Ropivacaine as a novel AKT1 specific inhibitor regulates the stemness of breast cancer.

BACKGROUND: Ropivacaine, a local anesthetic, exhibits anti-tumor effects in various cancer types. However, its specific functions and the molecular mechanisms involved in breast cancer cell stemness remain elusive. METHODS: The effects of ropivacaine on breast cancer stemness were investigated by in vitro and in vivo assays (i.e., FACs, MTT assay, mammosphere formation assay, transwell assays, western blot, and xenograft model). RNA-seq, bioinformatics analysis, Western blot, Luciferase reporter assay, and CHIP assay were used to explore the mechanistic roles of ropivacaine subsequently. RESULTS: Our study showed that ropivacaine remarkably suppressed stem cells-like properties of breast cancer cells both in vitro and in vivo. RNA-seq analysis identified GGT1 as the downstream target gene responding to ropivacaine. High GGT1 levels are positively associated with a poor prognosis in breast cancer. Ropivacaine inhibited GGT1 expression by interacting with the catalytic domain of AKT1 directly to impair its kinase activity with resultant inactivation of NF-κB. Interestingly, NF-κB can bind to the promoter region of GGT1. KEGG and GSEA analysis indicated silence of GGT1 inhibited activation of NF-κB signaling pathway. Depletion of GGT1 diminished stem phenotypes of breast cancer cells, indicating the formation of NF-κB /AKT1/GGT1/NF-κB positive feedback loop in the regulation of ropivacaine-repressed stemness in breast cancer cells. CONCLUSION: Our finding revealed that local anesthetic ropivacaine attenuated breast cancer stemness through AKT1/GGT1/NF-κB signaling pathway, suggesting the potential clinical value of ropivacaine in breast cancer treatment.

Lidocaine Inhibits Rat Prostate Cancer Cell Invasiveness and Voltage-Gated Sodium Channel Expression in Plasma Membrane.

There is increasing evidence, mostly from breast cancer, that use of local anaesthetics during surgery can inhibit disease recurrence by suppressing the motility of the cancer cells dependent on inherent voltage-gated sodium channels (VGSCs). Here, the possibility that lidocaine could affect cellular behaviours associated with metastasis was tested using the Dunning cell model of rat prostate cancer. Mostly, the strongly metastatic (VGSC-expressing) Mat-LyLu cells were used under both normoxic and hypoxic conditions. The weakly metastatic AT-2 cells served for comparison in some experiments. Lidocaine (1-500 µM) had no effect on cell viability or growth but suppressed Matrigel invasion dose dependently in both normoxia and hypoxia. Used as a control, tetrodotoxin produced similar effects. Exposure to hypoxia increased Nav1.7 mRNA expression but VGSCα protein level in plasma membrane was reduced. Lidocaine under both normoxia and hypoxia had no effect on Nav1.7 mRNA expression. VGSCα protein expression was suppressed by lidocaine under normoxia but no effect was seen in hypoxia. It is concluded that lidocaine can suppress prostate cancer invasiveness without effecting cellular growth or viability. Extended to the clinic, the results would suggest that use of lidocaine, and possibly other local anaesthetics, during surgery can suppress any tendency for post-operative progression of prostate cancer.

Effect of Intraligamentary Tramadol Hydrochloride on Anesthetic Success During Endodontic Management of Mandibular Molars: A Randomized Clinical Controlled Trial.

OBJECTIVE: Tramadol hydrochloride has shown local anesthetic properties similar to lidocaine, apart from a central analgesic effect. The present study evaluated the effect of the administration of tramadol alone or in addition to 2% lidocaine, as supplementary intraligamentary injections. METHODS: One hundred and five patients, with a failed primary inferior alveolar nerve block (IANB), were randomly allocated to one of the three supplementary intraligamentary groups: 2% lidocaine with 1: 80,000 epinephrine; tramadol hydrochloride (50 mg/mL); and 2% lidocaine with 1: 80,000 epinephrine plus tramadol hydrochloride. Patients received 1.2 mL doses (0.6 mL of each root). Patients reporting pain ≤54 on Heft Parker visual analogue scale (Heft-Parker VAS), were categorized as successful anesthesia. A finger pulse oximeter was used to measure the heart rates. The anesthetic success rates, gender, and type of tooth were compared using the Pearson chi-square test. The heart rates and age were statistically evaluated using the one-way analysis of variance test. The level of significance was set at 0.05 (p=0.05). RESULTS: The initial IANB was successful in 31% of cases. There were significant differences in the anesthetic success rates of different supplementary intraligamentary injections (χ2= 33.6, p<0.001, df=2). The 2% lidocaine-plus-tramadol resulted in significantly higher success rates than the two groups. There were no significant changes in the baseline heart rates of all groups (p>0.05). CONCLUSION: The addition of tramadol to 2% lidocaine with 1: 80,000 epinephrine, given as supplementary intraligamentary injection, can help in achieving successful anesthesia during the endodontic management of mandibular molars with irreversible pulpitis resistant to IANB injections.

Bupivacaine liposomal injectable suspension does not provide improved pain control in dogs undergoing abdominal surgery.

OBJECTIVE: To evaluate the difference in postoperative pain scores of dogs undergoing abdominal surgery receiving surgical incision infiltration of saline or bupivacaine liposomal injectable suspension (BLIS). ANIMALS: 40 dogs undergoing exploratory laparotomy. METHODS: Dogs were prospectively enrolled and randomized to receive either BLIS or saline surgical incision infiltration. All dogs received 5.3 mg of BLIS/kg or an equal volume of saline infiltrated in the muscle/fascia, subcutaneous tissue, and intradermal layer during closure. All dogs received a standardized postoperative pain management protocol. Pain assessment was performed at select time points postoperatively by blinded observers with an electronic algometer, short version of the Glasgow Composite Measure Pain Scale (GCMPS), and indirect measures of pain, including systolic blood pressure, heart rate, and serum cortisol levels. RESULTS: At day 0, blood pressure was higher in the saline group (149.6 vs 125.8 mm Hg; P = .006). At day 3, GCMPS was lower in the BLIS group (BLIS = 1, saline = 2, P = .027), though both average GCMPS scores were low and only 10 dogs were available for day 3 assessments (6 BLIS and 4 saline). No other differences in algometer readings, GCMPS scores, other measured parameters, or need for rescue analgesia were present between BLIS and saline groups at any time point. There was no difference in postoperative incisional infection rate or complications. CLINICAL RELEVANCE: Use of BLIS for exploratory laparotomy did not provide improved pain control over postoperative opioid administration alone. Patients that received BLIS had no increase in short-term complications.

Evaluation of pharmacological alternatives to reduce the pain and discomfort produced by electroejaculation in rams.

Electroejaculation (EE) represents the main technique for semen collection from domestic and wild animals independently of libido. However, the technique is associated with intense involuntary muscle contractions, vocalization, ataxia and lying down, caused by the electric stimulation of the nerves in the caudal epigastric region. These clinical manifestations represent important indicators of discomfort. In this context, the objective of this study was to evaluate two protocols of local anaesthetic blockade and two anatomical access for pharmacological desensitization of the caudal epigastric innervation as alternatives to promote comfort and reduce stress associated with EE in rams. For the study, four clinically healthy Dorper rams were selected. All animals were subjected to a design consisting of five semen collection treatments (n = 3 collections per treatment): T1-control, conventional EE without local anaesthetic blockade; T2, EE with ventral blockade (VB) of epigastric innervation using lidocaine hydrochloride 2%; T3, EE with VB of epigastric innervation using a combination of lidocaine hydrochloride 2% and fentanyl citrate; T4, EE with blockade of epigastric innervation through the perineal access using lidocaine hydrochloride 2%; T5, EE with blockade of epigastric innervation through the perineal access using a combination of lidocaine hydrochloride and fentanyl citrate. Seminal samples resulting from EE were subjectively evaluated for sperm motility and concentration, vigour and volume. Additionally, blood serum samples were collected for quantification of cortisol and creatine kinase (CK) enzyme. Assessments of stress and discomfort were conducted by measuring blood pressure, heart rate (HR) and respiratory rate (RR), as well as observing involuntary muscle contractions, ataxia and animal vocalization. No variations in blood pressure, sperm motility, vigour, CK, and cortisol were observed among the treatments. Individual variations were observed for the occurrence of vocalization (p = .0066), but there were no differences between the groups. Anaesthetic blockades conducted using the combination of lidocaine and fentanyl resulted in a lower incidence of ataxia during EE (p < .0001). It is concluded that the combination of fentanyl citrate and lidocaine hydrochloride results in less discomfort for animals undergoing EE, regardless of the anatomical access used for local anaesthetic blockades.

The impact of biological sex in peripheral nerve blockade: A prospective pharmacodynamic, pharmacokinetic and morphometric study in volunteers.

STUDY OBJECTIVE: The impact of biological sex in peripheral regional anaesthesia is largely unknown. We therefore designed a prospective study in volunteers to investigate the impact of biological sex on pharmacodynamic, pharmacokinetic and morphometric characteristics for peripheral nerve blockade. METHODS: The initial study plan was powered to include 90 volunteers to find a difference of 35 min in duration of sensory block (primary outcome variable) with 80% power and alpha error at 5%. After discussions in ethical review, a pilot study of 2 x 12 volunteers from each sex were studied. Female and male volunteers received ultrasound guided nerve blockade with 3.0 mL ropivacaine 7.5 mg mL-1. Sensory duration of blockade, as the primary outcome, was evaluated by pinprick testing. Secondary outcomes were sensory onset time of blockade, pharmacokinetic characteristics and the visibility of ulnar nerves using ultrasound. Analyses included Mann-Whitney U-statistics with P<0.05 (two-sided) as significant. RESULTS: After 24 participants, the median (IQR) duration of sensory blockade was 450 (420; 503) min in women and 480 (450; 510) min in men (P = 0.49). Sensory onset time of blockade, and ultrasound visibility of nerves were also similar between the study groups. The total drug exposure across time (AUC0-infinity) was significantly higher in women (P = 0.017). After a the planned power re-analysis after these 24 study paticipants, which suggested that > 400 subjects would be required with 80% power and alpha error of 5% to find significance for the primary outcome parameter for marginal differences, we terminated the study at this point. CONCLUSIONS: We did not detect significant differences between female and male study participants in terms of pharmacodynamic and morphometric characteristics after ultrasound guided ulnar nerve blocks. Women did show significantly greater pharmacokinetic ropivacaine exposures. The results of this study indicate that peripheral regional block pharmacodynamic characteristics are independent of the biological sex, whereas pharmacokinetic parameters are sex-dependent.

Comparison of lidocaine and lidocaine-xylazine for distal paravertebral anesthesia in dairy cattle.

OBJECTIVE: To determine the time of onset and duration of action of distal paravertebral blocks (DPB) in dairy cattle using lidocaine and lidocaine plus xylazine (LX). ANIMALS: 10 healthy adult Holstein cows. METHODS: Unilateral DPB were performed in 6 cows at L1, L2, and L4. They received 2 treatments (lidocaine and LX) in a blinded random crossover design. Due to treatment failure, 4 additional cows were enrolled. The lidocaine treatment received 1,800 mg (90 mL) of lidocaine, and treatment LX received 1,784 mg (89.2 mL) of lidocaine and 16 mg (0.8 mL) of xylazine. Anesthesia was assessed by response (rapid movements of the tail, directed movements of the feet, or turning of the head towards the site of the needle pricks) to 6 approximately 1-cm deep needle pricks to the paralumbar fossa with a 22-gauge hypodermic needle. The time of onset, duration of action, maximum sedation score, and average heart rate (HR) were compared between treatments. RESULTS: Duration of anesthesia was significantly prolonged after DPB in cows treated with LX (251.6 ± 96.94 minutes) compared to lidocaine (105.8 ± 35.9 minutes; P = .01). Treatment with LX was associated with significantly lower average heart rate (56 ± 3 beats/min) compared to cows treated with lidocaine (59 ± 3 beats/min; P = .045). The LX treatment was associated with mild sedation but was not significant (P = .063). CLINICAL RELEVANCE: The addition of xylazine to a lidocaine DPB provides a longer duration of anesthesia, is inexpensive and practical, and can be implemented with ease.

Stellate ganglion block for the management of electrical storm: An observational study.

INTRODUCTION: Electrical storm is a life-threatening emergency with a high mortality rate. When acute conventional treatment is ineffective, stellate ganglion block can help control arrhythmia by providing a visceral cervicothoracic sympathetic block. The objective of this study is to assess the effectiveness and safety of stellate ganglion block in the management of refractory arrhythmic storm. METHOD: Follow-up of a cohort of patients with refractory electrical storm that met the criteria for performing stellate ganglion block. The block was ultrasound-guided at C6 using local anaesthetic and a steroid - left unilateral first, bilateral if no response, followed by fluoroscopy-guided radiofrequency ablation at C7 if there was a favourable response but subsequent relapse. RESULTS: Seven patients were included. The in-hospital mortality rate was 14.29%. Four patients received unilateral and 3 bilateral stellate ganglion block. Six were ablated and 1 received an implantable cardioverter-defibrillator. Electrical storm was controlled temporarily beyond the effect of the local anaesthetic in all patients. Three patients underwent radiofrequency ablation and 2 underwent surgical thoracic sympathectomy. The only side effect was Horner's syndrome, which was observed in all cases after administering a stellate ganglion block with local anaesthetic. Two patients died after discharge and 4 are alive at the time of writing, 3 of them have not been re-admitted for ventricular events for more than 2 years. CONCLUSION: Ultrasound-guided stellate ganglion block is an effective and safe complement to standard cardiological treatment of refractory electrical storm.

Chloroprocaine antagonizes progression of breast cancer by regulating LINC00494/miR-3619-5p/MED19 axis.

Breast cancer, as the most prevalent female malignancy, leads the cancer-related death in women worldwide. Local anesthetic chloroprocaine exhibits antitumor potential, but its specific functions and underlying molecular mechanisms in breast cancer remain unclear. Here, we demonstrated chloroprocaine significantly inhibited proliferation, invasion and induced apoptosis of breast cancer cells in vitro. Tumor growth and pulmonary metastasis were also suppressed in BABL/c nude mice model with chloroprocaine treatment. LINC00494 was identified as one of the most downregulated long noncoding RNAs in chloroprocaine-treated breast cancer cells by high-throughput sequencing. Futhermore, high level of LINC00494 was positively associated with poor outcome of breast cancer patients. LINC00494 acted as a "miRNAs sponge" to compete with MED19 for the biding of miR-3619-5p, led to the upregulation of MED19. LINC00494/miR-3619-5p/MED19 axis participated in chloroprocaine-mediated inhibition of proliferation, invasion and promotion of apoptosis of breast cancer cells. Consequently, our finding suggested local anesthetic chloroprocaine attenuated breast cancer aggressiveness through LINC00494-mediated signaling pathway, which detailly revealed the clinical value of chloroprocaine during breast cancer treatment.

The use of granisetron on bupivacaine induced sciatic nerve block in rats.

PURPOSE: The effects of the 5-hydroxytryptamine (5-HT3) receptor antagonists on regional anaesthesia are complex and unclear. The present study was designed to test the hypothesis that granisetron, a selective 5-HT3 receptor antagonist, would decrease the duration of motor block, sensory block, and proprioception in a dose-dependent fashion in a rat model of bupivacaine-induced sciatic nerve blockade. MATERIALS AND METHODS: Thirty-eight male Wistar Albino rats that received unilateral sciatic nerve blocks were randomly divided into five experimental groups. Group B received a perineural of 0.3 ml of bupivacaine alone; Group BG800 received perineural 0.3 ml of bupivacaine and 800 µg of granisetron 10 min later; Group BG1200 received perineural 0.3 ml of bupivacaine and 1200 µg of granisetron 10 min later; Group BG1200IP received a perineural 0.3 ml of bupivacaine and an intraperitoneal injection of 1200 µg of granisetron 10 min later; and Group S was sham operated. A blinded investigator assessed motor, sensory and proprioception function every 10 min until the return of normal function. RESULTS: The medians for recovery times in Group B, Group BG800, Group BG1200, and Group BG1200IP were 105, 64, 85, and 120 min for motor function, respectively; 80, 64, 84, and 104 min for sensory function; 80, 63, 85, and 108 min were calculated for the proprioception function. The time to the return of normal motor, sensory, and proprioception function was not statistically significantly different between the groups (p > 0.05). Motor block did not develop in any of the rats in Group S. CONCLUSIONS: Local and systemic application of granisetron was not significantly decrease the duration of bupivacaine induced motor, sensory, and proprioception block of sciatic nerve in rat.

Buffered 2% articaine in buccal infiltration of mandibular molars: a randomized triple-blind clinical trial.

This crossover study aimed to compare the anesthetic effects of buffered 2% articaine with 1:200,000 epinephrine with that of non-buffered 4% articaine with 1:200,000 epinephrine. Forty-seven volunteers were administered two doses of anesthesia in the buccal region of the second mandibular molars in two sessions using 1.8 mL of different local anesthetic solutions. The onset time and duration of pulp anesthesia, soft tissue pressure pain threshold, and the score of pain on puncture and burning during injection were evaluated. The operator, volunteers, and statistician were blinded. There were no significant differences in the parameters: onset of soft tissue anesthesia (p = 0.80), duration of soft tissue anesthesia (p = 0.10), onset of pulpal anesthesia in the second (p = 0.28) and first molars (p = 0.45), duration of pulp anesthesia of the second (p = 0.60) and first molars (p = 0.30), pain during puncture (p = 0.82) and injection (p = 0.80). No significant adverse events were observed. Buffered 2% articaine with 1:200,000 epinephrine did not differ from non-buffered 4% articaine with 1:200,000 epinephrine considering anesthetic success, safety, onset, duration of anesthesia, and pain on injection.

The effects of local anesthetics on cancer cells.

During cancer surgery, the perioperative period is characterized by stress response and immunosuppression that can lead to further worsening of the disease and metastatic spread. Local anesthetics have antiproliferative, cytotoxic and antimetastatic effects on cancer cells in vitro. There is scientific evidence that local anesthetics possess anti-inflammatory effects, help to preserve normal immune function and reduce the possibility of metastatic spread. Anesthetic care affects pain, inflammation, and immunosuppression, which may have a great impact on the outcome of oncological patients. The use of local anesthetics during the perioperative period in oncological patients may have a beneficial effect on their survival and cancer recurrence. This article summarizes the effects of local anesthetics in vitro (Tab. 1, Fig. 1, Ref. 36). Keywords: local anesthetics, cancer cells.

Comparison of the effect of scalp block analgesia bupivacaine 0.25% and clonidine 2 µg/kg with bupivacaine 0.25% and dexamethasone 8 mg on cortisol levels and Numeric Rating Scale in craniotomy tumour.

INTRODUCTION: Craniotomy tumour is brain surgery that can induce a stress response. The stress response can be measured using haemodynamic parameters and plasma cortisol concentration. The stress response that occurs can affect an increase in sympathetic response, such as blood pressure and heart rate, which can lead to an increase in intracranial pressure. Scalp block can reduce the stress response to surgery and post-operative craniotomy tumour pain. The local anaesthetic drug bupivacaine 0.25% is effective in reducing post-operative pain and stress in the form of reducing plasma cortisol levels. The adjuvant addition of clonidine 2 µg/kg or dexamethasone may be beneficial. MATERIALS AND METHODS: A randomised control clinical trial was conducted at the Central Surgery Installation and Hasan Sadikin General Hospital Bandung and Dr. Mohammad Husein Hospital Palembang from December 2022 to June 2023. A total of 40 participants were divided into two groups using block randomisation. Group I receives bupivacaine 0.25% and clonidine 2 µg/kg, and group II receives bupivacaine 0.25% and dexamethasone 8 mg. The plasma cortisol levels of the patient will be assessed at (T0, T1 and T2). All the patient were intubated under general anesthaesia and received the drug for scalp block based on the group being randomised. Haemodynamic monitoring was carried out. RESULTS: There was a significant difference in administering bupivacaine 0.25% and clonidine 2µg/kg compared to administering bupivacaine 0.25% and dexamethasone 8 mg/kg as analgesia for scalp block in tumour craniotomy patients on cortisol levels at 12 hours post-operatively (T1) (p=0.048) and 24 hours post-surgery (T2) (p=0.027), while post-intubation cortisol levels (T0) found no significant difference (p=0.756). There is a significant difference in Numeric Rating Scale (NRS) at post-intubation (T0) (p=0.003), 12 hours post-operatively (T1) (p=0.002) and 24 hours post-surgery (T2) (p=0.004), There were no postprocedure scalp block side effects in both groups. CONCLUSION: The study found that scalp block with 0.25% bupivacaine and 2µg/kg clonidine is more effective in reducing NRS scores and cortisol levels compared bupivacaine 0.25% and dexamethasone 8mg in tumour craniotomy patients.

Peripheral nerve block adjuncts: which medication to choose? A narrative review of the current literature.

Enhancing the effect of peripheral nerve blockade by adding other classes of medications has long history of trial and error. Studies have identified multiple potentially beneficial adjuncts that work to either speed the onset of analgesia or prolong its duration. The benefits of these adjuncts must be weighed against the risks of systemic negative side effects. To date, the most commonly used adjuncts, and ones with the most robust scientific efficacy are, dexamethasone, dexmedetomidine and buprenorphine. This narrative review will discuss several classes of local anesthetic adjuncts and provide evidence for the clinical efficacy and side effect profile of the most commonly studied medications.

Effects of epinephrine, lidocaine, and prilocaine on viability and differentiation capacity of human adipose stem cells.

INTRODUCTION: Local anesthetics (LAs) are routinely administered in plastic and reconstructive surgery, e.g., as tumescent anesthesia adjunct in liposuction. Historically, these substances were assumed to act cytotoxically. Thus, the application of LA was avoided when handling adipose stem cells (ASCs). We recently determined that most LAs are not cytotoxic when ASCs are exposed to concentrations used for tumescent liposuction. However, there is limited information when combining LA with epinephrine and about the effects of prilocaine on ASCs. METHODS: We analyzed the effects of prilocaine or lidocaine in co-exposure with epinephrine on the viability of primary human ASCs, i.e., proliferation, metabolic activity, and cytotoxicity, using crystal violet-staining, PrestoBlue®-, and WST-1 assay. We quantified the impact of short-term incubation of lidocaine and epinephrine on the differentiation of ASCs into the adipogenic, chondrogenic, and osteogenic lineage. RESULTS: After 2 h, prilocaine (10 mM) significantly reduced metabolic activity and cell numbers, whereas lidocaine only inhibited metabolic activity. After 6 h, prilocaine (10 mM) and lidocaine significantly decreased metabolic activity as well as cell numbers. The application of high concentrations of epinephrine did not affect cell numbers but diminished metabolic activity. Combining lidocaine with epinephrine had no additional cytotoxic effect. Differentiation into the chondrogenic lineage was significantly inhibited by epinephrine. CONCLUSIONS: Deducing from our data, neither lidocaine combined with epinephrine nor prilocaine has a cytotoxic impact on ASCs in vitro at concentrations equivalent to those in tumescent anesthesia and has no long-lasting effect on the differentiation capacity of ASCs into the osteogenic and adipogenic lineage.

The effect of warming ropivacaine on ultrasound-guided subgluteal sciatic nerve block: a randomized controlled trial.

BACKGROUND: There is a long latent period for the sciatic nerve block before a satisfactory block is attained. Changes in the temperature of local anesthetics may influence the characters of the peripheral nerve block. This study was designed to evaluate the effect of warming ropivacaine on the ultrasound-guided subgluteal sciatic nerve block. METHODS: Fifty-four patients for distal lower limbs surgery were randomly allocated into warming group (group W, n = 27) or room tempeture group (group R, n = 27) with the ultrasound-guided subgluteal sciatic nerve block. The group W received 30 ml of ropivacaine 0.5% at 30℃ and the group R received 30 ml of ropivacaine 0.5% at 23℃. The sensory and motor blockade were assessed every 2 min for 30 min after injection. The primary outcome was the onset time of limb sensory blockade. RESULTS: The onset time of sensory blockade was shorter in group W than in group R (16 (16,18) min vs 22 (20,23) min, p < 0.001), and the onset time of motor blockade was also shorter in group W than in group R (22 (20,24) min vs 26 (24,28) min, p < 0.001). The onset time of sensory blockade for each nerve was shorter in group W than in group R (p < 0.001). No obvious differences for the duration of sensory and motor blockade and the patient satisfaction were discovered between both groups. No complications associated with nerve block were observed 2 days after surgery. CONCLUSIONS: Warming ropivacaine 0.5% to 30℃ accelerates the onset time of sensory and motor blockade in the ultrasound-guided subgluteal sciatic nerve block and it has no influence on the duration of sensory and motor blockade. TRIAL REGISTRATION: The trial was registered on October 3, 2022 in the Chinese Clinical Trial Registry ( https://www.chictr.org.cn/bin/project/edit?pid=181104 ), registration number ChiCTR2200064350 (03/10/2022).

The Local Anaesthetic Procaine Prodrugs ProcCluster® and Procaine Hydrochloride Impair SARS-CoV-2 Replication and Egress In Vitro.

As vaccination efforts against SARS-CoV-2 progress in many countries, there is still an urgent need for efficient antiviral treatment strategies for those with severer disease courses, and lately, considerable efforts have been undertaken to repurpose existing drugs as antivirals. The local anaesthetic procaine has been investigated for antiviral properties against several viruses over the past decades. Here, we present data on the inhibitory effect of the procaine prodrugs ProcCluster® and procaine hydrochloride on SARS-CoV-2 infection in vitro. Both procaine prodrugs limit SARS-CoV-2 progeny virus titres as well as reduce interferon and cytokine responses in a proportional manner to the virus load. The addition of procaine during the early stages of the SARS-CoV-2 replication cycle in a cell culture first limits the production of subgenomic RNA transcripts, and later affects the replication of the viral genomic RNA. Interestingly, procaine additionally exerts a prominent effect on SARS-CoV-2 progeny virus release when added late during the replication cycle, when viral RNA production and protein production are already largely completed.

Pharmacokinetics and metabolism of lidocaine HCl 2% with epinephrine in horses following a palmar digital nerve block.

BACKGROUND: Lidocaine is a local anesthetic that is sometimes administered in combination with epinephrine. The addition of epinephrine increases the time lidocaine remains at the site of administration, thus prolonging the duration of effect. Due to their potential to prevent the visual detection of lameness, the administration of local anesthetics is strictly regulated in performance and racehorses. Recent reports of positive regulatory findings for lidocaine in racehorses suggests a better understanding of the behavior of this drug is warranted. The objective of the current study was to describe serum and urine concentrations and the pharmacokinetics of lidocaine and its primary metabolites following administration in combination with epinephrine, as a palmar digital nerve block in horses. Twelve horses received a single administration of 1 mL of 2% lidocaine HCl (20 mg/horse) with epinephrine 1:100,000, over the palmar digital nerve. Blood samples were collected up to 30 h and urine samples up to 48 h post administration. Lidocaine and metabolite concentrations were determined by liquid chromatography- mass spectrometry and pharmacokinetic (non-compartmental and compartmental) analysis was performed. RESULTS: Serum concentrations of lidocaine and 3-hydroxylidocaine were above the LOQ of the assay at 30 h post administration and monoethylglycinexylidide (MEGX) and glycinexylidide (GX) were below detectable levels by 24 and 48 h, respectively. In urine, lidocaine, MEGX and GX were all non-detectable by 48 h post administration while 3-hydroxylidocaine was above LOQ at 48 h post administration. The time of maximal concentration for lidocaine was 0.26 h (median) and the terminal half-life was 3.78 h (mean). The rate of absorption (Ka) was 1.92 1/h and the rate of elimination (Kel) was 2.21 1/h. CONCLUSIONS: Compared to previous reports, the terminal half-life and subsequent detection time observed following administration of lidocaine in combination with epinephrine is prolonged. This is likely due to a decrease in systemic uptake of lidocaine because of epinephrine induced vasoconstriction. Results of the current study suggest it is prudent to use an extended withdrawal time when administering local anesthetics in combination with epinephrine to performance horses.

Assessment of cardiovascular alterations and catecholamines serum concentration after oral surgery in patients receiving local anesthetics with epinephrine: a randomized, blind, controlled clinical trial.

OBJECTIVES: A randomized controlled clinical trial was developed to evaluate the cardiovascular effects of local anesthetics with vasoconstrictors (LAVC) in healthy and hypertensive patients undergoing teeth extraction with lidocaine 2% with epinephrine 1:100,000. MATERIALS AND METHODS: Twenty patients were divided into control (CG - normotensive patients) and experimental groups (EG - hypertensive patients). The variables analyzed were heart rate (HR), oxygen saturation (SO2), systolic and diastolic blood pressure (SBP and DBP), serum catecholamine concentration (dopamine, epinephrine, and norepinephrine), ventricular and supraventricular extrasystoles (VES and SVES respectively), and ST segment depression. Data was obtained in three different moments (initial, trans, and final). Blood samples were taken to measure the catecholamines, and a Holter device was used to measure data from the electrocardiogram including a 24-h postoperative evaluation period. The Mann-Whitney test was used to identify differences between the two groups, and the Friedman test with the adjusted Wilcoxon posttest was used for intragroup evaluation for repeated measures. RESULTS: The EG presented a lower O2S in the initial period (p = 0,001) while the sysBP showed a statistical difference for the three evaluation periods with the EG presenting the highest values. The VES was higher for the EG during the 24-h postoperative evaluation period (p = 0,041). The SVES and the serum catecholamines showed were similar between the groups. The intragroup analysis revealed significant statistical difference for the sysBP in the EG with the trans period presenting the highest measurements. The extrasystole evaluation showed that the 24-h postoperative period presented most events with only the CG not presenting statistical difference for the variable VES during this period (p = 0,112). No ST segment depression was noticed for both groups. CONCLUSIONS: Teeth extraction with LAVC can be safely executed in hypertensive patients. Blood pressure should be monitored in these patients since the sysBP presented significant differences during the surgical procedures. Cardiac arrhythmia and the serum catecholamines concentration levels seem not to be altered by the surgical procedure. Also, serum catecholamines do not influence cardiovascular changes in this type of surgery. CLINICAL RELEVANCE: LAVC can be safely used in hypertensive patients and does not increase the risk of arrhythmias or cardiac ischemia.

The effects of pain following disbudding on calf memory.

Studies have found evidence of pain in the hours following hot-iron disbudding, but little is known about longer-lasting pain following this procedure. Work on humans and rats has shown that lasting pain can have negative effects on the formation and recall of memories. The objective of this study was to assess whether lasting pain following disbudding affects learning and memory in calves. A modified hole-board apparatus was used to assess how quickly calves were able to learn the locations of 4 bottles containing milk dispersed among 11 locations with empty bottles. At 14 d of age and after 6 d of training on this task, calves (n = 30) were randomly assigned to 3 treatments: disbudding with analgesic on the day of the procedure, disbudding with analgesic throughout the study, and sham disbudding. All calves were sedated, given a lidocaine cornual local block and a single injection of an nonsteroidal anti-inflammatory drugs. Starting on the day after their disbudding treatment, calves were tested daily using the modified hole-board apparatus. After 12 d of testing, the locations of the 4 milk-containing bottles were switched, and calves then relearned the locations of the rewarded bottles over the next 6 daily test sessions. We found general working memory (i.e., short-term memory) and reference memory (i.e., long-term memory) increased over the 12 d of testing, declined when locations were switched on d 13, and then again increased over the final 6 d of testing. We did not find an effect of treatment on any measure, perhaps because there was no lasting pain or because effects were too minor to detect using this test of spatial memory.