Longstanding Phenytoin Use as a Cause of Progressive Dyspnea.

CASE PRESENTATION: A 54-year-old South African man with a medical history of type 2 diabetes mellitus, seizure disorder, OSA, and latent TB presented to the ER with gradually progressive dyspnea over months. He also reported occasional dry cough and fatigue at presentation but denied fever, chills, chest pain, leg swelling, palpitations, or lightheadedness. He was treated with a course of levofloxacin for presumed community-acquired pneumonia as an outpatient without improvement and had tested negative for COVID-19. He denied occupational or environmental exposures or sick contacts, though he had traveled back to South Africa 1 year before presentation. He had complex partial seizures for the past 22 years, which had been well controlled on phenytoin (300 mg daily). His other home medications included dulaglutide, sertraline, and atorvastatin and had no recent changes. He quit smoking 30 years ago after smoking one pack per day for 10 years.

Isoliquiritigenin, an active ingredient of Glycyrrhiza, elicits antinociceptive effects via inhibition of Nav channels.

Glycyrrhiza extract has been used for the treatment of oral and gastric ulcers, but the analgesic mechanism remains unknown. In the present study, we investigated the effects of isoliquiritigenin, an active ingredient of Glycyrrhiza, on Nav channels in vitro and nociceptive behaviors in vivo. In an autopatch-clamp study, isoliquiritigenin inhibited the currents of Nav1.1, Nav1.3, Nav1.6, Nav1.7, and Nav1.8 in a channel expression system. In small- and medium-sized cultured trigeminal ganglion neurons, the compound suppressed Nav currents in many neurons (78%) and Kv currents in all neurons, dose-dependently. In current-clamp mode, isoliquiritigenin blocked action potential generation in many neurons (64%), but it conversely accelerated action potential generation in the remaining neurons. The opposing effects on action potentials were reproduced in a computational simulation of a modified Hodgkin-Huxley-based model, based on the electrophysiological data. In behavioral experiments, local treatment with isoliquiritigenin suppressed nociceptive behaviors in response to oral ulcer development or nociceptive TRP channel agonists in the oral mucosa and hind paw. These results suggest that isoliquiritigenin exerts an analgesic effect predominantly via inhibitory action on Nav channels on sensory nociceptive fibers. This pharmacological mechanism indicates that isoliquiritigenin is useful for pain relief and provides scientific evidence for Glycyrrhiza at the ingredient level.

Analgesic Effects of Topical Amitriptyline in Patients With Chemotherapy-Induced Peripheral Neuropathy: Mechanistic Insights From Studies in Mice.

Oral amitriptyline hydrochloride (amitriptyline) is ineffective against some forms of chronic pain and is often associated with dose-limiting adverse events. We evaluated the potential effectiveness of high-dose topical amitriptyline in a preliminary case series of chemotherapy-induced peripheral neuropathy patients and investigated whether local or systemic adverse events associated with the use of amitriptyline were present in these patients. We also investigated the mechanism of action of topically administered amitriptyline in mice. Our case series suggested that topical 10% amitriptyline treatment was associated with pain relief in chemotherapy-induced peripheral neuropathy patients, without the side effects associated with systemic absorption. Topical amitriptyline significantly increased mechanical withdrawal thresholds when applied to the hind paw of mice, and inhibited the firing responses of C-, Aß- and Aδ-type peripheral nerve fibers in ex vivo skin-saphenous nerve preparations. Whole-cell patch-clamp recordings on cultured sensory neurons revealed that amitriptyline was a potent inhibitor of the main voltage-gated sodium channels (Nav1.7, Nav1.8, and Nav1.9) found in nociceptors. Calcium imaging showed that amitriptyline activated the transient receptor potential cation channel, TRPA1. Our case series indicated that high-dose 10% topical amitriptyline could alleviate neuropathic pain without adverse local or systemic effects. This analgesic action appeared to be mediated through local inhibition of voltage-gated sodium channels. PERSPECTIVE: Our preliminary case series suggested that topical amitriptyline could provide effective pain relief for chemotherapy-induced peripheral neuropathy patients without any systemic or local adverse events. Investigation of the mechanism of this analgesic action in mice revealed that this activity was mediated through local inhibition of nociceptor Nav channels.

Comparison of the Effect of Adipocyte-derived Stem Cells and Curcumin Nanoliposomes with Phenytoin on Open Cutaneous Wound Healing in Rats.

BACKGROUND: Reducing the healing time of wounds can decrease the patient's immobility time and their medical costs, leading a faster return of the patients to daily work. OBJECTIVE: The aim of the present study is to compare the effect of adipose-derived stem cells and curcumin- containing liposomal nanoparticles with phenytoin on wound healing. METHODS: After anesthesia of the rats, open skin ulcers were made by a bistoury blade. Subsequently, stem cells were removed from the adipose tissue of the upper border of the epididymis. The originality of stem cells was then confirmed by the flow cytometry. The fusion method was used to prepare the liposome; and also, nanoliposomal particles were confirmed by using the DLS microscope. The percentage of recovery and the cell count was measured with IMAGEJ. The expression of genes was assessed by PCR. The number of fibroblasts was counted by immunohistochemistry techniques. The amount of collagen was determined by Tri-chromosome staining, and the number of capillaries was enumerated by H & E staining. RESULTS: The expression of the TGF-β1 gene, vascular number, wound healing rate and the number of fibroblasts increased significantly in adipose tissue-derived stem cells and curcumin nanoliposome groups (p<0.05); the wound surface was also decreased significantly (p<0.05). CONCLUSION: Based on the results of our research, adipose tissue-derived stem cells and curcumin nanoliposomes can heal wounds efficiently.

Application of Intravenous Lidocaine in Obese Patients Undergoing Painless Colonoscopy: A Prospective, Randomized, Double-Blind, Controlled Study.

OBJECTIVE: Propofol for procedural sedation and analgesia (PSA) for colonoscopy can result in a high prevalence of severe respiratory depression. Studies have shown that intravenous (IV) infusion of lidocaine can reduce propofol requirements significantly and increase the ventilatory response to carbon dioxide in humans. We tested the hypothesis that IV lidocaine could improve propofol-induced respiratory depression in obese patients during colonoscopy. METHODS: Ninety obese patients scheduled for painless colonoscopy were randomized to receive lidocaine (1.5 mg/kg, then 2 mg/kg/h, IV) or the same volume of 0.9% saline. Intraoperative sedation was provided by propofol. The primary outcome was the number of oxygen-desaturation episodes. Secondary outcomes were: the number of apnea episodes; total propofol consumption; time to the first hypoxia episode; time to consciousness loss; intraoperative hemodynamic parameters; awakening time; adverse events; duration of post-anesthesia care unit (PACU) stay; satisfaction of endoscopists and patients. RESULTS: Demographic characteristics between the two groups were comparable. The number of oxygen-desaturation episodes in group L (1.49±1.12) decreased by 0.622 (P=0.018) compared with that in group N (2.11±1.32), and the number of apnea episodes in group L decreased by 0.533 (P<0.001). Kaplan-Meier curves showed that the median time to the first hypoxia episode was longer in group L (86.78 s) than that in group N (63.83 s) (Log rank P=0.0008). The total propofol consumption, awakening time, and duration of PACU stay were reduced in group L. There was no significant difference in the prevalence of adverse events (P>0.05 for all). Satisfaction scores for endoscopists and patients in group L were higher than that in group N (P<0.001). CONCLUSION: Intravenous infusion of lidocaine could significantly reduce the number of oxygen-desaturation and apnea episodes in obese patients during painless colonoscopy. This method is worthy of clinical promotion. CLINICAL TRIALS REGISTRATION: ChiCTR2000028937.

Real world, open label experience with lacosamide against acute painful oxaliplatin-induced peripheral neurotoxicity.

We report the outcome of a pilot, open-label study that tested the potential of lacosamide (200 mg/bi.d) as an effective and safe symptomatic treatment against acute painful oxaliplatin-induced peripheral neurotoxicity (OXAIPN). Lacosamide was introduced in 18 colorectal cancer patients with evidence of clinically significant acute, painful OXAIPN after infusion of the third course (T1) of oxaliplatin-based chemotherapy (FOLFOX4) and was maintained until completion of all 12 courses (T4). The OXA-Neuropathy Questionnaire (OXA-NQ) was used to record the severity of acute OXAIPN; the PI-NRS estimated the severity of neuropathic pain, while the chronic OXAIPN was graded with TNSc. The EuroQOL (EQ-5D) instrument was also applied. The Patient Global Impression of Change (PGIC) scale measured the lacosamide-attributed perception of change. LCM-responders were considered those with ≥50% reduction in PI-NRS and OXA-NQ scores at T4, compared to T1. Patients experienced on T1 a median number of acute OXAIPN symptoms of 4 and had a median neuropathic pain severity score of 6, which was strongly related to lower quality of life, according to EQ-VAS (P < .001). At T4, 12 patients (66.7%) were classified as responders. A significant clinical improvement was documented in the severity of acute OXAIPN and neuropathic pain in relation to lacosamide (P < .001) at T4 compared to T1, which was associated with improved EQ-VAS scores (P < .001). Twelve patients scored PGIC ≥5 (lacosamide-attributed) at T4. There were no incidences of early drop-outs for safety reasons. Lacosamide appears to be an effective and well-tolerated symptomatic treatment against acute, painful OXAIPN.

Post-treatment with oxcarbazepine confers potent neuroprotection against transient global cerebral ischemic injury by activating Nrf2 defense pathway.

Oxcarbazepine (OXC), a voltage-gated sodium channel blocker, is an antiepileptic medication and used for the bipolar disorders treatment. Some voltage-gated sodium channel blockers have been demonstrated to display strong neuroprotective properties in models of cerebral ischemia. However, neuroprotective effects and mechanisms of OXC have not yet been reported. Here, we investigated the protective effect of OXC and its mechanisms in the cornu ammonis 1 subfield (CA1) of gerbils subjected to 5 min of transient global cerebral ischemia (tGCI). tGCI led to death of most pyramidal neurons in CA1 at 5 days after ischemia. OXC (100 and 200 mg/kg) was intraperitoneally administered once at 30 min after tGCI. Treatment with 200 mg/kg, not 100 mg/kg OXC, significantly protected CA1 pyramidal neurons from tGCI-induced injury. OXC treatment significantly decreased superoxide anion production, 4-hydroxy-2-nonenal and 8-hydroxyguanine levels in ischemic CA1 pyramidal neurons. In addition, the treatment restored levels of superoxide dismutases, catalase, and glutathione peroxidase. Furthermore, the treatment distinctly inhibited tGCI-induced microglia activation and significantly reduced levels of pro-inflammatory cytokines (interleukin-1ß and tumor necrosis factor-α). In particular, OXC treatment significantly enhanced expressions of nuclear factor erythroid 2-related factor 2 (Nrf2) and its downstream protein heme oxygenase-1 in ischemic CA1. The neuroprotective effects of OXC were abolished by brusatol (an inhibitor of Nrf2). Taken together, these results indicate that post-treatment of OXC can display neuroprotection against brain injuries following ischemic insults. This neuroprotection may be displayed by attenuation of oxidative stress and neuroinflammation, which can be mediated by activation of Nrf2 pathway.

Use of Cryopreserved Hepatocytes as Part of an Integrated Strategy to Characterize In Vivo Clearance for Peptide-Antibody Conjugate Inhibitors of Nav1.7 in Preclinical Species.

The identification of nonopioid alternatives to treat chronic pain has received a great deal of interest in recent years. Recently, the engineering of a series of Nav1.7 inhibitory peptide-antibody conjugates has been reported, and herein, the preclinical efforts to identify novel approaches to characterize the pharmacokinetic properties of the peptide conjugates are described. A cryopreserved plated mouse hepatocyte assay was designed to measure the depletion of the peptide-antibody conjugates from the media, with a correlation being observed between percentage remaining in the media and in vivo clearance (Pearson r = -0.5525). Physicochemical (charge and hydrophobicity), receptor-binding [neonatal Fc receptor (FcRn)], and in vivo pharmacokinetic data were generated and compared with the results from our in vitro hepatocyte assay, which was hypothesized to encompass all of the aforementioned properties. Correlations were observed among hydrophobicity; FcRn binding; depletion rates from the hepatocyte assay; and ultimately, in vivo clearance. Subsequent studies identified potential roles for the low-density lipoprotein and mannose/galactose receptors in the association of the Nav1.7 peptide conjugates with mouse hepatocytes, although in vivo studies suggested that FcRn was still the primary receptor involved in determining the pharmacokinetics of the peptide conjugates. Ultimately, the use of the cryopreserved hepatocyte assay along with FcRn binding and hydrophobic interaction chromatography provided an efficient and integrated approach to rapidly triage molecules for advancement while reducing the number of in vivo pharmacokinetic studies. SIGNIFICANCE STATEMENT: Although multiple in vitro and in silico tools are available in small-molecule drug discovery, pharmacokinetic characterization of protein therapeutics is still highly dependent upon the use of in vivo studies in preclinical species. The current work demonstrates the combined use of cryopreserved hepatocytes, hydrophobic interaction chromatography, and neonatal Fc receptor binding to characterize a series of Nav1.7 peptide-antibody conjugates prior to conducting in vivo studies, thus providing a means to rapidly evaluate novel protein therapeutic platforms while concomitantly reducing the number of in vivo studies conducted in preclinical species.

Mucoadhesive Electrospun Patch Delivery of Lidocaine to the Oral Mucosa and Investigation of Spatial Distribution in a Tissue Using MALDI-Mass Spectrometry Imaging.

Many oral mucosal conditions cause considerable and prolonged pain that to date has been difficult to alleviate via topical delivery, and the use of injection causes many patients dental anxiety and needle-prick pain. Therefore, developing a noninjectable drug delivery system as an alternative administration procedure may vastly improve the health and wellbeing of these patients. Recent advances in the development of mucoadhesive electrospun patches for the direct delivery of therapeutics to the oral mucosa offer a potential solution, but as yet, the release of local anesthetics from this system and their uptake by oral tissue have not been demonstrated. Here, we demonstrate the fabrication of lidocaine-loaded electrospun fiber patches, drug release, and subsequent uptake and permeation through the porcine buccal mucosa. Lidocaine HCl and lidocaine base were incorporated into the electrospun patches to evaluate the difference in drug permeation for the two drug compositions. Lidocaine released from the lidocaine HCl-containing electrospun patches was significantly quicker than from the lidocaine base patches, with double the amount of drug released from the lidocaine HCl patches in the first 15 min (0.16 ± 0.04 mg) compared to that from the lidocaine base patches (0.07 ± 0.01 mg). The permeation of lidocaine from the lidocaine HCl electrospun patches through ex vivo porcine buccal mucosa was also detected in 15 min, whereas permeation of lidocaine from the lidocaine base patch was not detected. Matrix-assisted laser desorption ionization-mass spectrometry imaging was used to investigate localization of lidocaine within the oral tissue. Lidocaine in the solution as well as from the mucoadhesive patch penetrated into the buccal mucosal tissue in a time-dependent manner and was detectable in the lamina propria after only 15 min. Moreover, the lidocaine released from lidocaine HCl electrospun patches retained biological activity, inhibiting veratridine-mediated opening of voltage-gated sodium channels in SH-SY5Y neuroblastoma cells. These data suggest that a mucoadhesive electrospun patch may be used as a vehicle for rapid uptake and sustained anesthetic drug delivery to treat or prevent oral pain.

Anti-metastatic effect of ranolazine in an in vivo rat model of prostate cancer, and expression of voltage-gated sodium channel protein in human prostate.

BACKGROUND: Voltage-gated Na+ channels (VGSCs) are functionally upregulated in rat and human prostate cancer (PCa) where channel activity promotes cellular invasiveness in vitro and metastasis in vivo. Ranolazine is a clinically used VGSC inhibitor/anti-anginal drug, which has been shown previously to inhibit breast cancer metastasis in vivo. METHODS: Using the Dunning model of rat PCa, the effect of ranolazine applied systemically (by gavage) was tested on the development of primary tumours and metastases following subcutaneous inoculation of Mat-LyLu cells into Copenhagen rats. In addition, human prostate tissue microarrays were used to determine VGSC protein expression in cancerous versus non-cancerous tissue. Several public databases were searched to compare Nav1.7/ SCN9A expression levels in 'normal' vs. PCa tissues. RESULTS: Ranolazine (2.5 and 5 µM) decreased the number of lung metastases by up to 63%. In contrast, primary tumourigenesis was not affected. Ranolazine also reduced the percentage of cells in the metastases expressing Nav1.7, the main VGSC subtype expressed in PCa, but the expression level was higher. In prostate tissue microarrays, VGSC protein expression was significantly higher in cancerous versus non-cancerous tissue. There was no correlation between the VGSC expression and either prostate-specific antigen or Gleason score. In public databases, little information could be found on Nav1.7 protein expression in PCa. In addition, the database information on Nav1.7 mRNA (SCN9A) expression levels did not correlate with previously reported upregulation in PCa cells and tissues. CONCLUSIONS: The main conclusions were (i) ranolazine inhibited metastasis and (ii) it was a subpopulation of cells with particularly high levels of Nav1.7 protein that reached the metastatic sites. These data extend earlier studies and suggest that Nav1.7 expression could serve as a functional biomarker of metastatic PCa and that VGSC blockers may be useful as anti-metastatic agents.

Pharmacological characterization of crotamine effects on mice hind limb paralysis employing both ex vivo and in vivo assays: Insights into the involvement of voltage-gated ion channels in the crotamine action on skeletal muscles.

The high medical importance of Crotalus snakes is unquestionable, as this genus is the second in frequency of ophidian accidents in many countries, including Brazil. With a relative less complex composition compared to other genera venoms, as those from the Bothrops genus, the Crotalus genus venom from South America is composed basically by the neurotoxin crotoxin (a phospholipase A2), the thrombin-like gyroxin (a serinoprotease), a very potent aggregating protein convulxin, and a myotoxic polypeptide named crotamine. Interestingly not all Crotalus snakes express crotamine, which was first described in early 50s due to its ability to immobilize animal hind limbs, contributing therefore to the physical immobilization of preys and representing an important advantage for the envenoming efficacy, and consequently, for the feeding and survival of these snakes in nature. Representing about 10-25% of the dry weight of the crude venom of crotamine-positive rattlesnakes, the polypeptide crotamine is also suggested to be of importance for antivenom therapy, although the contribution of this toxin to the main symptoms of envenoming process remains far unknown until now. Herein, we concomitantly performed in vitro and in vivo assays to show for the first time the dose-dependent response of crotamine-triggered hind limbs paralysis syndrome, up to now believed to be observable only at high (sub-lethal) concentrations of crotamine. In addition, ex vivo assay performed with isolated skeletal muscles allowed us to suggest here that compounds active on voltage-sensitive sodium and/or potassium ion channels could both affect the positive inotropic effect elicited by crotamine in isolated diaphragm, besides also affecting the hind limbs paralysis syndrome imposed by crotamine in vivo. By identifying the potential molecular targets of this toxin, our data may contribute to open new roads for translational studies aiming to improve the snakebite envenoming treatment in human. Interestingly, we also demonstrate that the intraplantal or intraperitoneal (ip) injections of crotamine in mice do not promote pain. Therefore, this work may also suggest the profitable utility of non-toxic analogs of crotamine as a potential tool for targeting voltage-gated ion channels in skeletal muscles, aiming its potential use in the therapy of neuromuscular dysfunctions and envenoming therapy.

The peptide toxin δ-hexatoxin-MrIX inhibits fast inactivation of NaVs in mouse cerebellar granule cells.

Spider venom is rich in peptide toxins that could be used to explore the structure and function of voltage-gated sodium channels (NaVs). This study has characterized a 44-amino acid peptide toxin, δ-hexatoxin-MrIX (δ-HXTX-MrIX), from the venom of the spider Macrothele raveni. δ-hexatoxin-MrIX potently inhibited the fast inactivation of NaVs in mouse cerebellar granule cells (CGCs) with an EC50 of 35.3 ±â€¯5.9 nM. The toxin shifted both the steady-state activation and the steady-state inactivation curves of CGC NaVs to the hyperpolarized direction. δ-hexatoxin-MrIX also acted on NaV1.3 and NaV1.4 channels heterologously expressed in HEK293T cells, as well as on NaVs in acutely isolated cockroach DUM neurons. However, the NaV1.5, NaV1.7 and NaV1.8 channels were resistant to δ-hexatoxin-MrIX. The toxin inhibited the fast inactivation of NaV1.3 and NaV1.4 with high affinity (EC50 values of 82.0 ±â€¯3.0 nM and 24.0 ±â€¯4.7 nM, respectively), but the saturating dose of toxin showed distinct efficacy on these two types of channels. δ-hexatoxin-MrIX is a peptide toxin acting on CGC NaVs and could be used as a pharmacological tool to explore the role of NaVs in granule cell maturation during cerebellum development.

Vitex negundo induces an anticonvulsant effect by inhibiting voltage gated sodium channels in murine Neuro 2A cell line.

Vitex negundo (Vn) extract is famous for the treatment of neurological diseases such as migraine and epilepsy. These neurological diseases have been associated with abnormally increased influx of sodium ions into the neurons. Drugs that inhibit voltage gated sodium channels can be used as potent anti-epileptics. Till now, the effects of Vn on sodium channels have not been investigated. Therefore, we have investigated the effects of methalonic fraction of Vn extract in Murine Neuro 2A cell line. Cells were cultured in a defined medium with or without the Vn extract (100 µg/ml). Sodium currents were recorded using whole-cell patch clamp method. The data show that methanolic extract of Vn inhibited sodium currents in a dose dependent manner (IC50 =161µg/ml). Vn (100 µg/ml) shifted the steady-state inactivation curve to the left or towards the hyper polarization state. However, Vn did not show any effects on outward rectifying potassium currents. Moreover, Vn (100 µg/ml) significantly reduced the sustained repetitive (48±4.8%, P<0.01) firing from neonatal hippocampal neurons at 12 DIV. Hence, our data suggested that inhibition of sodium channels by Vn may exert pharmacological effects in reducing pain and convulsions.

A mutant of the Buthus martensii Karsch antitumor-analgesic peptide exhibits reduced inhibition to hNav1.4 and hNav1.5 channels while retaining analgesic activity.

Scorpion toxins can kill other animals by inducing paralysis and arrhythmia, which limits the potential applications of these agents in the clinical management of diseases. Antitumor-analgesic peptide (AGAP), purified from Buthus martensii Karsch, has been proved to possess analgesic and antitumor activities. Trp38, a conserved aromatic residue of AGAP, might play an important role in mediating AGAP activities according to the sequence and homology-modeling analyses. Therefore, an AGAP mutant, W38G, was generated, and effects of both AGAP and the mutant W38G were examined by whole-cell patch clamp techniques on the sodium channels hNav1.4 and hNav1.5, which were closely associated with the biotoxicity of skeletal and cardiac muscles, respectively. The data showed that both W38G and AGAP inhibited the peak currents of hNav1.4 and hNav1.5; however, W38G induced a much weaker inhibition of both channels than AGAP. Accordingly, W38G exhibited much less toxic effect on both skeletal and cardiac muscles than AGAP in vivo The analgesic activity of W38G and AGAP were verified in vivo as well, and W38G retained analgesic activity similar to AGAP. Inhibition to both Nav1.7 and Nav1.8 was involved in the analgesic mechanism of AGAP and W38G. These findings indicated that Trp38 was a key amino acid involved in the biotoxicity of AGAP, and the AGAP mutant W38G might be a safer alternative for clinical application because it retains the analgesic efficacy with less toxicity to skeletal and cardiac muscles.

The effects of intravenous lignocaine on depth of anaesthesia and intraoperative haemodynamics during open radical prostatectomy.

BACKGROUND: Lignocaine is a local anaesthetic agent, which is also commonly used as a perioperative analgesic adjunct to accelerate rehabilitation and enhance recovery after surgery. Lignocaine's systemic effects on intraoperative haemodynamics and volatile anaesthetic requirements are not well explored. Therefore, we evaluated the effects of intravenous lignocaine on intraoperative volatile agent requirements and haemodynamics in patients undergoing major abdominal surgery. METHODS: We performed an analysis of 76 participants who underwent elective open radical retropubic prostatectomy. Patients received lignocaine (1.5 mg/kg loading dose) followed by an infusion (1.5 mg/kg/h) for the duration of surgery, or saline at an equivalent rate. The aims of the study were to evaluate the end-tidal sevoflurane concentration required to maintain a bispectral index of between 40 and 60. Measurements included intraoperative blood pressure, heart rate, and the volume of intravenous fluids and dosage of vasoactive medications administered. RESULTS: The average end-tidal sevoflurane concentration was lower in the Lignocaine group compared to saline [1.49% (SD: 0.32) vs. 1.89% (SD: 0.29); 95% CI 0.26-0.5, p < 0.001]. In the Lignocaine group, the average mean arterial pressure was 80.3 mmHg (SD: 4.9) compared to 85.1 mmHg (SD: 5.4) in the Saline group (95% CI 2.4-7.1, p < 0.001). Systolic blood pressure was also lower in the Lignocaine group: 121.7 mmHg (SD: 6.1) vs. 128.0 mmHg (SD: 6.4) in the Saline group; 95% CI 3.5-9.2, p < 0.001, as was the mean heart rate [Lignocaine group: 74.9 beats/min (SD: 1.8) vs. 81.5 beats/min (SD: 1.7) in the Saline group, 95% CI 4.1-9.1, p < 0.001]. Maintenance fluid requirements were higher in the Lignocaine group: 3281.1 mL (SD: 1094.6) vs. 2552.6 mL (SD: 1173.5) in the Saline group, 95% CI 206-1251, p = 0.007. There were no differences in the use of vasoactive drugs. CONCLUSIONS: Intravenous lignocaine reduces volatile anaesthetic requirements and lowers blood pressure and heart rate in patients undergoing open radical prostatectomy.

Inhibition of Voltage-Gated Na+ Channels by Bupivacaine Is Enhanced by the Adjuvants Buprenorphine, Ketamine, and Clonidine.

BACKGROUND AND OBJECTIVES: Regional anesthesia includes application of local anesthetics (LAs) into the vicinity of peripheral nerves. Prolongation or improvement of nerve blocks with LAs can be accomplished by coapplication with adjuvants, including buprenorphine, ketamine, and clonidine. While the mechanisms mediating prolonged or improved LA-induced effects by adjuvants are poorly understood, we hypothesized that they are likely to increase LA-induced block of voltage-gated Na channels. In this study, we investigated the inhibitory effects of the LA bupivacaine alone and in combination with the adjuvants on neuronal Na channels. METHODS: Effects of bupivacaine, buprenorphine, ketamine, and clonidine on endogenous Na channels in ND7/23 neuroblastoma cells were investigated with whole-cell patch clamp. RESULTS: Bupivacaine, buprenorphine, ketamine, and clonidine are concentration- and state-dependent inhibitors of Na currents in ND7/23 cells. Tonic block of resting channels revealed an order of potency of bupivacaine (half-maximal inhibitory concentration [IC50] 178 ± 8 µM) > buprenorphine (IC50 172 ± 25) > clonidine (IC50 824 ± 55 µM) > ketamine (IC50 1377 ± 92 µM). Bupivacaine and buprenorphine, but not clonidine and ketamine, induced a strong use-dependent block at 10 Hz. Except for clonidine, all substances enhanced fast and slow inactivation. The combination of bupivacaine with one of the adjuvants resulted in a concentration-dependent potentiation bupivacaine-induced block. CONCLUSIONS: We demonstrate that buprenorphine, ketamine, and clonidine directly inhibit Na channels and that they potentiate the blocking efficacy of bupivacaine on Na channels. These data indicate that block of Na channels may account for the additive effects of adjuvants used for regional anesthesia.

Clinical Micro-Dose Studies to Explore the Human Pharmacokinetics of Four Selective Inhibitors of Human Nav1.7 Voltage-Dependent Sodium Channels.

BACKGROUND: The emergence of genetic data linking Nav1.7 sodium channel over- and under- expression to human pain signalling has led to an interest in the treatment of chronic pain through inhibition of Nav1.7 channels. OBJECTIVE: We describe the pharmacokinetic (PK) results of a clinical microdose study performed with four potent and selective Nav1.7 inhibitors and the subsequent modelling resulting in the selection of a single compound to explore Nav1.7 pharmacology at higher doses. METHODS: A clinical microdose study to investigate the intravenous and oral PK of four compounds (PF-05089771, PF-05150122, PF-05186462 and PF-05241328) was performed in healthy volunteers. PK parameters were derived via noncompartmental analysis. A physiologically-based PK (PBPK) model was used to predict exposure and multiples of Nav1.7 50 % inhibitory concentration (IC50) for each compound at higher doses. RESULTS: Plasma clearance, volume of distribution and bioavailability ranged from 45 to 392 mL/min/kg, 13 to 36 L/kg and 38 to 110 %, respectively. The PBPK model for PF-05089771 predicted a 1 g oral dose would be required to achieve exposures of approximately 12× Nav1.7 IC50 at maximum concentration (C max), and approximately 3× IC50 after 12 h (minimum concentration [C min] for a twice-daily regimen). Lower multiples of Nav1.7 IC50 were predicted with the same oral doses of PF-05150122, PF-05186462, and PF-05241328. In a subsequent single ascending oral dose clinical study, the predictions for PF-05089771 compared well with observed data. CONCLUSION: Based on the human PK data obtained from the microdose study and subsequent modelling, PF-05089771 provided the best opportunity to explore Nav1.7 blockade for the treatment of acute or chronic pain conditions.

Single versus repetitive injection of lignocaine in the management of carpal tunnel syndrome--a randomized controlled trial.

The aim of this study was to determine the efficacy of single versus repetitive injection of lignocaine into the carpal tunnel for the management of carpal tunnel syndrome. The 42 patients included were randomly assigned to two Groups: group 1 was injected with 4 mL of 1% lignocaine once and Group 2 was injected with 4 mL of 1% lignocaine twice a week for 2 weeks. Clinical and electrophysiological evaluations were performed at the study onset, and at 6 and 12 weeks following the final injection. Initially, the groups were similar with respect to clinical and electrophysiological findings. All parameters in Group 2 improved 6 weeks post treatment (p < 0.05), and these improvements persisted at 12 weeks post treatment (p < 0.05). Repetitive local lignocaine injection was effective in reducing the symptoms of carpal tunnel syndrome and improving electrophysiological findings.

Intravenous lidocaine for cancer pain without electrocardiographic monitoring: a retrospective review.

BACKGROUND: Intravenous lidocaine infusion has been clearly demonstrated as effective for pain in randomized controlled trials, but the belief that cardiac monitoring is required for safe administration is a barrier to access in the palliative care setting. There are also multiple infusion protocols reported in the literature. We have been administering lidocaine infusions for severe cancer pain at the BC Cancer Agency (BCCA) since 2003, without electrocardiographic (ECG) monitoring. Our simple protocol is for 5 mg/kg to be infused over 1 hour, with the option for subsequent doses to be increased if necessary, up to a maximum of 10 mg/kg. Our aim with this study is to share 11 years of our experience with this protocol. METHODS: This is a retrospective case series. Records of patients who received at least one lidocaine infusion for pain between 2003 and 2013 at the BCCA were reviewed. The primary end points were the documentation of clinical benefit and adverse effects. RESULTS: A total of 122 lidocaine infusions were administered in 51 individual patients. Twenty-five (49%) had a major response, 12 (23.5%) had a minor response, and 14 (27.5%) were considered nonresponders. Twenty-two (43.1%) patients were noted to have some adverse effect during at least one of the infusions, but only 1 (1.9%) patient had the infusion permanently discontinued. The most common side effects were drowsiness (30.7%), perioral numbness (13.4%), nausea (5.7%), and minor fluctuations of blood pressure (3.8%). CONCLUSIONS: This case series demonstrates that our protocol of infusional lidocaine can be beneficial to patients with cancer with severe opioid-refractory pain, and can safely be administered with close observation and vital sign monitoring, without ECG monitoring. Lidocaine infusion is a useful option to consider when other pain treatments have not been successful. Although only approximately half of patients will respond well, there is little harm to be expected from a trial of lidocaine infusion and responders can be repeatedly treated. This treatment could be delivered in palliative care units, hospices, or even patients' homes, providing suitable nursing supervision can be provided.