Local Tissue Toxicity Research Articles

Locally administered nanosuspension increases delivery of estradiol for the treatment of vaginal atrophy in mice.

Vaginal atrophy affects up to 57% of post-menopausal women, with symptoms ranging from vaginal burning to dysuria. Estradiol hormone replacement therapy may be prescribed to alleviate these symptoms, though many vaginal products have drawbacks including increased discharge and local tissue toxicity due to their hypertonic nature. Here, we describe the development and characterization of a Pluronic F127-coated estradiol nanosuspension (NS) formulation for improved vaginal estradiol delivery. We compare the pharmacokinetics to the clinical comparator vaginal cream (Estrace) and demonstrate increased delivery of estradiol to the vaginal tissue. We utilized ovariectomized (OVX) mice as a murine model of post-menopausal vaginal atrophy and demonstrated equivalent efficacy in vaginal re-epithelialization when dosed with either the estradiol NS or Estrace cream. Further, we demonstrate compatibility of the estradiol NS with vaginal bacteria in vitro. We demonstrate that a Pluronic F127-coated estradiol NS may be a viable option for the treatment of post-menopausal vaginal atrophy.

Naja naja snake venom-induced local toxicities in mice is by inflammasome activation

Snake bite envenomation causes tissue damage resulting in acute and chronic inflammatory responses. Inflammasome activation is one of the factors involved in tissue damage in a mouse model of snake envenomation. The present study examines the potency of Indian Big Four snake venoms in the activation of inflammasome and its role in local and systemic tissue toxicity. Among Indian Big Four snake venoms, Naja naja venom activated NLRP3 inflammasome in mouse macrophages. Activation of NLRP3 inflammasome was also observed in mouse foot paw and thigh muscle upon administration of N. naja venom. Intraperitoneal administration of N. naja venom cause systemic lung damage showed activation of NLRP3 inflammasome. Treatment with MCC950, a selective NLRP3 inflammasome inhibitor effectively inhibited N. naja venom-induced activation of caspase-1 and liberation of IL-1β in macrophages. In mice, MCC950 partially inhibited the activation of NLRP3 inflammasome in N. naja venom administered foot paw and thigh muscle. In conclusion, the present data showed that inflammasome is one of the host responses involved in N. naja snake venom-induced toxicities. The inhibition of inflammasome activation will provide new insight into better management of snake bite-induced local tissue damage.

Escalating SBRT Dose to Hypoxic Centers of Large Pulmonary Tumors via Simultaneous Integrated Boost Confers Effective Local Control with Minimal Toxicity

Hypoxia confers radio-resistance to tumor cells and drives malignant disease progression. SBRT treatment of large (>5.0 cm) pulmonary tumors pose significant dosimetric challenges in minimizing dose to adjacent organs at risk (OARs). Here, we detail the use of SBRT with simultaneous integrated boost (SIB) to the hypoxic centers of large pulmonary masses with effective local control and minimal normal tissue toxicity. Highly conformal treatment plans utilized 3-4 non-coplanar VMAT arcs with 6MV-FFF (1400 MU/min) and 4D-CT on TrueBeam to deliver 50 Gy in 5 fractions to the planning target volume (PTV). SIB dose of 60 Gy was delivered to a 1-cm internal margin from the gross tumor volume (GTV). Dose was calculated using Acuros-based engine. Pre-treatment Conebeam CT imaging was used for patient setup and verification. Treatments were delivered in < 15 minutes. Patients underwent post-treatment clinical evaluation and CT imaging in 3-month intervals to assess changes in tumor size and post-radiation sequelae. Clinical outcomes reported include treatment response and toxicity. Twenty-six patients with large, centrally (n = 13) or peripherally (n = 13) located tumors were evaluated; this included 16 NSCLC patients with T2-T3N0 disease and 5 with pulmonary metastases from distant sites. One patient had declined surgery, while 25/26 (96.1%) were deemed medically inoperable. All plans met RTOG-0813 requirements for target coverage and dose to OARs. Median follow-up interval was 11 months (0 to 23 months). Twenty-one of 26 (80.7%) patients received post-treatment CT imaging within 6 months of SBRT. Local control was achieved in 20/21 (95.2%) patients; one patient with a peripherally located tumor progressed outside the treatment field. Acute toxicity profile amongst the 25 patients assessed included grade 1 fatigue (n = 2), grade 1 rib pain (n = 1), and grade 2 pulmonary fibrosis (n = 1). Otherwise, 22/25 (88%) patients reported no radiation induced toxicities. Subgroup analysis was performed on patients with centrally located tumors, defined as located <2 cm from the hilum, heart, or bronchial trees. One of 13 (7.6%) patients with central tumors reported grade 1 rib pain; otherwise, no radiation induced adverse effects were observed. All patients with centrally located lung tumors experienced local control on surveillance imaging. SBRT with SIB to the hypoxic centers of large pulmonary masses is a safe, efficacious treatment that confers improved local control while maintaining dose to adjacent OARs. This study demonstrates the feasibility of delivering doses up to 60 Gy to the hypoxic centers of large lung tumors, while decreasing local tumor burden, minimizing treatment mobility, and improving clinic workflow. SBRT with SIB shortens treatment course to 5 fractions (in contrast to the traditional daily 30 fractions), thus improving patient comfort and compliance.

Dual drug-loaded PLGA fibrous scaffolds for effective treatment of breast cancer in situ.

Advanced metastatic breast cancer remains nearly an incurable disease. In situ therapy may help patients with worse prognoses have better clinical outcomes by significantly reducing systematic toxicity. Dural-drug fibrous scaffold was created and assessed using an in-situ therapeutic strategy, simulating the preferred regimens advised by the National Comprehensive Cancer Network. DOX, a once-used chemotherapy drug is embedded into scaffolds and produces a fast release for two cycles to kill tumor cells. PTX, a hydrophobic drug is continuously injected and produces a gradual release for up to two cycles to treat long cycles. Chosen drug loading system and the designated fabrication parameter controlled the releasing profile. Drug carrier system complied with the clinical regimen. It demonstrated both in vitro and in vivo anti-proliferative effects on the breast cancer model. The dosage of an intratumoral injection to drug capsules, the local tissue toxicity could be significantly reduced. To optimized intravenous injection with dual drugs, fewer side effects and a higher survival rate were seen even in the large tumor model (450-550mm3). Drug delivery system makes the precise accumulation of the topical drug concentration possible, simulating clinically successful therapy and possibly offering better clinical treatment options for solid tumors.

Novel Imaging Biomarkers to Assess Oncologic Treatment-Related Changes.

Cancer therapeutics cause various treatment-related changes that may impact patient follow-up and disease monitoring. Although atypical responses such as pseudoprogression may be misinterpreted as treatment nonresponse, other changes, such as hyperprogressive disease seen with immunotherapy, must be recognized early for timely management. Radiation necrosis in the brain is a known response to radiotherapy and must be distinguished from local tumor recurrence. Radiotherapy can also cause adverse effects such as pneumonitis and local tissue toxicity. Systemic therapies, like chemotherapy and targeted therapies, are known to cause long-term cardiovascular effects. Thus, there is a need for robust biomarkers to identify, distinguish, and predict cancer treatment-related changes. Radiomics, which refers to the high-throughput extraction of subvisual features from radiologic images, has been widely explored for disease classification, risk stratification, and treatment-response prediction. Lately, there has been much interest in investigating the role of radiomics to assess oncologic treatment-related changes. We review the utility and various applications of radiomics in identifying and distinguishing atypical responses to treatments, as well as in predicting adverse effects. Although artificial intelligence tools show promise, several challenges-including multi-institutional clinical validation, deployment in health care settings, and artificial-intelligence bias-must be addressed for seamless clinical translation of these tools.

Cytotoxicity of Venoms and Cytotoxins from Asiatic Cobras (Naja kaouthia, Naja sumatrana, Naja atra) and Neutralization by Antivenoms from Thailand, Vietnam, and Taiwan.

Envenoming by cobras (Naja spp.) often results in extensive local tissue necrosis when optimal treatment with antivenom is not available. This study investigated the cytotoxicity of venoms and purified cytotoxins from the Monocled Cobra (Naja kaouthia), Taiwan Cobra (Naja atra), and Equatorial Spitting Cobra (Naja sumatrana) in a mouse fibroblast cell line, followed by neutralization of the cytotoxicity by three regional antivenoms: the Thai Naja kaouthia monovalent antivenom (NkMAV), Vietnamese snake antivenom (SAV) and Taiwanese Neuro bivalent antivenom (NBAV). The cytotoxins of N. atra (NA-CTX) and N. sumatrana (NS-CTX) were identified as P-type cytotoxins, whereas that of N. kaouthia (NK-CTX) is S-type. All venoms and purified cytotoxins demonstrated varying concentration-dependent cytotoxicity in the following trend: highest for N. atra, followed by N. sumatrana and N. kaouthia. The antivenoms moderately neutralized the cytotoxicity of N. kaouthia venom but were weak against N. atra and N. sumatrana venom cytotoxicity. The neutralization potencies of the antivenoms against the cytotoxins were varied and generally low across NA-CTX, NS-CTX, and NK-CTX, possibly attributed to limited antigenicity of CTXs and/or different formulation of antivenom products. The study underscores the need for antivenom improvement and/or new therapies in treating local tissue toxicity caused by cobra envenomings.

QX-OH/Levobupivacaine: A Structurally Novel, Potent Local Anesthetic Produces Fast-Onset and Long-Lasting Regional Anesthesia in Rats.

PurposeLocal anesthetics (LAs) are an important alternative for postoperative analgesia; however, the short duration of LAs limits their use. Thus, we previously developed LL-1, a mixture of QX-OH and levobupivacaine (LB) that produces regional anesthesia for more than 10 h in rats. The aim of this study is to investigate the long-acting mechanism of LL-1 in vivo and in vitro.MethodsRegional anesthetic effects and local toxicity of the LL-1, QX-OH and LB treatment groups were investigated in a sciatic nerve block rat model. Whole-cell patch-clamping recordings were used to measure the inhibition Nav currents (INa) in ND7/23 cells.ResultsThe onset of LL-1 (35mM QX-OH+10mM LB) and 10 mM LB was 10 min, which was much faster than 35 mM QX-OH (27 [18, 60] min, t[12] = −4.535, p = 0.001). The duration of LL-1 (35mM QX-OH+10 mM LB) was significantly longer than 35 mM QX-OH or 10 mM LB alone (F[3, 35] = 191.336, p < 0.0001). No differences in local tissue toxicity were found between LL-1 and LB. In patch-clamping recordings, 5 mM QX-OH produced ~20% inhibition of INa currents. LB at 40 μM inhibited INa by 65.51%±3.63%, while QX-OH 2 mM+LB 40 μM inhibited INa by 77.37%±3.36% (t[14] = 2.358, p = 0.025), and QX-OH 5 mM+LB 40 μM inhibited INa by 83.88%±1.57% (t[13] = 4.191, p = 0.0003). Furthermore, INa inhibition by QX-OH+LB was more persistent than that of LB alone during washout.ConclusionLL-1 can produce an additive and stable inhibition of Nagv currents, which can contribute to the long-lasting regional anesthetic action.

Evaluation of a Triple Antibiotic Paste as a Root Canal Obturating Material for Deciduous Teeth: A Study Protocol

Background: Teeth with infected root canals, secondary to endodontic infections are a common problem in primary as well as permanent dentition. The key to successful endodontic treatment is seen only after the complete removal of infection from root canals. Systemic antibiotics have limited reach to endodontic spaces. In pediatric dentistry, difficulties in antimicrobial control require the development of a new root canal obturating paste with broad antimicrobial activity, minimal tissue toxicity, and high safety index. In this experimental study, a new Triple Antibiotic Obturating Paste (TAOP) will be developed and its efficacy will be evaluated.&#x0D; Methods and Design: This is a pre-clinical in-vitro microbiological and in-vivo animal study, utilizing laboratory-grown white Wistar rats aged 2-3 months and weighing 200-300 grams. The antibiotic sensitivity test (AST) will be conducted using 21 standard aerobic and anaerobic microbial strains for determining potency through serial dilution and agar diffusion assay. The systemic and local tissue toxicity will be assessed by inserting the test and control materials into the dorsal connective tissues of the experimental rats. The antimicrobial efficacy of triple antibiotic obturating paste [thermo-modulated in-situ polymeric hydrogel matrix of TAOP, containing chitosan-carbopol and poloxamer blended with clindamycin (5%), metronidazole (5%), and doxycycline (1%)] will be evaluated against Metapex [Ca(OH)2-Iodoform paste] on endodontic microflora. The microbiological study data will be evaluated through One-way ANOVA trailed by ‘Tuckey’s post hoc test’ for intergroup as well as, t-test for intragroup comparison. The animal study data will be evaluated through One-way ANOVA for intergroup and ‘paired t-test’ for intragroup comparison.&#x0D; Results: The newly developed bio-degradable obturating material will be more suitable than the conventionally used one, to eliminate resistant endodontic pathogens from root canal systems, along with good pharmacokinetic and pharmacodynamic responses as well as minimal local and systematic tissue toxicity when used in primary teeth.&#x0D; Conclusion: The application of such novel multi-antibiotic formulation as an obturating material not only will achieve efficient disinfection of the endodontic spaces but also increase chances of therapeutic success due to the elimination of side effects associated with cytotoxicity and material properties as it contains most of the bioresorbable organic ingredients.

First Evaluation of Temporal and Spatial Fractionation in Proton Minibeam Radiation Therapy of Glioma-Bearing Rats.

Simple SummaryProton minibeam radiation therapy (pMBRT) is a novel therapeutic approach based on a distinct dose delivery method: the dose distributions follow a pattern with regions of peaks (high doses) and valleys (low doses). pMBRT was shown to be able to widen the therapeutic window in glioma-bearing rats. In previous studies the irradiation was performed in one single fraction. The work reported in this manuscript is the first evaluation detailing the response of glioma-bearing rats to a temporal fractionation in proton minibeam radiation therapy, delivered under a crossfire geometry. A significant increase of the median survival time was obtained when the dose was delivered over two sessions as opposed to in a single fraction. This result could facilitate the path towards pMBRT treatments.(1) Background: Proton minibeam radiation therapy (pMBRT) is a new radiotherapy technique using spatially modulated narrow proton beams. pMBRT results in a significantly reduced local tissue toxicity while maintaining or even increasing the tumor control efficacy as compared to conventional radiotherapy in small animal experiments. In all the experiments performed up to date in tumor bearing animals, the dose was delivered in one single fraction. This is the first assessment on the impact of a temporal fractionation scheme on the response of glioma-bearing animals to pMBRT. (2) Methods: glioma-bearing rats were irradiated with pMBRT using a crossfire geometry. The response of the irradiated animals in one and two fractions was compared. An additional group of animals was also treated with conventional broad beam irradiations. (3) Results: pMBRT delivered in two fractions at the biological equivalent dose corresponding to one fraction resulted in the highest median survival time, with 80% long-term survivors free of tumors. No increase in local toxicity was noted in this group with respect to the other pMBRT irradiated groups. Conventional broad beam irradiations resulted in the most severe local toxicity. (4) Conclusion: Temporal fractionation increases the therapeutic index in pMBRT and could ease the path towards clinical trials.

Pharmacokinetic and safety assessment of carboplatin-impregnated calcium sulfate hemihydrate beads in eight rats.

Evaluate local tissue toxicity and plasma platinum (Pt) in vivo after subcutaneous implantation of carboplatin-impregnated calcium sulfate hemihydrate (CI-CSH) beads. In vivo experimental study. Eight male Sprague-Dawley rats. CI-CSH beads were implanted subcutaneously (5mg carboplatin/rat; 13.5mg/kg carboplatin; 7.08 mg/kg Pt; 1.18 mg/m2 Pt) in eight rats (d0). Wound healing (daily), radiographic bead dissolution (weekly), systemic Pt uptake (plasma-Pt), local tissue Pt (d28), and histologic changes compared to nonincised and incised catheterization sites (d28) were assessed. Blood and tissue samples were analyzed by inductively coupled plasma mass spectrometry for Pt, and pharmacokinetic analysis was performed using noncompartmental methods. One rat died at d10, the remainder survived until d28. No wound complications were seen. The CI-CSH implantation site had higher histopathology scores than the other sites for necrosis (p=.013) and fibrosis (p=.013). Beads decreased in density radiographically (d0 to d28) (p=.062). Peak plasma-Pt concentration was 225.78 ng/ml at 12 h, and decreased over time, but Pt was still detectable on d28. The elimination half-life was 5.03 ± 1.13 days. Only 1.69% of implanted Pt remained in the beads at d28. CI-CSH beads incited microscopic mild inflammation but wound healing was not impaired. Pt was absorbed systemically and the release from the beads was near complete at d28. Piled CI-CSH bead implantation is well tolerated in rats with similar elution profile as previously described. Beads were radiographically visible at d28. Minimal Pt was detected systemically suggesting Pt release does not match bead dissolution.

Desgaste das próteses da articulação temporomandibular: uma revisão narrativa

Temporomandibular joint (TMJ) prostheses can be a stock or custom-made replacement of the related maxillomandibular structures such as condyle and fossa. In the last years, several materials and design have been assessed in an attempt to improve the mechanical performance of TMJ prostheses. This study aims to report literature data on the wear of temporomandibular joint prostheses and potential biological risks to the patients. Studies reported a significant deterioration of the sliding contact surfaces of TMJ prostheses. Material loss as a result of wear causes condyle/fossa mismatch and the modification of contact pressure and chewing forces loading. As a further consequence of wear, metal particles are released to the surrounding tissues with a high risk of local tissue toxicity and systemic toxicity through the bloodstream. The presence of particles induces the stimulation of inflammatory reactions depending on the concentration and size of debris.

A Preliminary Analysis of the Wear Pathways of Sliding Contacts on Temporomandibular Joint Total Joint Replacement Prostheses

In the last years, several materials and design have been assessed in an attempt to improve the mechanical performance of temporomandibular joint total joint replacement (TMJ TJR) prostheses. However, the wear of the TMJ TJR condyle to the polymer-based fossa component during loading and sliding movements. That promotes the release of debris and risks of toxicity to the surrounding tissues. The purpose of this study was to perform a narrative literature review on the wear of TMJ TJR sliding contacts and potential toxicity of metallic debris to the patients. Previous studies reported a significant deterioration of the sliding contact surfaces of TMJ TJR prostheses. Material loss as a result of wear can cause a TMJ TJR condyle/fossa mismatch and the modification of the contact pressure and chewing loading. As a further consequence of wear, metal particles are released to the surrounding tissues with a high risk of local tissue and systemic toxicity through the bloodstream. The presence of particles induces the stimulation of inflammatory reactions depending on the concentration and size of debris. Thus, CoCr-based condyle release metallic ions and sub-micron particles that can be engulfed by macrophages or internalized by other tissue cells. The wear and material loss of TMJ TJR could be decreased by design optimization and novel materials with low friction and contact pressure. That consequently decrease the amount of metallic ions and particles to the surrounding tissues, preventing peri-prosthetic inflammatory reactions.

Results of radiotherapy in squamous cell laryngeal cancer: A tomotherapy center experience.

Laryngeal cancer is a common type of head and neck cancer (HNC). Radiotherapy (RT) is a mainstay for curative treatment. Intensity-modulated RT (IMRT) is a standard technique today, as it provides of higher survival and local control and lower normal tissue toxicity. One of IMRT devices is helical tomotherapy (HT). The HT treatment results of HNC patients have been reported in few studies. We aimed to investigate the results of squamous cell laryngeal carcinoma patients treated with helical tomotherapy. Forty-five laryngeal cancer patients were selected according to the inclusion criteria. Radiotherapy (RT) plans were set in the Hi-Art HT planning system. Image-gated RT (IGRT) technique was used. Appropriate patients received simultaneous cisplatin. Treatment response rates were evaluated at the post-RT third and sixth months. Survival times were calculated with the Kaplan-Meier method. The factors affecting the treatment results were evaluated using Log-rank and Cox regression tests. A P value of less than 0.05 was accepted as statistically significant. The median age was 65 (28-84) years. The median symptom duration was 6 (1-60) months. The RT dose for the early and the locally advanced disease was median 63 Gy (60.75-66) and 66 Gy (60-70), respectively. The RT interruption was median two (0-20) days. The patients were followed up to 25 (1-45) months. Grade 2 xerostomia and dysphagia rates were 55% and 7%, respectively. The 3-year estimates of overall survival (OS), disease-free survival (DFS), metastasis-free survival (DMFS), and locoregional recurrence-free survival (RRFS) were 71.7%, 60.4%, 84.9%, and 68.5%, respectively. In univariate analysis, the presence of N2 disease was a negative prognostic for DFS (P = 0.05) and DMFS (P = 0.003). RT interruption >2 days was a negative prognostic for OS (P = 0.005), DFS (P = 0.02), and RRFS (P = 0.023). In the multivariate analysis, symptom duration >6 months was found to be the only significant factor for DFS (P < 0.05). Intensity-modulated radiation with HT achieved comparable clinical outcomes with acceptable toxicity in laryngeal carcinoma.

An Ingestible Self-Polymerizing System for Targeted Sampling of Gut Microbiota and Biomarkers.

A proof-of-concept for the fabrication of a self-polymerizing system for sampling of gut microbiome in the upper gastrointestinal (GI) tract is presented. An orally ingestible microdevice is loaded with the self-polymerizing reaction mixture to entrap gut microbiota and biomarkers. This polymerization reaction is activated in the aqueous environment, like fluids in the intestinal lumen, and causes site-specific microsampling in the gastrointestinal tract. The sampled microbiota and protein biomarkers can be isolated and analyzed via high-throughput multiomic analyses. The study utilizes a hollow microdevice (Su-8, ca. 250 μm), loaded with an on-board reaction mixture (iron chloride, ascorbic acid, and poly(ethylene glycol) diacrylate monomers) for diacrylate polymerization in the gut of an animal model. An enteric-coated rat capsule was used to orally gavage these microdevices in a rat model, thereby, protecting the microdevices in the stomach (pH 2), but releasing them in the intestine (pH 6.6). Upon capsule disintegration, the microdevices were released in the presence of luminal fluids (in the small intestine region), where iron chloride reacts with ascorbic acid, to initiate poly(ethylene glycol) diacrylate polymerization via a free radical mechanism. Upon retrieval of the microdevices, gut microbiota was found to be entrapped in the polymerized hydrogel matrix, and genomic content was analyzed via 16s rRNA amplicon sequencing. Herein, the results show that the bacterial composition recovered from the microdevices closely resemble the bacterial composition of the gut microenvironment to which the microdevice is exposed. Further, histological assessment showed no signs of local tissue inflammation or toxicity. This study lays a strong foundation for the development of untethered, non-invasive microsampling technologies in the gut and advances our understanding of host-gut microbiome interactions, leading to a better understanding of their commensal behavior and associated GI disease progression in the near future.

Clinical and Dosimetric Comparison of Interstitial Applications Using Martinez Universal Perineal Interstitial Template (MUPIT) and Syed–Neblett Template for Carcinoma Cervix

MUPIT and Syed–Neblett Template are the two commonly used systems for interstitial brachytherapy for gynecological cancers in India. A retrospective study was done to compare and evaluate the outcome, dosimetric data and the toxicities of the two perineal template-based high dose rate brachytherapies in patients diagnosed of cervical cancer and vaginal carcinoma. Between January 2010 and January 2013, 62 patients treated with interstitial transperineal brachytherapy using MUPIT and Syed–Neblett Template at a tertiary care center of Eastern India were included in the study. The median EBRT dose was 50 Gy; ISRT (interstitial brachytherapy) dose was 21 Gy. The dosimetric data and clinical outcome and the toxicity profile were obtained from our file archive and TPS archives. These were correlated with follow-up status regarding toxicity and locoregional recurrence and control. During the study period, 62 patients received ISRT of which 8 were of vault recurrence. Of these 62 patients, 37 were treated using Syed–Neblett and 25 using MUPIT. Median age was 45 years; ISRT dose was similar in both groups (21 Gy in 3 fractions once a week). The mean EQD2 to the 2 cc bladder and 2 cc rectum was 75.4 Gy and 72.21 Gy in the Syed cohort and 76.83 Gy and 75.38 Gy in the MUPIT cohort, respectively (p = 0.12 and 0.09). Acute toxicity was mostly grade 1 and 2 genitourinary (%) or grade 1 and 2 rectal (%). Most common late toxicity was gastrointestinal bleeding and dysuria: 16.22% and 8.35% in the Neblett arm and 18.18 and 9% in the MUPIT arm. With a median follow-up of 27 months, the local control rate was 53% in the Neblett arm and 67% in the MUPIT arm (p = .32). Though there were differences between the dose volumes received by the OAR and the target, the local control rates and long-term normal tissue toxicity were found to be not significantly different between the two systems of transperineal brachytherapy for cervical cancers.

High-frequency, low-intensity ultrasound and microbubbles enhance nerve blockade

Site 1 sodium channel blockers (S1SCBs such as tetrodotoxin [TTX] and the saxitoxins) are ultrapotent local anesthetics that bind extracellular domains of voltage-dependent sodium channels [1]. S1SCBs do not cross the blood brain barrier and have low affinity for the cardiac sodium channel isoform [2,3], and so do not cause seizures [4] or arrhythmias, making TTX an attractive alternative to conventional local anesthetics [5,6]. Local anesthesia with S1SCBs has been described in numerous reports in animal models [7–11], and is now starting to be applied in humans [12] [13]. However, due to their very hydrophilic nature S1SCBs have limited penetration to peripheral nerves even with local injection, and require relatively high concentrations to achieve consistent nerve blockade [9]. Those high concentrations can be associated with systemic toxicity. One approach to enhancing the effect of S1SCBs has been to co-inject them with second or third drugs with adjuvantic effects [7,8,14,15]. However, such couplings can entail the side-effects of the second drugs, such as the local tissue toxicity of “conventional” amino-amide and amino-ester local anesthetics or the vasoconstriction and/or tachycardia seen with epinephrine. An alternative approach is to enhance the penetration of S1SCBs to the nerve. Previously we have shown that co-injection of TTX with chemical permeation enhancers could enhance the effect of S1SCBs, albeit with some adverse tissue reaction at high concentrations [16,17]. Ultrasound-mediated drug delivery has the potential to enhance nerve blockade without adverse tissue reaction. Acoustic waves can enhance drug delivery through the sclera [18], the stratum corneum [19,20], across barriers within the gastrointestinal tract [21,22], and the blood brain barrier [23,24]. The effect of high-frequency ultrasound on drug flux across skin (sonophoresis) can be enhanced by exogenous microbubbles [25,26]. In this study, we hypothesized that ultrasound treatment would increase the flux of hydrophilic molecules, such as S1SCBs, across biological barriers to the surface of the peripheral nerve. We used TTX as a model S1SCB. We studied high-frequency, low-intensity ultrasound (HFLIU), parameters similar to those used in clinical imaging. This frequency and intensity range is theoretically safe for a broad range of applications. We evaluated the effects of HFLIU with and without the addition of exogenous microbubbles on TTX-mediated nerve blockade. We also verified whether effects of ultrasound and microbubbles were applicable to local anesthetics in general by testing their effect on the amino-amide local anesthetic bupivacaine.

Low-Energy Intraoperative Radiation Therapy and Competing Risks of Local Control and Normal Tissue Toxicity

Low-Energy Intraoperative Radiation Therapy and Competing Risks of Local Control and Normal Tissue Toxicity

The quaternary lidocaine derivative QX-314 in combination with bupivacaine for long-lasting nerve block: Efficacy, toxicity, and the optimal formulation in rats.

ObjectiveThe quaternary lidocaine derivative (QX-314) in combination with bupivacaine can produce long-lasting nerve blocks in vivo, indicating potential clinical application. The aim of the study was to investigate the efficacy, safety, and the optimal formulation of this combination.MethodsQX-314 and bupivacaine at different concentration ratios were injected in the vicinity of the sciatic nerve in rats; bupivacaine and saline served as controls (n = 6~10). Rats were inspected for durations of effective sensory and motor nerve blocks, systemic adverse effects, and histological changes of local tissues. Mathematical models were established to reveal drug-interaction, concentration-effect relationships, and the optimal ratio of QX-314 to bupivacaine.Results0.2~1.5% QX-314 with 0.03~0.5% bupivacaine produced 5.8~23.8 h of effective nerve block; while 0.5% bupivacaine alone was effective for 4 h. No systemic side effects were observed; local tissue reactions were similar to those caused by 0.5% bupivacaine if QX-314 were used < 1.2%. The weighted modification model was successfully established, which revealed that QX-314 was the main active ingredient while bupivacaine was the synergist. The formulation, 0.9% QX-314 plus 0.5% bupivacaine, resulted in 10.1 ± 0.8 h of effective sensory and motor nerve blocks.ConclusionThe combination of QX-314 and bupivacaine facilitated prolonged sciatic nerve block in rats with a satisfactory safety profile, maximizing the duration of nerve block without clinically important systemic and local tissue toxicity. It may emerge as an alternative approach to post-operative pain treatment.

Biocompatible hybrid allyl 2-cyanoacrylate and hydroxyapatite mixed for bio-glue

Despite cyanoacrylate’s numerous advantages such as good cosmetic results and fast application for first aid, drawbacks such as brittleness and local tissue toxicity have limited their application. In this study, to improve both the biocompatibility and mechanical properties of cyanoacrylate, allyl 2-cyanocarylate was pre-polymerized and mixed with poly(L-lactide-co-ε-caprolactone) (PLCL, 50:50) as biodegradable elastomer and mixed with hydroxyapatite (HA) as multifunctional bio-glue for variety body application. Hybridized allyl 2-cyanoacrylate (Hybridized Cy) was mixed with pre-polymerization allyl 2-cynaocarylate and PLCL. For the evaluation of various properties of hybridized Cy/HA bio-glue mixtures, bond strength, surface analysis (SEM, XRD), cell viability, and biocompatibility were confirmed. Especially, optimal condition for hybridized Cy/HA bio-glue was determined as 1.2 wt% HA mixture ratio through bond strength. Surface morphology has smooth form to increase HA mixture ratio. Cell viability increased with optimal ration of hybridized Cy/HA. These results indicate that hybridized Cy/HA bio-glue can be used widely as advanced adhesive in various fields.

A new F(abʹ)2 antivenom for the treatment of crotaline envenomation in children

Study objectiveTo evaluate the efficacy and safety of a new F(abʹ)2 antivenom preparation in the treatment of Crotalinae envenomation in children. MethodsWe present a case series of children younger than 16 years who suffered Crotalinae envenomation and were treated with a new F(abʹ)2 antivenom. Envenomated children treated with the new antivenom were assessed for efficacy of the product, defined as improvement of any hemotoxicity (hypofibrinogenemia, defined as fibrinogen <150 mg/dL, or thrombocytopenia, defined as platelets <150 000/mm3), and the cessation of the advancement of swelling. Safety was also evaluated by monitoring for adverse events. A secondary parameter assessed in these children was recurrent hemotoxicity after initial control of signs and symptoms with follow-up visits and laboratory testing on posttreatment days 5, 8, and 15. ResultsTwenty-one children received the F(abʹ)2 antivenom. Efficacy was achieved in all children receiving the product with initial control of swelling and improvement in those with hemotoxicity. No patients suffered anaphylaxis or any other serious adverse events from the F(abʹ)2 treatment. There were no cases of recurrent hemotoxicity recorded in the study between time of initial control and postinfusion day 15. ConclusionsIn this series of children, the F(abʹ)2 antivenom appeared to be both safe and effective in the treatment of hemotoxicity and local tissue toxicity (swelling) from Crotalinae envenomation.