concentration, coagulation parameters, inflammatory marker levels, perioperative visual analog scale (VAS) pain score, transfusion rates, postoperative hospital stay, and incidence of thromboembolic events.
Results: Total blood loss in group A (668.84±230.95mL) was lower than in group B (940.96±359.22 mL) and C (1166.52±342.85 mL, p < 0.05). We also found that compared with group B, postoperative hip pain, biomarker level of inflammation, visual analogue score (VAS) pain score in group A were significantly improved. The transfusion rate and unit of group A were significantly lower than group C (8 patients ; 17.5 units), but there was no statistical difference between group A (no transfusion) and group B (2 patients; 4 units). No differences were observed in thromboembolic and other outcomes among the groups.
Discussion: The combined application of topic CSS and TXA is more effective than TXA alone following THA in regard of reducing total blood loss. In addition, CSS combined with TXA is better than TXA alone in terms of improving postoperative hip pain and reducing the level of inflammatory factors.
Level of evidence: I; randomized controlled study
The carbazochrome (3) solubility in solvent mixtures of DMF (N,N-dimethylformamide, 1) + methanol (2), DMF (1) + ethanol (2), DMF (1) + n-propanol (2), and dimethyl sulfoxide (DMSO, 1) + water (2) was measured by the static method within the temperature range from (278.15 to 318.15) K under atmospheric pressure, p = 101.0 kPa. The solubility of carbazochrome increased with rising mass fraction of DMF or DMSO and temperature. The Jouyban–Acree, van’t Hoff–Jouyban–Acree, and Apelblat–Jouyban–Acree models were used to correlate the obtained solubility, and the Apelblat–Jouyban–Acree model provided better correlation results. The parameters of preferential solvation (δx1,3) were acquired from the mixture properties with the method of inverse Kirkwood–Buff integrals. The values of δx1,3 changed nonlinearly with the DMF/DMSO (1) proportion in the studied mixed solvents. The carbazochrome was solvated preferentially by alcohol or water in alcohol or water-rich solutions and preferentially solvated by DMF/DMSO in DMF/DMSO-rich mixtures. It could be speculated that in DMF/DMSO-rich mixtures the interaction by acidic hydrogen bonding with the basic sites of carbazochrome played a significant role in carbazochrome solvation.
Background:
Hereditary hemorrhagic telangiectasia (HHT) is a dominantly inherited genetic vascular disorder in which epistaxis is the most frequent manifestation, responsible for high morbidity. Management of this symptom has no standard, and local treatments are often aggressive. Their efficacy is variable and has not been proven. Anti-angiogenic drugs, such as bevacizumab, are a new treatment strategy. Its systemic administration in patients with HHT improves liver damage-related symptoms and epistaxis. To limit the systemic adverse effects of bevacizumab and to ease administration, a local administration seems suitable.
Primary objective:
To evaluate the tolerance of increasing doses of bevacizumab administered as a nasal spray in patients with HHT-related epistaxis. Secondary objectives were to study the bioavailability and efficacy of bevacizumab against epistaxis when given as a nasal spray.
Methodology:
Phase 1, randomized, double-blind, placebo-controlled, monocentric study performed sequentially (dose escalation) on 5 groups of 8 patients. Each group was made up of 6 verum and 2 placebos. Five increasing doses of bevacizumab nasal spray (25 mg/mL) were evaluated: 12.5, 25, 50, 75 and 100 mg.
Results:
A total of 40 patients were included between October 2011 and October 2012. Bevacizumab nasal spray was well tolerated in all patients and the drug was not detected in their serum. No dose limiting toxicity was observed. No efficacy was observed at any dose in this study.
Conclusion:
Based on these results, bevacizumab nasal spray is a safe treatment of epistaxis in HHT. However, a randomized Phase 2 study is needed to determine its efficacy.
Trial registration:
ClinicalTrials.gov Identifier #NCT01507480.
Hereditary Haemorrhagic Telangiectasia (HHT) or Rendu-Osler-Weber syndrome, is an autosomal dominant rare disease characterized by localized angiodysplasia. This is manifested as epistaxis, mucocutaneous and gastrointestinal telangiectases, and arteriovenous malformations in the pulmonary, cerebral or hepatic circulation. The prevalence is between 1 in 5,000 to 8,000, although it is higher in some regions. The most frequent clinical manifestation of HHT is epistaxis, normally from light to moderate from the 4(th) decade of life. However, many patients show severe epistaxis which may interfere with their quality of life. The epistaxis is due to telangiectasia on the nasal mucosa. These are focally dilated postcapilar venules, which in advanced phases show many layers of smooth muscle cells without elastic fibers, and very frequently directly connect with dilated arterioles. As a consequence of these vascular alterations, telangiectases are very sensitive to slight trauma and even to the friction with the air when breathing, which gives rise to nose bleeds. Unfortunately, there is no optimal pharmacological treatment for the epistaxis in HHT. The use of antifibrinolytic agents for the treatment of HHT has been studied recently by our group as an effective relief for nasal and gastric haemorrhages. This work represents a systematic review and the beginning of a systematic laboratory work we are now conducting in our lab to screen for "orphan drugs" as therapeutic agents in HHT. In this context, the use of hormones, immunosuppresants and anti-angiogenic agents are under preclinical study in our laboratory.
Epistaxis is the most common manifestation of hereditary hemorrhagic telangiectasia (HHT), affecting approximately 90% of patients at some point during their lifetime. Bleeding is chronic and varies from mild, self-limited episodes to severe, transfusion-dependent or life-threatening epistaxis. Treatment options vary from conservative, nonsurgical management to more aggressive surgical approaches. A number of treatment options have been introduced in recent years. There is little consensus in the literature regarding treatment algorithms. The objective of this investigation was to provide a contemporary review of HHT-related epistaxis, including pathophysiology, disease manifestations, and state-of-the-art treatment modalities.
A systematic review of the literature for HHT-related epistaxis was performed using the search terms "hereditary hemorrhagic telangiectasia" and "epistaxis." Additional literature search regarding current recommendations for HHT evaluation and recent developments in genetic mechanisms, pathophysiology, and treatment of HHT was also performed.
A total of 308 articles were identified and reviewed for appropriateness of inclusion whereas 64 articles met inclusion criteria. Treatment options range from topical and hormonal therapy to more aggressive surgical modalities. Most treatment descriptions are case series, with few randomized controlled trials. A number of new and novel therapies have been introduced in recent years.
HHT is a heterogeneous disease requiring multidisciplinary evaluation and treatment. Therapeutic options for HHT-related epistaxis vary from conservative, nonsurgical measures to more aggressive surgical treatments. A graduated treatment plan is recommended. Patients present with a wide degree in variation of severity of epistaxis, and treatment is best tailored to the individual patient. ©2012 ARSAAOA, LLC.
Hereditary haemorrhagic telangiectasia, inherited as an autosomal dominant trait, affects approximately 1 in 5000 people. The abnormal vascular structures in HHT result from mutations in genes (most commonly endoglin or ACVRL1) whose protein products influence TGF-ß superfamily signalling in vascular endothelial cells. The cellular mechanisms underlying the generation of HHT telangiectasia and arteriovenous malformations are being unravelled, with recent data focussing on a defective response to angiogenic stimuli in particular settings. For affected individuals, there is often substantial morbidity due to sustained and repeated haemorrhages from telangiectasia in the nose and gut. Particular haematological clinical challenges include the management of severe iron deficiency anaemia; handling the intricate balance of antiplatelet or anticoagulants for HHT patients in whom there are often compelling clinical reasons to use such agents; and evaluation of apparently attractive experimental therapies promoted in high profile publications when guidelines and reviews are quickly superseded. There is also a need for sound screening programmes for silent arteriovenous malformations. These occur commonly in the pulmonary, cerebral, and hepatic circulations, may haemorrhage, but predominantly result in more complex pathophysiology due to consequences of defective endothelium, or shunts that bypass specific capillary beds. This review will focus on the new evidence and concepts in this complex and fascinating condition, placing these in context for both clinicians and scientists, with a particular emphasis on haematological settings.
Hereditary hemorrhagic telangiectasia (HHT)-related epistaxis leads to alterations in social functioning and quality of life. Although more than 95% experience epistaxis, there is considerable variability of severity. Because no standardized method exists to measure epistaxis severity, the purpose of this study was to determine factors associated with patient-reported severity to develop a severity score.
Prospective, survey-based study.
HHT care providers and a focus group of patients were interviewed to determine epistaxis-associated factors. From this, an electronic survey was developed and administered to patients with HHT. Descriptive analyses were performed with calculations of means and medians for continuous and proportions for categorical variables. Multiple ordinal logistic and linear regression models were developed to determine risk factors for epistaxis severity.
Nine hundred respondents from 21 countries were included. Eight hundred fifty-five (95%) subjects reported epistaxis. The mean (standard deviation) age was 52.1 (13.9) years, and 61.4% were female. Independently associated risk factors for self-reported epistaxis severity included epistaxis frequency (odds ratio [OR] 1.57), duration (OR 2.17), intensity (OR 2.45), need for transfusion (OR 2.74), anemia (OR 1.44), and aggressiveness of treatment required (OR 1.53, P < .001 for all).
Risk factors for increasing epistaxis severity in patients with HHT include frequency, duration, and intensity of episodes; invasiveness of prior therapy required to stop epistaxis; anemia; and the need for blood transfusion. From these factors, an epistaxis severity score will be presented.
To the Editor: Hereditary hemorrhagic telangiectasia is an autosomal dominant disease characterized by epistaxis, cutaneous telangiectases, and visceral arteriovenous malformations.1 Aminocaproic acid, an antifibrinolytic drug, can reduce epistaxis in hereditary hemorrhagic telangiectasia,2 but its effect is inconsistent.3 We successfully treated three patients who had hereditary hemorrhagic telangiectasia with tranexamic acid, another antifibrinolytic drug. The first patient was a 69-year-old man who received 1 g of tranexamic acid four times daily. After three months of therapy, he reported an improvement in his epistaxis and his hemoglobin level rose from 10.3 g per deciliter to 12.3 g per deciliter. The second patient . . .