Targeted local anesthesia: a novel slow-release Fe3O4-lidocaine-PLGA microsphere endowed with a magnetic targeting function.

PURPOSE: Lidocaine microspheres can prolong the analgesic time to 24-48 h, which still cannot meet the need of postoperative analgesia lasting more than 3 days. Therefore, we added Fe3O4 to the lidocaine microspheres and used an applied magnetic field to attract Fe3O4 to fix the microspheres around the target nerves, reducing the diffusion of magnetic lidocaine microspheres to the surrounding tissues and prolonging the analgesic time. METHODS: Fe3O4-lidocaine-PLGA microspheres were prepared by the complex-emulsion volatilization method to characterize and study the release properties in vitro. The neural anchoring properties and in vivo morphology of the drug were obtained by magnetic resonance imaging. The nerve blocking effect and analgesic effect of magnetic lidocaine microspheres were evaluated by animal experiments. RESULTS: The mean diameter of magnetically responsive lidocaine microspheres: 9.04 ± 3.23 µm. The encapsulation and drug loading of the microspheres were 46.18 ± 3.26% and 6.02 ± 1.87%, respectively. Magnetic resonance imaging showed good imaging of Fe3O4-Lidocain-PLGA microspheres, a drug-carrying model that slowed down the diffusion of the microspheres in the presence of an applied magnetic field. Animal experiments demonstrated that this preparation had a significantly prolonged nerve block, analgesic effect, and a nerve anchoring function. CONCLUSION: Magnetically responsive lidocaine microspheres can prolong analgesia by slowly releasing lidocaine, which can be immobilized around the nerve by a magnetic field on the body surface, avoiding premature diffusion of the microspheres to surrounding tissues and improving drug targeting.

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.

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.

Putting the Pacific fat sleeper Dormitator latifrons (Pisces: Eleotridae) to sleep: effects of clove oil and lidocaine anesthetic.

Among the different handling techniques in aquaculture, the use of anesthetics has had a growing interest focused on guaranteeing animal welfare, and reducing possible stress situations during general handling. The aim of this study was to present the use of eugenol and lidocaine with non-invasive anesthesia procedures in Dormitator latifrons, in which the different stages of anesthesia (induction and recovery) were determined. One hundred and twenty healthy fish of average weight of 73.59 ± 13.53 g and standard length of 17 ± 1.36 cm were used. The experimental fish were subjected to fasting for 24 h prior to the tests. Five fish were subjected to eugenol (25, 50, 100, and 200 µL/L), and lidocaine (100, 200, 300, and 400 mg/L), in triplicate. The time to reach deep and recovery anesthesia were recorded and the data analyzed using ANOVA (α= 0.05). Organisms exposed to anesthetics evidenced early episodes of fast, short-distance swimming (initial hyperactivity) for short periods of time. Survival was 100% with both compounds and concentrations. Fish exposed to a eugenol concentration of 200 µL/L had longer anesthesia times and took longer time to recover (P<0.05). The most effective concentrations for eugenol and lidocaine were of 200 µL/L and 400 µL/L in juvenile fish, promoting rapid inductions, without compromising the conditions for the recovery of the fish. This work provides practical information for handling and transportation D. latiforns with the least possible stress and ensuring animal welfare.

Suppression of the excitability of rat nociceptive secondary sensory neurons following local administration of the Phytochemical, (-)-Epigallocatechin-3-gallate.

The phytochemical, polyphenolic compound, (-)-epigallocatechin-3-gallate (EGCG), is the main catechin found in green tea. Although a modulatory effect of EGCG on voltage-gated sodium and potassium channels has been reported in excitable tissues, the in vivo effect of EGCG on the excitability of nociceptive sensory neurons remains to be determined. Our aim was to investigate whether local administration of EGCG to rats attenuates the excitability of nociceptive spinal trigeminal nucleus caudalis (SpVc) neurons in response to mechanical stimulation in vivo. Extracellular single unit recordings were made from SpVc neurons in response to orofacial mechanical stimulation of anesthetized rats. The mean firing frequency of SpVc wide-dynamic range neurons following both non-noxious and noxious mechanical stimuli was significantly inhibited by EGCG in a dose-dependent and reversible manner. The mean magnitude of inhibition by EGCG on SpVc neuronal discharge frequency was similar to that of the local anesthetic, 1% lidocaine. Local injection of half-dose of lidocaine replaced the half-dose of EGCG. These results suggest that local injection of EGCG suppresses the excitability of nociceptive SpVc neurons, possibly via the inhibition of voltage-gated sodium channels and opening of voltage-gated potassium channels in the trigeminal ganglion. Therefore, administration of EGCG as a local anesthetic may provide relief from trigeminal nociceptive pain without side effects.

Effect of local administration of eicosapentaenoic acid on the jaw-opening reflex in rats.

Although eicosapentaenoic acid (EPA) application in vitro inhibits voltage-gated Na+ (Nav) channels in excitable tissues, the acute local effect of EPA on the jaw-opening reflex in vivo remains unknown. The aim of the present study was to determine whether local administration of EPA to adult male Wistar rats could attenuate the excitability of the jaw-opening reflex in vivo, including nociception. The jaw-opening reflex evoked by electrical stimulation of the tongue was recorded by a digastric muscle electromyogram (dEMG) in pentobarbital-anesthetized rats. The amplitude of the dEMG response was significantly increased in proportion to the electrical stimulation intensity (1×-5× threshold). At 3×, local administration of EPA dose-dependently inhibited the dEMG response, lasting 60 min, with maximum inhibition observed within approximately 10 min. The mean magnitude of dEMG signal inhibition by EPA was almost equal to that observed with a local anesthetic, 1% lidocaine, and with a half dose of lidocaine plus a half dose of EPA. These findings suggest that EPA attenuates the jaw-opening reflex, possibly by blocking Nav channels of primary nerve terminals, and strongly support the idea that EPA is a potential therapeutic agent and complementary alternative medicine for the prevention of acute trigeminal nociception.

Lidocaine Nerve Block Diminishes the Effects of Therapeutic Electrical Stimulation to Enhance Nerve Regeneration in Rats.

BACKGROUND: Although electrical stimulation (ES) can improve nerve regeneration, the impact of nerve block, such as lidocaine (Lido), on the therapeutic benefits of ES remains unclear. We used a rat tibial nerve transection-and-repair model to explore how either preoperative (PreOp) or postoperative (PostOp) nerve block affects ES-related improvement in regeneration. METHODS: Lewis rats were used in 1 of 2 studies. The first evaluated the effects of extraneural Lido on both healthy and injured nerves. In the second study, rats were randomized to 5 experimental groups: No ES (negative control), PreOp Lido, ES + PreOp Lido, PostOp + ES, and ES (positive control). All groups underwent tibial nerve transection and repair. In both studies, nerves were harvested for histological analysis of regeneration distal to the injury site. RESULTS: Application of extraneural Lido did not damage healthy or injured nerve based on qualitative histological observations. In the context of nerve transection and repair, the ES group exhibited improved axon regeneration at 21 days measured by the total number of myelinated fibers compared with No ES. Fiber density and percentage of neural tissue in the ES group were greater than those in both No ES and PreOp Lido + ES groups. ES + PostOp Lido was not different from No ES or ES group. CONCLUSIONS: Extraneural application of Lido did not damage nerves. Electrical stimulation augmented nerve regeneration, but Lido diminished the ES-related improvement in nerve regeneration. Clinical studies on the effects of ES to nerve regeneration may need to consider nerve block as a variable affecting ES outcome.

Comparative study to assess the effect of ropivacaine and a mixture of lidocaine and bupivacaine on intraocular pressure after peribulbar anesthesia for cataract surgery.

Purpose: To compare the efficacy of ropivacaine with a mixture of lidocaine and bupivacaine in peribulbar anesthesia for cataract surgery, in terms of post-block intraocular pressure (IOP). Methods: A one-year comparative study was done to compare two anesthetic solutions in peribulbar anesthesia for cataract surgery, from January 2020 to December 2020 at a tertiary health care hospital. Two hundred patients (40-70 years of age) planned for small-incision cataract surgery with posterior chamber intraocular lens (IOL) implantation under peribulbar anesthesia were included in the study. A single-site inferotemporal injection was given till a total eyelid drop was observed. The IOP was measured at four time-points: before block (control), 1-, 5-, and 15-minute post-block with a tonometer. Results: The 1-minute post-block mean IOP in both the groups was higher than the baseline levels. This reflected raised intraorbital pressure secondary to peribulbar injection of local anesthetic. However, the rise in 1-minute post-block IOP was significantly less in the ropivacaine group. The 5- and 15-min post-block mean IOP values in the ropivacaine group were significantly lower than the corresponding values of the lidocaine-bupivacaine group and baseline (control) ropivacaine values. Conclusion: The results of this study support that ropivacaine as a local anesthetic drug for peribulbar block for small-incision cataract surgery can be a suitable alternative to the lidocaine-bupivacaine combination. Studies involving a larger sample size are required to consider ropivacaine as a superior drug to the lidocaine-bupivacaine combination.

Inhibition of Nematocyst Discharge from Pelagia noctiluca (Cnidaria: Scyphozoa)-Prevention Measures against Jellyfish Stings.

Pelagia noctiluca stings are common in Mediterranean coastal areas and, although the venom is non-lethal, they are painful. Due to its high toxicity and abundance, P. noctiluca is considered a target species for the focus of research on active ingredients to reduce the symptoms of its sting. To determine the effect of 31 substances and formulations on nematocyst discharge, we performed three tests: (1) screening of per se discharge activator solutions, (2) inhibitory test with nematocyst chemical stimulation (5% acetic acid) and (3) inhibitory test quantifying the hemolytic area. Ammonia, barium chloride, bleach, scented ammonia, carbonated cola, lemon juice, sodium chloride and papain triggered nematocyst discharge. All of them were ruled out as potential inhibitors. Butylene glycol showed a reduction in nematocyst discharge, while the formulations of 10% lidocaine in ethanol, 1.5% hydroxyacetophenone in distilled water + butylene glycol, and 3% Symsitive® in butylene glycol inhibited nematocyst discharge. These last results were subsequently correlated with a significant decrease in hemolytic area in the venom assays versus seawater, a neutral solution. The presented data represent a first step in research to develop preventive products for jellyfish stings while at the same time attempting to clarify some uncertainties about the role of various topical solutions in P. noctiluca first-aid protocols.

In Vitro Drug Screening Using iPSC-Derived Cardiomyocytes of a Long QT-Syndrome Patient Carrying KCNQ1 & TRPM4 Dual Mutation: An Experimental Personalized Treatment.

Congenital long QT syndrome is a type of inherited cardiovascular disorder characterized by prolonged QT interval. Patient often suffer from syncopal episodes, electrocardiographic abnormalities and life-threatening arrhythmia. Given the complexity of the root cause of the disease, a combination of clinical diagnosis and drug screening using patient-derived cardiomyocytes represents a more effective way to identify potential cures. We identified a long QT syndrome patient carrying a heterozygous KCNQ1 c.656G>A mutation and a heterozygous TRPM4 c.479C>T mutation. Implantation of implantable cardioverter defibrillator in combination with conventional medication demonstrated limited success in ameliorating long-QT-syndrome-related symptoms. Frequent defibrillator discharge also caused deterioration of patient quality of life. Aiming to identify better therapeutic agents and treatment strategy, we established a patient-specific iPSC line carrying the dual mutations and differentiated these patient-specific iPSCs into cardiomyocytes. We discovered that both verapamil and lidocaine substantially shortened the QT interval of the long QT syndrome patient-specific cardiomyocytes. Verapamil treatment was successful in reducing defibrillator discharge frequency of the KCNQ1/TRPM4 dual mutation patient. These results suggested that verapamil and lidocaine could be alternative therapeutic agents for long QT syndrome patients that do not respond well to conventional treatments. In conclusion, our approach indicated the usefulness of the in vitro disease model based on patient-specific iPSCs in identifying pharmacological mechanisms and drug screening. The long QT patient-specific iPSC line carrying KCNQ1/TRPM4 dual mutations also represents a tool for further understanding long QT syndrome pathogenesis.

Buffering lidocaine heightens aversion to cornual nerve injections in dairy calves.

Best practice is to numb the horn buds before disbudding dairy calves, which can be achieved by injecting lidocaine, a local anesthetic, around the cornual nerve. In humans, the acute pain that occurs upon injection of lidocaine can be reduced by neutralizing the pH of the solution with an alkalizing agent, such as sodium bicarbonate. We evaluated whether buffering lidocaine would reduce calves' behavioral and physiological responses to cornual nerve blocks on the left and right sides of the head. Female Holstein calves were assigned to 1 of 3 treatments: cornual nerve blocks with 5.5 mL of unbuffered lidocaine (n = 9), buffered lidocaine (n = 9), or a sham procedure with no needle inserted (n = 9). Calves that received either type of lidocaine struggled more during the injection than sham calves. However, contrary to our hypothesis, struggling was most marked in calves that received buffered lidocaine. Similarly, calves administered unbuffered or buffered lidocaine had elevated heart rates for 1 or 3 min after the first injection, respectively, compared with at the end of the 5-min observation period. Calves in the buffered treatment had lower eye temperatures in the first half of the observation period compared with the second half, consistent with responses cattle show to other aversive procedures, but no changes over time were observed in the other 2 treatments. We detected no treatment differences in heart rate variability measures. These results suggest that cornual nerve blocks are aversive, at least in the short term, and that buffering the lidocaine worsens the calf's response to this procedure.

Evaluating the Preemptive Analgesic Effect of Photo-biomodulation Therapy on Pain Perception During Local Anesthesia Injection in Children: A Split-mouth Triple-blind Randomized Controlled Clinical Trial.

To evaluate the impact of photobiomodulation therapy (PBMT) on injection pain perception and compare it with a topical oral anesthetic gel. A total of 30 patients of 6 to 9 years-old seeking pulpotomy treatment of maxillary secondary primary molars of both sides were considered for this split-mouth triple-blind randomized clinical trial. On one side of the maxilla, the low-level laser (diode laser, 808 nm, 250 mW; 16.25 J; 32.5 J cm-2 ) was irradiated upon the buccal gingiva of the tooth, while a Benzocaine 20% topical anesthetic gel was applied on the other side. A gel with the same taste (strawberry) was applied for the placebo. The Wong-Baker Faces Pain Rating Scale was used to evaluate the injection pain and postoperation pain at two timestamps, 1 h and 24 h after treatment. Patients' heart rate was also evaluated. Paired t, Wilcoxon signed-rank test, McNemar and Friedman tests were used for statistical analyses. Results demonstrated that PBMT could significantly decrease the injection pain perception and heart rate alternations compared to the topical anesthetic gels (P = 0.000). However, no significant differences were documented between the two methods concerning the 1-h (P = 0.26) and 24-h (P = 1.00) postoperation pain. PBMT can be an effective nonpharmacological technique for controlling injection pain.

The Effect of Commonly Used Local Anesthetic on Bacterial Growth.

INTRODUCTION: Liposomal bupivacaine (LB) has emerged as a superior form of local anesthetic across numerous surgical subspecialties. The purpose of this study is to evaluate the ex-vivo antimicrobial effects of LB in comparison with traditional local anesthetics. METHODS: A standardized inoculum of bacteria commonly associated with surgical site infection was inoculated into a suspension of 1% lidocaine, 0.25% bupivacaine, Exparel (proprietary liposomally packaged 1.3% bupivacaine), and normal saline as a growth control. RESULTS: In all five bacteria tested, the medium inoculated with traditional local anesthetics reduced growth to a greater degree than LB-inoculated plates. Both conventional local anesthetics reduced the growth of all bacteria when compared with the control with the exception of methicillin-susceptible Staphylococcus aureus growth in bupivacaine. LB-inoculated plates had equivalent growth to the control in all plates with the exception of Escherichia coli plates which demonstrated superior growth. CONCLUSIONS: The results of this simple ex-vivo model suggest that the liposomal packaging of bupivacaine may decrease this local anesthetic's innate antibacterial properties.

Digit Replantation under Wide-Awake Local Anesthesia.

BACKGROUND: Digit replantation under wide-awake local anesthesia is a challenging method, and there are only a few works of literature on this procedure. This article describes the authors' clinical experience in finger replantation under wide-awake local anesthesia compared to general anesthesia. METHODS: Fifty-one patients who received single finger replantation after initial sharp amputation were included in the study, of whom 16 received wide-awake local anesthesia and 35 general anesthesia treatment. The indications for wide-awake local anesthesia were sharp amputation injury, estimated operation time less than 3 hours, and cooperative patients. The wide-awake local anesthesia was performed with 1% or 2% lidocaine infiltrated at the volar midpoint of the metacarpophalangeal joint of the affected digit without sedation medications. Demographic data included surgical outcome, waiting time, operation time, and hospital stay. RESULTS: A total of 51 consecutive patients were included in this study. There were significantly shorter waiting times and operation times in the wide-awake local anesthesia group. The other parameters showed no significant differences. The overall success rate was 76.47 percent, with a mean overall operation time of 207 minutes. CONCLUSIONS: In selected patients, finger replantation can be successfully performed under wide-awake local anesthesia, which has lower anesthesia risk and fewer medical expenses than general anesthesia. The method is feasible for single-digit replantation. Therefore, the finger replantation under wide-awake local anesthesia is a practicable alternative to general anesthesia. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, III.

Tumescent local anesthesia versus general anesthesia for subcutaneous implantable cardioverter-defibrillator implantation.

BACKGROUND: Subcutaneous implantable cardioverter-defibrillator (S-ICD) is an effective alternative to transvenous implantable cardioverter-defibrillator. General anesthesia (GA) is considered the standard sedation approach because of the pain caused by the manipulation of subcutaneous tissue with S-ICD implantation. However, GA carries several limitations, including additional risk of adverse events, prolonged in-room times, and increased costs. OBJECTIVE: The purpose of this study was to define the effectiveness and safety of tumescent local anesthesia (TLA) in comparison to GA in patients undergoing S-ICD implantation. METHODS: We performed a prospective, nonrandomized, controlled, multicenter study of patients referred for S-ICD implantation between 2019 and 2020. Patients were allocated to either TLA or GA on the basis of patient's preferences and/or anesthesia service availability. TLA was prepared using lidocaine, epinephrine, sodium bicarbonate, and sodium chloride. All patients provided written informed consent, and the institutional review board at each site provided approval for the study. RESULTS: Sixty patients underwent successful S-ICD implantation from July 2019 to November 2020. Thirty patients (50%) received TLA, and the rest GA. There were no differences between groups with regard to baseline characteristics. In-room and procedural times were significantly shorter with TLA (107.6 minutes vs 186 minutes; P < .0001 and 53.2 minutes vs 153.7 minutes; P < .0001, respectively). Pain was reported less frequently by patients who received TLA. The use of opioids was significantly reduced in patients who received TLA (23% vs 62%; P = .002). CONCLUSION: TLA is an effective and safe alternative to GA in S-ICD implantation. The use of TLA is associated with shorter in-room and procedural times, less postprocedural pain, and reduced usage of opioids and acetaminophen for analgesia.

Effects of vasopressin on anesthetic response time and circulatory dynamics of lidocaine.

This study aimed to investigate the hypothesis that vasopressin extends the anesthetic response time of lidocaine and does not affect the circulatory dynamics. Rats were sedated with isoflurane; subsequently, breathing was maintained through mechanical ventilation. We infiltrated the first molar area of the upper left jaw with saline (NS, test solution), 2% lidocaine (L), 0.025 IU vasopressin-supplemented 2% lidocaine, 0.05 IU vasopressin-supplemented 2% lidocaine, 0.1 IU vasopressin-supplemented 2% lidocaine, and 0.2 IU vasopressin-supplemented 2% lidocaine (VL4). Further, anesthetic response times were measured up to 30 min using electric pulp testing methods (n = 4). The anesthetic response times of NS, L, and VL4 were measured up to 45 min with the aforementioned results as reference values (n = 7). The circulatory dynamics of NS, L, VL4, and 0.2 IU vasopressin (V) were measured up to 45 min using a non-invasive blood pressure measuring device. VL4 extended the anesthetic response times of lidocaine compared to L (p < 0.05). Further, V and VL4 significantly increased the systolic and diastolic blood pressure and significantly decreased the pulse rate (p < 0.05). VL4 is not a suitable addition to the local anesthetic solution used in dentistry. Further study is needed to determine vasopressin concentration that extends the anesthetic effect without affecting the circulatory dynamics.

Lidocaine-loaded reduced graphene oxide hydrogel for prolongation of effects of local anesthesia: In vitro and in vivo analyses.

Lidocaine is widely used as a local anesthetic for alleviation of post-operative pain and for management of acute and chronic painful conditions. Although several approaches are currently used to prolong the duration of action, an effective strategy to achieve neural blockage for several hours remains to be identified. In this study, a lidocaine-loaded Pluronic® F68-reduced graphene oxide hydrogel was developed to achieve sustained release of lidocaine. Fourier transform infrared spectroscopy, X-ray diffraction, and Raman spectroscopy confirmed the synthesis of Pluronic® F68-reduced graphene oxide. Transmission electron microscopy showed wrinkled, flat nanosheets with micelles attached. The developed hydrogel showed desirable pH, viscosity, adhesiveness, hardness, and cohesiveness for topical application. The ex vivo release study demonstrated the ability of the Pluronic® F68-reduced graphene oxide hydrogel to prolong release up to 10 h, owing to the strong π-π interactions between the graphene oxide and the lidocaine. In comparison with a commercial lidocaine ointment, the developed graphene oxide hydrogel showed sustained anesthetic effect in the radiant heat tail flick test and sciatic nerve block model. Thus, this study demonstrates the potential of using Pluronic® F68-reduced graphene oxide nanocarriers to realize prolonged effects of local anesthesia for effective pain management.

QbD-Based Investigation of Dermal Semisolid in situ Film-Forming Systems for Local Anaesthesia.

PURPOSE: The aim of our research work was to develop dermally applicable, lidocaine hydrochloride (LID-HCl)-containing semisolid in situ film-forming systems (FFSs) using the Quality by Design (QbD) approach to increase drug permeation into the skin. METHODS: Silicones were used to improve the properties of formulations and to increase the permeation through the skin. The QbD approach was applied to ensure quality-based development. With initial risk assessment, the critical material attributes (CMAs) and the critical process parameters (CPPs) were identified to ensure the required critical quality attributes (CQAs). RESULTS: During the initial risk assessment, four high-risk CQAs, namely in vitro drug release, in vitro drug permeation, drying properties, and mechanical properties, and three medium-risk CQAs, namely pH, viscosity, and film appearance were identified and investigated. Moreover, four high-risk CMAs were also considered during the formulation: permeation enhancing excipients, drying excipients, film-forming excipients, and emollients. During the experiments, LID-HCl influenced these critical parameters highly, thereby reducing the drying time. The formulation containing 25% silicone showed the best mechanical properties (49 mN skin adhesion, 20.3% film flexibility, 1.27 N film burst strength), which could predict better patient adherence. In addition, in vitro permeation studies showed that formulation containing 50% silicone has the fastest permeation rate. The flux of diffused API was 6.763 µg/cm2/h, which is much higher compared to the silicone-free formulation (1.5734 µg/cm2/h), and it can already be observed in the lower part of the dermis in 0.5 hour. CONCLUSION: Our results show that LID-HCl has great influence on the critical parameters of FFSs. The silicone content can improve the applicability of formulations and has a favorable effect on the permeation rate of LID-HCl into the skin.

Conditioned place aversion of caustic paste and hot-iron disbudding in dairy calves.

Cauterization by hot iron and application of caustic paste are 2 common methods of disbudding calves. In this study, we compared the affective experience of these 2 procedures on young dairy calves using conditioned place aversion. Male dairy calves (n = 14; 7 ± 2 d old) were disbudded by both thermal and chemical methods (1 horn bud at a time, 48 h apart). Calves received treatments in pens made visually distinct with either red squares or blue triangles on the walls. Calves were restricted to these treatment pens for 6 h following disbudding. For all treatments, calves received a sedative (xylazine, 0.2 mg/kg), local anesthetic (lidocaine, 5 mL), and analgesic (meloxicam, 0.5 mg/kg). Calves were then tested for conditioned place aversion at 48, 72, and 96 h after their last treatment. During tests, calves were placed in a neutral pen connected to both treatment pens where they had previously been disbudded. Time spent in each treatment pen was recorded until calves chose to lie down for 1 min (latency to lie down: 31.0 ± 8.6 min). During the first test (48 h after last disbudding), calves spent more time in the pen associated with hot-iron disbudding compared with what would be expected by chance (intercept: 73.5%, 95% CI: 56.5, 90.5) and fewer calves lay down in the caustic paste pen than in the hot-iron pen (3 vs. 10 lying events). No evidence of preference for the hot-iron pen was found in the following test sessions (72 and 96 h since last disbudding). These results suggest that calves initially remember caustic paste disbudding as a more negative experience than hot-iron disbudding, even with the use of sedation, local anesthesia, and analgesia.

Onset, Duration, and Pain Score Obtained Using Lidocaine Mixed With Epinephrine and Bicarbonate in Plastic Surgery.

The aim of this study was to systematically review the effects of lidocaine mixed with epinephrine and bicarbonate in plastic surgery in terms of onset, duration, and the pain score.In PubMed, Embase, Web of Science, and the Cochrane Library, the terms "epinephrine" AND "lidocaine" AND "plastic surgery" were searched, resulting in 210 titles. Among them, 25 full papers were reviewed, 11 were excluded, and 5 mined papers were added. Therefore, 19 papers were analyzed.The mean time for the onset of maximum vasoconstriction caused by lidocaine with epinephrine (LE) ranged from 1.3 minutes (1:50,000 epinephrine) to 25.9 minutes (1:100,000 epinephrine). The mean duration of vasoconstriction caused by LE ranged from 40 minutes (1:100,000 epinephrine) to 136.7 minutes (1:50,000 epinephrine) on the forearm, and 60 minutes (1:100,000 and 1:200,000 epinephrine) on the face. The mean duration of local anesthesia ranged from 112.0 minutes (1:1,600,000 epinephrine) to 480 minutes (1:80,000 epinephrine). Before sodium bicarbonate (SB) was mixed with 1% lidocaine and 1:100,000 epinephrine, the mean pH ranged from 4.05 to 4.24. After mixing SB with 1% lidocaine and 1:100,000 epinephrine, the solution became alkalized, and the mean pH ranged from 7.05 to 7.66. For alkalization, the ratio of LE to SB was 9:1 to 10:1. Before alkalization of LE, the mean pain score ranged from 2.35 to 7.6. In contrast, after alkalizing the mixture by adding 8.4% SB, the mean pain score ranged from 0.64 to 4.3.The results of this study may be helpful for using lidocaine in plastic surgery.