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1.  Local anaesthesia in inguinal herniorrhaphy: influence of dextran and saline solutions on duration of action of bupivacaine. 
Because recent clinical trials have shown that dextran solutions can prolong the local anaesthetic action of 0.25% bupivacaine, a prospective double blind trial was performed in patients (n = 50) undergoing uncomplicated elective inguinal herniorrhaphy under local anaesthesia alone. Patients were randomised prior to infiltration of local anaesthesia into 2 groups: 0.5% bupivacaine (30 ml) diluted with an equal volume of either 0.9% saline or an equal volume of dextran 110. There was no significant difference in duration nor degree of postoperative anaesthesia between the two groups. Dextran solutions were found to be significantly more acidic than saline solutions and the possible effects of this on bupivacaine kinetics are discussed.
PMCID: PMC2498385  PMID: 2431648
2.  Efficacy profile of liposome bupivacaine, a novel formulation of bupivacaine for postsurgical analgesia 
Journal of Pain Research  2012;5:107-116.
Background
Liposome bupivacaine is a novel formulation of the local anesthetic bupivacaine, designed to provide prolonged postsurgical analgesia. This analysis examined pooled efficacy data as reflected in cumulative pain scores from 10 randomized, double-blind liposome bupivacaine clinical studies in which the study drug was administered via local wound infiltration.
Methods
A total of 823 patients were exposed to liposome bupivacaine in 10 local wound infiltration studies at doses ranging from 66 mg to 532 mg in five surgical settings; 446 patients received bupivacaine HCl (dose: 75–200 mg) and 190 received placebo. Efficacy measures were assessed through 72 hours after surgery.
Results
Overall, 45% of patients were male and 19% were ≥65 years of age. In the analysis of cumulative pain intensity scores through 72 hours, liposome bupivacaine was associated with lower pain scores than the comparator in 16 of 19 treatment arms assessed, achieving statistically significant differences compared with bupivacaine HCl (P < 0.05) in five of 17 treatment arms. These results were supported by results of other efficacy measures, including time to first use of opioid rescue medication, proportion of patients avoiding opioid rescue medication, total postsurgical consumption of opioid rescue medication, and patient/care provider satisfaction with postoperative analgesia. Local infiltration of liposome bupivacaine resulted in significant systemic plasma levels of bupivacaine, which could persist for 96 hours; systemic plasma levels of bupivacaine following administration of liposome bupivacaine were not correlated with local efficacy. Liposome bupivacaine and bupivacaine HCl were generally well tolerated.
Conclusion
Based on this integrated analysis of multiple efficacy measures, liposome bupivacaine appears to be a potentially useful therapeutic option for prolonged reduction of postsurgical pain in soft tissue and orthopedic surgeries.
doi:10.2147/JPR.S30861
PMCID: PMC3346068  PMID: 22570563
pain; postsurgical; wound infiltration; local anesthetic; analgesic
3.  Comparison between Lidocaine and Bupivacaine as Local Anesthetics with Diflunisal for Postoperative Pain Control after Lower Third Molar Surgery 
Anesthesia Progress  1988;35(1):1-4.
The effect of lidocaine and bupivacaine on postoperative pain were compared in a double blind crossover study. Diflunisal (500 mg) was used as an analgesic and given before commencement of the surgical procedure.
Bilateral impactions of lower third molars were removed on two occasions, four weeks apart, in a sample of 26 Chinese patients. One local anesthetic was used on one occasion and the alternate on the second. Pain intensity was indicated on a visual analogue scale hourly for eight hours, beginning one hour after the start of surgery.
Pain at each postoperative hour was lower after bupivacaine and more patients indicated little or no pain after bupivacaine than after lidocaine. This was not reflected in patients' preference: 12 preferring lidocaine, 11 bupivacaine, and 3 indicating no preference, an important reason being a shorter period of numbness with lidocaine.
Although diflunisal was given preoperatively, the postoperative course was not complicated by alveolitis in any case.
While bupivacaine plus diflunisal resulted in less postoperative pain than lidocaine plus diflunisal, some patients were willing to sustain some pain after oral surgery if sensation was regained sooner.
PMCID: PMC2190058  PMID: 3422792
4.  Effective postoperative pain prevention through administration of bupivacaine and diclofenac. 
Anesthesia Progress  1994;41(1):6-10.
The efficacies of bupivacaine and lidocaine together with a preoperatively administered single-dose oral combination of normal- and sustained-release preparations of diclofenac in preventing postoperative pain after third molar removal were compared in a double-blind crossover study. Bilaterally impacted lower third molars were removed in two sessions. Each patient was given one type of local anesthetic on one session and the other in the second. Pain was recorded using a visual analog scale. When the diclofenac combination (150 mg) was given before the operation, postoperative analgesia was better with bupivacaine plus diclofenac than with lidocaine plus diclofenac. Twenty-five out of 40 patients preferred bupivacaine to lidocaine for local anesthesia. It is possible to achieve effective postoperative pain prevention by combining bupivacaine and preoperative normal- and sustained-release preparations of diclofenac.
PMCID: PMC2148714  PMID: 8629744
5.  Improving Wound Healing with Topical Gene Therapy 
Advances in Wound Care  2012;1(5):218-223.
Background
Impaired wound healing remains a major clinical problem with many etiologies. Altering gene expression to enhance healing is an innovative therapeutic approach. In recent years, we have developed a means to topically silence genes at the post-transcriptional level to locally alter wounds and improve the healing process.
The Problem
Many types of chronic wounds have been associated with alterations in the expression of genes that mediate healing. Targeting the expression of these genes in a way that can improve healing while limiting systemic side effects has been very challenging.
Basic/Clinical Science Advances
Our laboratory's recent work has focused on the use of topically applied small interfering ribonucleic acid (siRNA) to inhibit messenger RNA expression of certain mediators involved in healing in two different types of cutaneous injury—radiation-induced cutaneous injury and the diabetic excisional wound. By successfully inhibiting specific gene mediators with topical siRNA, we reversed downstream signaling pathways, which led to expedited wound healing in diabetic wounds and restoration to a more normal phenotype in radiation-induced skin injuries.
Clinical Care Relevance
The signaling pathways and gene mediators that we targeted and inhibited in murine models are present in humans. Applying parallel treatment strategies in humans may provide novel means of treating these burdensome and costly conditions.
Conclusion
Our novel method for local gene silencing is effective in treating various types of cutaneous murine wounds. Topical gene silencing with siRNA obviates the side effects of systemic medication and has the potential to be effective in healing or preventing a wide array of cutaneous human conditions.
doi:10.1089/wound.2011.0322
PMCID: PMC3623595  PMID: 24527309
6.  Androgen receptor–mediated inhibition of cutaneous wound healing 
Impaired wound healing states in the elderly lead to substantial morbidity, mortality, and a cost to the USHealth Services of over $9 billion per annum. In addition to intrinsic aging per se causing delayed healing, studies have suggested marked sex-differences in wound repair. We report that castration of male mice results in a striking acceleration of local cutaneous wound healing, and is associated with a reduced inflammatory response and increased hair growth. Using a hairless mouse model, we have demonstrated that testosterone reduction stimulates the healing response not through hair follicle epithelial/mesenchymal cell proliferation, but directly via effects on wound cell populations. We suggest that endogenous testosterone inhibits the cutaneous wound healing response in males and is associated with an enhanced inflammatory response. The mechanisms underlying the observed effects involve a direct upregulation of proinflammatory cytokine expression by macrophages in response to testosterone. Blockade of androgen action systemically, via receptor antagonism, accelerates healing significantly, suggesting a specific target for future therapeutic intervention in impaired wound healing states in elderly males.
doi:10.1172/JCI15704
PMCID: PMC151108  PMID: 12208862
7.  Therapeutic Effect of Total Ginseng Saponin on Skin Wound Healing 
Journal of Ginseng Research  2011;35(3):360-367.
In this study, we investigated the effects of total ginseng saponin (TGS) on the cutaneous wound healing process using histological analysis. A total of 24 ICR mice, 5-weeks-old, were used for all in vivo experiments. Mice were divided into control and TGS-treated groups and four equidistant 1-cm full-thickness dorsal incisional wounds were created. The wounds were extracted at days 1, 3, 5, and 7 post-injury for histomorphometrical analysis including wound area and contracture measurements, keratinocyte migration rate, and calculation of infiltrating inflammatory cells. The results showed that the wound area was smaller and keratinocyte migration rate was higher in the TGS-treated group than that of the control group from days 3 to 7. Inflammatory cells in the TGS-treated group at days 1 and 3 were reduced compared to the control group. Wound contraction in the TGS-treated group was greater than in the control group on days 3 to 5, and collagen deposition in the TGS-treated group was higher than in the control group during wound healing. The results indicate a beneficial effect of TGS when used to treat skin wounds.
doi:10.5142/jgr.2011.35.3.360
PMCID: PMC3659532  PMID: 23717081
Panax ginseng; Skin wound healing; Total ginseng saponin; Mice
8.  Is Lidocaine Infiltration Really Necessary in Micro Ear Surgeries performed Under General Anaesthesia? 
To study the role of infiltrating 2% Lidocaine in Micro ear surgeries performed under general anaesthesia. To measure the impact of infiltration of 2% Lidocaine in post operative pain relief and per operative bleeding. A Double blinded, Prospective randomized comparative study was conducted in a tertiary care referral centre. A total of 30 patients planned for micro ear surgeries under general anaesthesia (Tympanoplasty and Cortical mastoidectomy) for CSOM tubotympanic disease were selected and divided into two groups randomly by the chief senior consultant. Group A patients received local infiltration of 2% Lidocaine with one in 200,000 adrenaline and Group B patients received infiltration of one in 200,000 adrenaline in distilled water alone. Operating surgeon assessed the bleeding in the surgical field using Boezaart’s grading system. Post operative pain was assessed using a visual analog scale. Pain scores of these patients were assessed in the 1st, 4 and 24th h post operatively and recorded. The mean post operative pain score in the 1st h for the patients in Group A was 0.93 and for patients in Group B was two. The difference in the pain scores between the two groups was significant (P < 0.02).The difference in the mean post operative pain scores between the two groups in the 4 and 24th h were not significant (P < 0.1).Per operatively, grade III bleeding was present in 73% of patients in group B and only 33% of patients had grade III bleeding in group A. Infiltration of 2% Lidocaine has a significant impact over the grade of bleeding in the operative field and also on 1st h post operative pain relief. It did not have a significant influence on the pain relief in the 4 and 24th h post operatively.
doi:10.1007/s12070-011-0328-1
PMCID: PMC3477438  PMID: 24294573
Lidocaine; Local infiltration; Micro ear surgery; General anaesthesia
9.  Percutaneous regional compared with local anaesthesia for facial lacerations: a randomised controlled trial 
Objective: Facial lacerations are usually repaired after local infiltration of an anaesthetic agent. Regional nerve blocks of the face offer several theoretical advantages over local infiltration. This study compared the pain of injection and anaesthetic efficacy of percutaneous regional and local anaesthesia for facial lacerations.
Study design: Randomised clinical trial.
Participants: Convenience sample of emergency department patients with facial lacerations requiring suturing in anatomical areas innervated by a regional nerve (supraorbital, infraorbital, or mental).
Interventions: Facial lacerations treated using standard wound care. Lacerations were randomised to local or regional infiltration of lidocaine (lignocaine) 1% with adrenaline (epinephrine) 1:100 000 using a number 27 needle.
Outcomes: Pain of injection on 100 mm visual analogue scale (VAS) and need for rescue anaesthetic infiltration before suturing.
Data analysis: Group comparisons were with Student's t test and χ2 test. This study had 80% power to detect a 20 mm difference in pain of injection (two tailed, α = 0.05).
Results: 36 patients were randomised to local (18) and regional (18) anaesthesia. Mean (SD) age was 20 (14); 19% were female. Groups were similar in baseline characteristics. Patients in the regional anaesthesia group experienced more pain during infiltration than patients in the local anaesthesia group (42.4 mm v 24.8 mm, mean difference 17.6 mm (95% CI 0.3 to 35.6 mm) and were more likely to require additional infiltration of a local anaesthetic (28% v 0%, (95% CI 6% to 50%)) than patients in the local anaesthetic group.
Conclusions: Local infiltration of anaesthetics for facial lacerations is less painful and results in more effective anaesthesia than percutaneous regional infiltration.
doi:10.1136/emj.2003.008722
PMCID: PMC1726525  PMID: 15611540
10.  Ala42S100A8 Ameliorates Psychological-Stress Impaired Cutaneous Wound Healing 
Brain, behavior, and immunity  2009;23(6):755-759.
Although wound healing is generally a successful, carefully orchestrated and evolutionary sound process, it can be disregulated by extrinsic factors such as psychological stress. In the SKH-1 restraint stress model of cutaneous wound healing, the rate of wound closure is approximately 30% slower in stressed mice. Delay in healing is associated with exaggerated acute inflammation and deficient bacterial clearance at the wound site. It has been suggested that wound hypoxia may contribute to the mechanisms of impaired cutaneous wound healing in the mouse SKH-1 model.
Optimal healing of a cutaneous wound is a stepwise repair program. In its early phase, an inflammatory oxidative burst generated by neutrophils is observed. 40% of neutrophils cytosolic protein weight is comprised of two calcium binding proteins S100A8 and S100A9. Our previous work has shown that S100A8 act as an oxidation sensitive repellent of human neutrophils in-vitro. Ala42S100A8, a site-directed mutant protein is resistant to oxidative inhibition and inhibits neutrophil recruitment in-vivo.
Accordingly, we tested the hypothesis that S100A8 may ameliorate wound healing in this model. We examined the effect of wild type and ala42S100A8 for their ability to ameliorate wound closure rates. The data indicated that a single local application of ala42S100A8 ameliorated the decreased rate of wound closure resulting from stress. This occurred without significantly affecting wound bacterial clearance. Wild type S100A8 only had a partial beneficial effect on the rate of wound closure. Those findings support further translational studies of S100 based intervention to ameliorate impaired wound healing.
doi:10.1016/j.bbi.2009.03.006
PMCID: PMC2710400  PMID: 19336252
Wound healing; calprotectin; S100A8; oxidation; psychological stress; neutrophils; bacterial clearance; cutaneous; translational
11.  Local analgesia for infant pyloromyotomy. Does wound infiltration with bupivacaine affect postoperative behaviour? 
A series of 20 infants undergoing general anaesthesia for pyloromyotomy were studied in a randomised, blind and controlled trial to determine the postoperative behavioural and cardiorespiratory effects of wound infiltration of bupivacaine. Ten infants received bupivacaine (0.6 ml/kg, 0.25% = 1.5 mg/kg) injected intradermally into the wound during general anaesthesia and 10 infants received general anaesthesia only. Postoperatively, an independent observer assessed conscious level, crying, posture and facial expression using a simple numerical scoring system, and also recorded heart and respiratory rates over a 2-h period. Infants who had received bupivacaine were observed to have higher respiratory rates and behaviour scores, although these differences were not statistically significant. These results indicate that wound infiltration with bupivacaine offers no obvious advantage to infants following pyloromyotomy.
PMCID: PMC2499188  PMID: 2221770
12.  Low dose levobupivacaine 0.5% with fentanyl in spinal anaesthesia for transurethral resection of prostate surgery 
BACKGROUND:
Levobupivacaine 0.5% and bupivacaine 0.5% were shown to be equally effective in spinal anaesthesia. In previous studies, low dose bupivacaine with an intrathecal opioid was used successfully in urological surgery. The aim of this study was to evaluate the clinical effectiveness and block quality of low dose levobupivacaine, and compare it with low dose bupivacaine when they are combined with fentanyl in transurethral resection of prostate surgery.
METHODS:
Forty nine patients undergoing transurethral prostate surgery were enrolled in this prospective, randomized and double blind study. Patients in levobupivacaine group received 5 mg levobupivacaine + 25 μg fentanyl and bupivacaine group received 5 mg bupivacaine + 25 μg fentanyl. Demographic data, surgery times, hemodynamic parameters, block qualities and patient and surgeon satisfactions were recorded.
RESULTS:
Demographic data, surgery times and patient and surgeon satisfactions were similar in both groups. Hemodynamic parameters were comparable and stable during the procedure in both groups. Sensory block characteristics were comparable and clinically effective in both groups. While 3 patients in bupivacaine group had Bromage score of 3 at the beginning of the surgery, no patient in levobupivacaine group had this score and this difference was significant (p = 0.042). Bromage scores at the end of the surgery were comparable in both groups.
CONCLUSIONS:
In conclusion, for transurethral prostate surgery 5 mg levobupivacaine with 25 μg fentanyl can provide stable hemodynamic profile, patient and surgeon satisfaction and effective sensorial blockade with less motor blockade in spinal anaesthesia; so it could be used at low doses as a good alternative to bupivacaine.
PMCID: PMC3063440  PMID: 21448386
Levobupivacaine; Bupivacaine; Fentanyl; Anaesthesia; Spinal; Transurethral Resection of Prostate
13.  An ear punch model for studying the effect of radiation on wound healing 
Purpose
Radiation and wound combined injury represents a major clinical challenge because of the synergistic interactions that lead to higher morbidity and mortality than either insult would produce singly. The purpose of this study was to develop a mouse ear punch model to study the physiological mechanisms underlying radiation effects on healing wounds.
Materials and methods
Surgical wounds were induced by a 2 mm surgical punch in the ear pinnae of MRL/MpJ mice. Photographs of the wounds were taken and the sizes of the ear punch wounds were quantified by image analysis. Local radiation to the ear was delivered by orthovoltage X-ray irradiator using a specially constructed jig that shields the other parts of body.
Results
Using this model, we demonstrated that local radiation to the wound area significantly delayed the healing of ear punch wounds in a dose-dependent fashion. The addition of sublethal whole body irradiation (7 Gy) further delayed the healing of ear punch wounds. These results were replicated in C57BL/6 mice; however, wound healing in MRL/MpJ mice was accelerated.
Conclusions
These data indicate that the mouse ear punch model is a valuable model to study radiation and wound combined injury.
doi:10.3109/09553002.2011.568575
PMCID: PMC3193941  PMID: 21480768
radiation; wound healing; combined injury; ear punch model; MRL/MpJ mice; in vivo imaging
14.  Loss of Innervation and Axon Plasticity Accompanies Impaired Diabetic Wound Healing 
PLoS ONE  2013;8(9):e75877.
Loss of cutaneous innervation from sensory neuropathy is included among mechanisms for impaired healing of diabetic skin wounds. The relationships between cutaneous axons and their local microenvironment during wound healing are challenged in diabetes. Here, we show that secondary wound closure of the hairy dorsal skin of mice is delayed by diabetes and is associated with not only a pre-existing loss of cutaneous axons but substantial retraction of axons around the wound. At 7d following a 3mm punch wound, a critical period of healing and reinnervation, both intact skin nearby the wound and skin directly at the wound margins had over 30-50% fewer axons and a larger deficit of ingrowing axons in diabetics. These findings contrasted with a pre-existing 10-15% deficit in axons. Moreover, new diabetic ingrowing axons had less evidence of plasticity. Unexpectedly, hair follicles adjacent to the wounds had a 70% reduction in their innervation associated with depleted expression of hair follicular stem cell markers. These impairments were associated with the local upregulation of two established axon regenerative ‘roadblocks’: PTEN and RHOA, potential but thus far unexplored mediators of these changes. The overall findings identify striking and unexpected superimposed cutaneous axon loss or retraction beyond that expected of diabetic neuropathy alone, associated with experimental diabetic skin wounding, a finding that prompts new considerations in diabetic wounds.
doi:10.1371/journal.pone.0075877
PMCID: PMC3786937  PMID: 24098736
15.  The direct perfusion of surgical wounds with local anaesthetic solution: an approach to postoperative pain? 
A simple technique of wound perfusion with bupivacaine (Marcain) which provides sustained postoperative analgesia is described. No complications nor side effects related to toxicity, hypersensitivity, infection, or impaired wound healing were encountered. Postoperative pain was reduced and analgesic requirements were significantly lower in patients undergoing both intermittent (P less than 0.01) and continuous (P = 0.1) wound perfusion (Student t test). Perfusion with isotonic saline was also found to be effective. This may represent a true therapeutic effect attributable to the removal or dilution of pain mediating substances in the wound.
PMCID: PMC2494327  PMID: 6347012
16.  Effects of Suppository Acetaminophen, Bupivacaine Wound Infiltration, and Caudal Block With Bupivacaine on Postoperative Pain in Pediatric Inguinal Herniorrhaphy 
Anesthesiology and Pain Medicine  2012;1(4):243-247.
Background:
The control of postoperative pain is important in children, and poor pain control leads to organ dysfunction and behavioral problems.
Objectives:
We compared the analgesic effects of suppository acetaminophen, bupivacaine wound infiltration, and caudal block with bupivacaine on postoperative pain in pediatric inguinal herniorrhaphy.
Patients and Methods:
In this double-blinded, randomized controlled clinical trial, 90 children of American Society of Anesthesiologists (ASA) grade I-II, aged between 3 months and 7 years, and scheduled for elective unilateral inguinal herniorrhaphy under general anesthesia were assigned to three equal groups. Patients in the first group received 20 mg/kg of suppository acetaminophen. In the second group, 2 mg/kg of 0.5% bupivacaine was infiltrated in the incisional site, and in the third group, a caudal block was performed with 0.75 mL/kg of 0.25% bupivacaine. The Face, Legs, Activity, Cry, Consolability (FLACC) pain scale was applied 30 minutes after operation. Thereafter, the FLACC score was obtained every hour during the next 6 hours. If the FLACC score was 4 or over, we administered 0.5 mg/kg of intravenous meperidine. The data was transferred to SPSS-10 software and analyzed statistically with chi-square and analysis of variance tests. P < 0.05 was considered significant.
Results:
The mean analgesic duration in the acetaminophen, bupivacaine infiltration, and caudal block groups was 4.07, 5.40, and 5.37 hours, respectively. Significant differences were not observed between the bupivacaine infiltration and caudal block groups (P = 0.9), but the differences between the bupivacaine infiltration and acetaminophen groups (P = 0.034) and the caudal block and acetaminophen groups (P = 0.039) were significant. With regard to meperidine administration, significant differences were not observed between the bupivacaine infiltration and caudal block groups (P = 0.848), but significant differences were observed between these two groups and the acetaminophen group (P < 0.05).
Conclusions:
Patients in the bupivacaine infiltration and caudal block groups had less postoperative pain than those in the acetaminophen group and received lower amount of meperidine. We concluded that in children, bupivacaine infiltration and caudal block with bupivacaine produce better analgesia than suppository acetaminophen. It seems that bupivacaine infiltration is better than caudal block because of its simplicity, lower incidence of complications, and failure rate.
doi:10.5812/aapm.3551
PMCID: PMC4018710  PMID: 24904808
Bupivacaine; Anesthesia, Caudal; Pediatrics; Analgesia; Suppositories; Acetaminophen
17.  Local Anesthetics Induce Apoptosis in Human Thyroid Cancer Cells through the Mitogen-Activated Protein Kinase Pathway 
PLoS ONE  2014;9(2):e89563.
Local anesthetics are frequently used in fine-needle aspiration of thyroid lesions and locoregional control of persistent or recurrent thyroid cancer. Recent evidence suggests that local anesthetics have a broad spectrum of effects including inhibition of cell proliferation and induction of apoptosis in neuronal and other types of cells. In this study, we demonstrated that treatment with lidocaine and bupivacaine resulted in decreased cell viability and colony formation of both 8505C and K1 cells in a dose-dependent manner. Lidocaine and bupivacaine induced apoptosis, and necrosis in high concentrations, as determined by flow cytometry. Lidocaine and bupivacaine caused disruption of mitochondrial membrane potential and release of cytochrome c, accompanied by activation of caspase 3 and 7, PARP cleavage, and induction of a higher ratio of Bax/Bcl-2. Based on microarray and pathway analysis, apoptosis is the prominent transcriptional change common to lidocaine and bupivacaine treatment. Furthermore, lidocaine and bupivacaine attenuated extracellular signal-regulated kinase 1/2 (ERK1/2) activity and induced activation of p38 mitogen-activated protein kinase (MAPK) and c-jun N-terminal kinase. Pharmacological inhibitors of MAPK/ERK kinase and p38 MAPK suppressed caspase 3 activation and PARP cleavage. Taken together, our results for the first time demonstrate the cytotoxic effects of local anesthetics on thyroid cancer cells and implicate the MAPK pathways as an important mechanism. Our findings have potential clinical relevance in that the use of local anesthetics may confer previously unrecognized benefits in the management of patients with thyroid cancer.
doi:10.1371/journal.pone.0089563
PMCID: PMC3931808  PMID: 24586874
18.  Modification of local anesthetic toxicity by vasoconstrictors. 
Anesthesia Progress  1989;36(3):79-87.
We studied the effects of epinephrine or levonordefrin on the toxicity (convulsions) and lethality of four local anesthetics in mice. Appropriate doses of procaine, lidocaine, tetracaine or bupivacaine--either alone or in combination with 15 mcg/kg epinephrine or levonordefrin--were injected intravenously into the tail vein of male mice. Dose-response curves were constructed from the data obtained, and the CD50 and LD50 values for each local anesthetic alone and in combination with each of the vasoconstrictors were calculated by probit analysis. Both epinephrine and levonordefrin decreased the toxicity and lethality of procaine with respect to dose. Epinephrine, but not levonordefrin, increased the toxicity and lethality of bupivacaine as well as the lethality of tetracaine. Neither vasoconstrictor significantly affected the toxicity of lidocaine in mice but in rats epinephrine markedly increased lidocaine's lethality under identical conditions. Tight physical restraint decreased the LD50 values of all four local anesthetics and eliminated any modifying effect of the vasoconstrictor.
PMCID: PMC2148661  PMID: 2700426
19.  Exercise, Obesity, and Cutaneous Wound Healing: Evidence from Rodent and Human Studies 
Advances in Wound Care  2014;3(1):71-79.
Significance: Impaired cutaneous wound healing is a major health concern. Obesity has been shown in a number of studies to impair wound healing, and chronic nonhealing wounds in obesity and diabetes are a major cause of limb amputations in the United States.
Recent Advances: Recent evidence indicates that aberrant wound site inflammation may be an underlying cause for delayed healing. Obesity, diabetes, and other conditions such as stress and aging can result in a chronic low-level inflammatory state, thereby potentially affecting wound healing negatively.
Critical Issues: Interventions which can speed the healing rate in individuals with slowly healing or nonhealing wounds are of critical importance. Recently, physical exercise training has been shown to speed healing in both aged and obese mice and in older adults. Exercise is a relatively low-cost intervention strategy which may be able to be used clinically to prevent or treat impairments in the wound-healing process.
Future Directions: Little is known about the mechanisms by which exercise speeds healing. Future translational studies should address potential mechanisms for these exercise effects. Additionally, clinical studies in obese humans are necessary to determine if findings in obese rodent models translate to the human population.
doi:10.1089/wound.2012.0377
PMCID: PMC3900100  PMID: 24761347
20.  Local Toxicity from Local Anesthetic Polymeric Microparticles 
Anesthesia and analgesia  2013;116(4):794-803.
Background
Local tissue injury from sustained release formulations for local anesthetics can be severe. There is considerable variability in reporting of that injury. We investigated the influence of the intrinsic myotoxicity of the encapsulated local anesthetic (lidocaine, low; bupivacaine, high) on tissue reaction in rats.
Methods
Cytotoxicity from a range of lidocaine and bupivacaine concentrations was measured in C2C12 myotubes over 6 days. Rats were given sciatic nerve blocks with 4 microparticulate formulations of lidocaine and bupivacaine: 10% (w/w) lidocaine poly-lactic-co-glycolic acid (PLGA), 10% (w/w) bupivacaine PLGA, 50% (w/w) lidocaine PLGA, and 50% (w/w) bupivacaine PLGA. Effectiveness of nerve blockade was assessed by a modified hotplate test and weight-bearing measurements. Myotoxicity was scored in histologic sections of injection sites. Bupivacaine and lidocaine release kinetics from the particles were measured.
Results
Median sensory blockade duration for 50% (w/w) lidocaine was 255 (90–540) min versus 840 (277–1215) min for 50% (w/w) bupivacaine (P=0.056). All microparticulate formulations resulted in myotoxicity. The choice of local anesthetic did not influence the severity of myotoxicity. Median myotoxicity scores for 50% (w/w) lidocaine compared to 50% (w/w) bupivacaine at 4 days was 3.4 (2.1–4.2) vs. 3.3 (2.9–3.5)(P=0.44) and at 14 days 1.9 (1.8–2.4) versus 1.7 (1.3–1.9)(P=0.23) respictively.
Conclusions
Lidocaine and bupivacaine PLGA microspheres resulted in similar degrees of myotoxicity, irrespective of drug loading. Intrinsic myotoxicity did not predict tissue injury from sustained release of these anesthetics. Caution is warranted in the use of such devices near muscle and nerve.
doi:10.1213/ANE.0b013e31828174a7
PMCID: PMC3606664  PMID: 23460564
21.  Estrogen promotes cutaneous wound healing via estrogen receptor β independent of its antiinflammatory activities 
The Journal of Experimental Medicine  2010;207(9):1825-1833.
Post-menopausal women have an increased risk of developing a number of degenerative pathological conditions, linked by the common theme of excessive inflammation. Systemic estrogen replacement (in the form of hormone replacement therapy) is able to accelerate healing of acute cutaneous wounds in elderly females, linked to its potent antiinflammatory activity. However, in contrast to many other age-associated pathologies, the detailed mechanisms through which estrogen modulates skin repair, particularly the cell type–specific role of the two estrogen receptors, ERα and ERβ, has yet to be determined. Here, we use pharmacological activation and genetic deletion to investigate the role of both ERα and ERβ in cutaneous tissue repair. Unexpectedly, we report that exogenous estrogen replacement to ovariectomised mice in the absence of ERβ actually delayed wound healing. Moreover, healing in epidermal-specific ERβ null mice (K14-cre/ERβL2/L2) largely resembled that in global ERβ null mice. Thus, the beneficial effects of estrogen on skin wound healing are mediated by epidermal ERβ, in marked contrast to most other tissues in the body where ERα is predominant. Surprisingly, agonists to both ERα and ERβ are potently antiinflammatory during skin repair, indicating clear uncoupling of inflammation and overall efficiency of repair. Thus, estrogen-mediated antiinflammatory activity is not the principal factor in accelerated wound healing.
doi:10.1084/jem.20100500
PMCID: PMC2931162  PMID: 20733032
22.  Gadolinium enhancement of cauda equina after combined spinal–epidural anaesthesia 
The British Journal of Radiology  2010;83(993):e192-e194.
The occurrence of neurological symptoms after spinal anaesthesia has been reported with several local anaesthetics including lidocaine, prilocaine, mepivacaine, tetracaine and bupivacaine. Although hyperbaric bupivacaine is known to induce neurological symptoms less frequently than lidocaine, a few cases of cauda equina syndrome (CES) following the intraspinal injection of bupivacaine have been reported in the English literature. We describe lumbar MRI findings for a 29-year-old woman presenting with CES after caesarean section.
doi:10.1259/bjr/32314637
PMCID: PMC3473412  PMID: 20739341
23.  Therapeutic potential of bone marrow-derived mesenchymal stem cells for cutaneous wound healing 
Despite advances in wound care, many wounds never heal and become chronic problems that result in significant morbidity and mortality to the patient. Cellular therapy for cutaneous wounds has recently come under investigation as a potential treatment modality for impaired wound healing. Bone marrow-derived mesenchymal stem cells (MSCs) are a promising source of adult progenitor cells for cytotherapy as they are easy to isolate and expand and have been shown to differentiate into various cell lineages. Early studies have demonstrated that MSCs may enhance epithelialization, granulation tissue formation, and neovascularization resulting in accelerated wound closure. It is currently unclear if these effects are mediated through cellular differentiation or by secretion of cytokines and growth factors. This review discusses the proposed biological contributions of MSCs to cutaneous repair and their clinical potential in cell-based therapies.
doi:10.3389/fimmu.2012.00192
PMCID: PMC3392692  PMID: 22787462
mesenchymal stem cells; wound healing; differentiation; paracrine signaling; tissue engineering
24.  Deletion of a Tumor Necrosis Superfamily Gene in Mice Leads to Impaired Healing that Mimics Chronic Wounds in Humans 
Wound Repair and Regeneration  2012;20(3):353-366.
Proper healing of cutaneous wounds progresses through a series of overlapping phases. Non-healing wounds are defective in one or more of these processes and represent a major clinical problem. A critical issue in developing treatments for chronic wounds is the paucity of animal models to study the mechanisms underlying the defects in healing. Here we show that deletion of Tumor Necrosis Factor Superfamily Member 14 (TNFSF14/LIGHT) leads to impaired wounds in mice that have the characteristics of non-chronic and chronic ulcers. These wounds show: (1) Excessive production of cytokines, in particular three chemokines (KC/CXCL8, MCP-1/CCL2, IP-10/CXCL10), that may be key to the abnormal initiation and resolution of inflammation; (2) defective basement membranes, explaining blood vessel leakage and disruption of dermal/epidermal interactions; (3) granulation tissue that contains high levels of Coll III whereas Coll I is virtually absent and does not form fibrils. We also see major differences between non-chronic and chronic wounds, with the latter populated by bacterial films and producing eotaxin, a chemokine that attracts leukocytes that combat multicellular organisms (which biofilms can be considered to be). This new mouse model captures many defects observed in impaired and chronic human wounds, and provides a vehicle to address their underlying cell and molecular mechanisms.
doi:10.1111/j.1524-475X.2012.00785.x
PMCID: PMC3349437  PMID: 22564230
Inflammation; repair; regeneration; cytokines; chemokines
25.  Recombinant basic fibroblast growth factor stimulates wound healing in healing-impaired db/db mice 
The stimulatory effect of recombinant basic fibroblast growth factor (bFGF) on wound healing was assessed using healing-impaired (db/db) mice. Full-thickness wounds were made in female diabetic C57BL/KsJ db/db mice, and their normal (db/+) littermates with a punch biopsy instrument. Recombinant bFGF was applied locally to the open wound once a day. The mice were later killed and histological sections of the wounds were prepared. The degree of wound healing was evaluated using several histological parameters such as degree of reepithelialization, granulation tissue thickness, matrix density, number of infiltrated cells, and number of capillaries. Wounds from normal mice displayed good reepithelialization rates and granulation tissue formation, while wounds from db/db mice had poor responses, especially in the dermal parameters. Although the application of bFGF to wounds in the normal (db/+) mice had little effect, application of bFGF to wounds in db/db mice induced significant responses in all of the dermal parameters compared with nontreated db/db mice (p less than 0.001). In the presence of bFGF, these parameters approximated those observed in nontreated littermates. A minimum of 0.5 microgram bFGF in either single or multiple applications was required for a significant effect. bFGF that was either boiled or pretreated with neutralizing antibody had little stimulatory effect. Time-course experiments indicated that the granulation response in bFGF-treated mice peaked between 8 and 12 d, and decreased after 12 d, while matrix density continued to increase until the 18th day (p less than 0.05). The breaking strength of healed linear wounds in db/db mice was also decreased when compared with heterozygous littermates. This parameter was also improved by the administration of bFGF to the wounds (p less than 0.05).
PMCID: PMC2188158  PMID: 2358777

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