Severe methemoglobinemia from topical anesthetic spray: case report, discussion and qualitative systematic review.

CJEM. 2001 Jan;3(1):51-6

Authors: Abu-Laban RB, Zed PJ, Purssell RA, Evans KG

Few health care professionals realize that topical anesthetic spray can cause methemoglobinemia. We describe a 56-year-old woman who was transferred to our emergency department when severe cyanosis and chest pain developed after administration of topical oropharyngeal benzocaine and lidocaine during outpatient endoscopy. Investigations revealed a methemoglobin level of 51%. Despite rapid diagnosis and treatment with methylene blue, pulmonary edema consistent with adult respiratory distress syndrome developed, endotracheal intubation was required, and the patient suffered a lengthy course in the intensive care unit. This article presents a detailed discussion of the pathophysiology, diagnosis and treatment of methemoglobinemia, as well as a qualitative systematic review of the English literature on methemoglobinemia induced by topical anesthetic. The implications of this condition for emergency physicians are also outlined.

PMID: 17612444 [PubMed - in process]

Après le déluge: microbial landscape of New Orleans after the hurricanes.

Proc Natl Acad Sci U S A. 2007 May 29;104(22):9103-4

Authors: Dobbs FC

PMID: 17519330 [PubMed - indexed for MEDLINE]

[Henna tattooing in children: natural or temporary?]

An Sist Sanit Navar. 2007 Jan-Apr;30(1):131-4

Authors: Lasa EM, Cojocariu Z, Arroabarren E, Echechipía S, Marín MP, Tabar AI

BACKGROUND: Tattoos of natural red/brown henna obtained from the indigenous tree Lawsonnia have been traditionally performed with a few side-effects. Nowadays black henna tattoos are usually performed even in children. The addition of several chemical agents to improve its cosmetic properties has increased the risk of developing contact dermatitis after exposure. Our aim is to determine the causative agents of contact dermatitis in two children wearing henna tattoos. MATERIAL AND METHODS: Case 1: A 12-year-old girl with no atopy presented local vesicles 10 hours after a black henna tattoo was applied. She had presented similar symptoms with a previous tattoo. Case 2: A 7-year-old atopic boy presented vesicles 2 weeks after a black henna tattoo was applied. He had dyed his hair previously without side effects. Both patients cured, after 3-4 weeks of treatment with topic corticosteroids, with residual hypo-pigmentation. Skin prick test with natural and commercial henna and epicutaneous test with TRUE-TEST, PABA derivatives compounds tests, textile dyes and natural and commercial henna were performed. RESULTS: The epicutaneous tests were positive for p-Metilaminophenol, p-Aminobencene, p-Phenilendiamine and p-Toluenodiamine in both patients. The first patient had also positive tests for Benzocaine, Hydroquinone, Isobutyl p-aminobenzoate, Yellow 1 and Orange 1 disperse; the second one for Red 1 and Orange 1 disperse. In both cases the prick and epicutaneous tests for henna were negative. CONCLUSIONS: Two children presented contact dermatitis after black henna tattoo due to added additives such as paraphenilendiamine.

PMID: 17491615 [PubMed - indexed for MEDLINE]

Evaluation of three topical anaesthetic agents against pain: a clinical study.

Indian J Dent Res. 2006 Oct-Dec;17(4):155-60

Authors: Nayak R, Sudha P

AIM: To compare pain responses of children during local anaesthetic infiltration at bilateral buccal sites prepared with topical application of EMLA 5% cream, benzocaine 18% gel or lignocaine 5% ointment and also to find out the rapidity of onset of action of these agents. METHODS: 60 healthy children aged 6 to 12 years old, received bilateral buccal infiltration following application of topical anaesthetic agents applied in a double blind design. Pain responses were compared based on subject self report using visual analogue scale (VAS) and operator assessment using Sound -Eye -Motor (SEM) scale. RESULTS: Benzocaine gel had the rapidest onset of action. EMLA 5% cream proved to be superior in pain reduction compared to benzocaine and lignocaine. Taste acceptance was better with benzocaine gel. Further studies are required for EMLA cream with an improved formulation more suitable for mucosal application before its routine use in dentistry.

PMID: 17217210 [PubMed - indexed for MEDLINE]

Transportation of juvenile tambaqui (Colossoma macropomum) in a closed system.

Braz J Biol. 2006 May;66(2A):493-502

Authors: Gomes LC, Araujo-Lima CA, Chippari-Gomes AR, Roubach R

The objective of this study was to investigate the effect of density, duration and the use of additives to the water during the transportation of juvenile tambaqui (Colossoma macropomum) and use of this data to establish a safe transportation protocol for the species. The tested products and dosages were: salt (1000, 2000 and 3000 mg/L), gypsum (100, 300 and 500 mg/L) and benzocaine (10, 20 and 30 mg/L). Fish were transported in closed systems (plastic bag) at different densities and time periods of up to 24 h. Fish survival (FS) and water quality parameters were monitored immediately after transportation. The remaining fish were kept in floating cages in order to evaluate mortality which occurred up to 96 h after transportation (S96). The best fish density, additives dosages and time period of the transportation was estimated with a general linear model. The effect of the condition factor on FS and S96 was also evaluated. As expected, FS and S96 were significantly related to time and density. FS but not S96, were also were significantly related to treatment. FS with gypsum treatment was not different from controls and FS with table salt and benzocaine treatments were significantly reduced. The condition factor was not related to either FS or S96. FS was inversely correlated with carbon dioxide concentration. It was concluded that the additives did not improve fish transportation survival. Linear models were developed to predict the best transportation densities as a function of time.

PMID: 16862304 [PubMed - indexed for MEDLINE]

Benzocaine-induced methemoglobinemia.

Anesth Prog. 2005;52(4):136-9

Authors: Hegedus F, Herb K

A case is reported in which a patient developed methemoglobinemia-induced cyanosis while under general anesthesia during surgery for multiple fascial space infections. The cause of methemoglobinemia was 20% benzocaine spray used for local anesthesia before intubation. Acutely developing methemoglobinemia is infrequently encountered in clinical practice. When confronted with cyanosis in the absence of cardiac or pulmonary disease, one must seriously consider the diagnosis of methemoglobinemia. The etiology of methemoglobinemia, the causative agents, the diagnosis, and the emergency treatment required are discussed.

PMID: 16596913 [PubMed - indexed for MEDLINE]

Severe methemoglobinemia complicating topical benzocaine use during endoscopy in a toddler: a case report and review of the literature.

Pediatrics. 2006 Apr;117(4):e806-9

Authors: Dahshan A, Donovan GK

Severe methemoglobinemia resulting from the use of topical benzocaine has been reported in adults as a rare complication. Here we report a case of severe acquired methemoglobinemia resulting from topical use of benzocaine spray during diagnostic upper gastrointestinal endoscopy in a 3-year-old boy with repeated episodes of hematemesis 3 weeks posttonsillectomy. He developed marked cyanosis and became increasingly agitated immediately after completion of his unremarkable endoscopic procedure, which was performed under intravenous sedation. He did not respond to maximum supplemental oxygen and had increased respiratory effort. His pulse oximetry dropped to 85%, but simultaneous arterial blood-gas analysis showed marked hypoxemia (Po2 = 29%) and severe methemoglobinemia (methemoglobin = 39%). His cyanosis and altered mental status promptly resolved after intravenous administration of methylene blue. In patients with methemoglobinemia, pulse oximetry tends to overestimate the actual oxygen saturation and is not entirely reliable. Posttonsillectomy bleeding is a rare but occasionally serious complication that could occur weeks after the surgery, although it more commonly occurs within the first few days. Physicians should remain aware of the possibility of its late onset. This case illustrates the severity of acquired methemoglobinemia that may result from even small doses of topical benzocaine and highlights the fact that prompt treatment of the disorder can be life saving. We question the rationale for routine use of topical anesthetic spray for sedated upper gastrointestinal endoscopy in children. By bringing the attention of pediatricians to this rare but serious complication, we hope that it will result in its improved recognition and possible prevention.

PMID: 16585290 [PubMed - indexed for MEDLINE]

Targeting of calcineurin to an NFAT-like docking site is required for the calcium-dependent activation of the background K+ channel, TRESK.

J Biol Chem. 2006 May 26;281(21):14677-82

Authors: Czirják G, Enyedi P

The two-pore domain K(+) channel, TRESK (TWIK-related spinal cord K(+) channel) is activated in response to the calcium signal by the calcium/calmodulin-dependent protein phosphatase, calcineurin. In the present study we report that calcineurin also interacts with TRESK via an NFAT-like docking site, in addition to its enzymatic action. In its intracellular loop, mouse TRESK possesses the amino acid sequence, PQIVID, which is similar to the calcineurin binding consensus motif, PXIXIT (where X denotes any amino acids), necessary for NFAT (nuclear factor of activated T cells) activation and nuclear translocation. Mutations of the PQIVID sequence of TRESK to PQIVIA, PQIVAD, or PQAVAD increasingly deteriorated the calcium-dependent activation in the listed order and correspondingly reduced the benzocaine sensitivity (a property discriminating activated channels from resting ones), when it was measured after the calcium signal in Xenopus oocytes. Microinjection of VIVIT peptide, designed to inhibit the NFAT-calcineurin interaction specifically, also eliminated TRESK activation. The intracellular loop of TRESK, expressed as a GST fusion protein, bound constitutively active calcineurin in vitro. PQAVAD mutation as well as addition of VIVIT peptide to the reaction abrogated this calcineurin binding. Wild type calcineurin was recruited to GST-TRESK-loop in the presence of calcium and calmodulin. These results indicate that the PQIVID sequence is a docking site for calcineurin, and its occupancy is required for the calcium-dependent regulation of TRESK. Immunosuppressive compounds, developed to target the NFAT binding site of calcineurin, are also expected to interfere with TRESK regulation, in addition to their desired effect on NFAT.

PMID: 16569637 [PubMed - indexed for MEDLINE]

The local anesthetic butamben inhibits and accelerates low-voltage activated T-type currents in small sensory neurons.

Anesth Analg. 2006 Jan;102(1):141-5

Authors: Beekwilder JP, van Kempen GT, van den Berg RJ, Ypey DL

Butamben (BAB) is a local anesthetic that can be used in epidural suspensions for long-term selective suppression of dorsal root pain signal transmission and in ointments for the treatment of skin pain. Previously, high-voltage activated N-type calcium channel inhibition has been implicated in the analgesic effect of BAB. In the present study we show that low-voltage activated or T-type calcium channels may also contribute to this effect. Typical transient T-type barium currents, selectively evoked by low-voltage (-40 mV) clamp stimulation of small (approximately 20 microm diameter) dorsal root ganglion neurons from newborn mice, were inhibited by BAB with an IC50 value of approximately 200 microM. Furthermore, 200 microM BAB accelerated T-type current activation, deactivation, and inactivation kinetics, comparable to earlier observations for N-type calcium channels. Finally, 200 microM BAB had no effect on the midpoint potential and slope factor of the activation curve, although it caused a approximately 3 mV hyperpolarizing shift of the inactivation curve, without affecting the slope factor. We conclude that BAB inhibits T-type calcium channels with a mechanism associated with channel kinetics acceleration.

PMID: 16368819 [PubMed - indexed for MEDLINE]

Local anaesthetics inhibit signalling of human NMDA receptors recombinantly expressed in Xenopus laevis oocytes: role of protein kinase C.

Br J Anaesth. 2006 Jan;96(1):77-87

Authors: Hahnenkamp K, Durieux ME, Hahnenkamp A, Schauerte SK, Hoenemann CW, Vegh V, Theilmeier G, Hollmann MW

BACKGROUND: N-methyl-D-aspartate (NMDA)-receptor activation contributes to postoperative hyperalgesia. Studies in volunteers have shown that intravenous local anaesthetics (LAs) prevent the development of hyperalgesic pain states. One potential explanation for this beneficial effect is the inhibition of NMDA receptor activation. Therefore, we studied the effects of LA on NMDA receptor function. METHODS: The human NR1A/NR2A NMDA receptor was expressed recombinantly in Xenopus laevis oocytes. Peak currents were measured by voltage clamp in Mg- and Ca2+-free, Ba2+-containing Tyrode's solution. Holding potential was -70 mV. Oocytes were stimulated with glutamate/glycine (at EC50) with or without 10 min prior incubation in bupivacaine, levobupivacaine, S-(-)-ropivacaine, or lidocaine (all at 10(-9)-10(-4) M), procaine (10(-4) M), R-(+)-ropivacaine (10(-4) M), QX314 (permanently charged, 5 x 10(-4) M) extracellularly or intracellularly or benzocaine (permanently uncharged, 5 x 10(-3) M). We also determined the effect of the protein kinase C (PKC) inhibitors chelerythrine (5 x 10(-5) M), calphostin C (3 x 10(-6) M) and Ro 31-8220 (10(-7) M), and the effect of PKC activation with phorbolester (10(-6) M). RESULTS: Non-injected oocytes were unresponsive to agonist application, but oocytes expressing NMDA receptors responded with inward currents (1.1+/-0.08 microA). All LA concentration-dependently inhibited agonist responses. The inhibition was reversible and stereoselective. Intracellular QX314 reduced responses to 59% of control, but extracellular QX314 was without effect. Benzocaine reduced responses to 33% of control. PKC inhibitors had no additional inhibitory effect beyond that of bupivacaine. The effect of PKC activation was abolished in the presence of bupivacaine. CONCLUSION: All LA tested inhibited the activation of human NMDA receptors in a concentration dependent fashion. This effect may contribute to reduced hyperalgesia and opiate tolerance observed after systemic administration of LA. The effect is independent of the charge of LA; site of action is intracellular. The mechanism of action may be mediated by inhibition of PKC.

PMID: 16299047 [PubMed - indexed for MEDLINE]

Molecular modeling of local anesthetic drug binding by voltage-gated sodium channels.

Mol Pharmacol. 2005 Dec;68(6):1611-22

Authors: Lipkind GM, Fozzard HA

Voltage-gated sodium (Na+) channels are targets for local anesthetic (LA) drugs that bind in the inner pore of the channel with affinities related to the channel gating states. Our core model of the sodium channel (P loops and S5 and S6 segments from each of the four domains) was closed because it was developed using coordinates from the KcsA channel crystallographic structure. We developed a model of the activated, open channel based on the structure of the open MthK channel, which was characterized by bends at the S6 glycine or serine residues. This created a conformation that allowed energetically appropriate docking of the LA drugs. The alkylamino head of ionizable LA molecules was docked closer to the selectivity filter and in association with Phe-1579 of IVS6 and Leu-1280 of IIIS6 (Nav1.4), and the aromatic ring interacted with Tyr-1586 of IVS6 and Asn-434 of IS6. Comparison of multiple LA drugs showed relative binding affinities in the model consistent with experimental studies. The ionizable LA alkylamino heads interact primarily by van der Waals forces that position the charge so as to create a positive electrostatic barrier for cation permeation. Permanently uncharged benzocaine could be docked in the closed conformation as well, stabilizing the closed conformation. The structurally different anticonvulsant lamotrigine and one of its derivatives have a binding site that fully overlaps with that of the LA drugs. The open, activated channel creates the high-affinity binding site for these sodium channel blocker drugs, and block may be mainly electrostatic.

PMID: 16174788 [PubMed - indexed for MEDLINE]

Benzocaine-induced methemoglobinemia during transesophageal echocardiography.

J Am Osteopath Assoc. 2005 Aug;105(8):381-4

Authors: Birchem SK

Acquired or toxic methemoglobinemia is an uncommon complication of topically administered anesthetic agents in patients of all ages-but particularly in pediatric and elderly patients. This report describes a case of acquired methemoglobinemia that occurred after benzocaine spray was applied orally to a 69-year-old white woman weighing 175 lb who was undergoing transesophageal echocardiography. Patient care was successfully managed. Fundamental concepts regarding methemoglobinemia are also reviewed to heighten physician awareness of this potentially life-threatening complication associated with the application of common topical anesthetic agents.

PMID: 16166392 [PubMed - indexed for MEDLINE]

Tricaine (MS-222) is a safe anesthetic compound compared to benzocaine and pentobarbital to induce anesthesia in leopard frogs (Rana pipiens).

Pharmacol Rep. 2005 Jul-Aug;57(4):467-74

Authors: Cakir Y, Strauch SM

Tricaine (MS-222) is used commonly for sedation, immobilization, and anesthesia of poikilothermic animals. The anesthetic efficacy of different concentrations of MS-222 was compared to benzocaine and pentobarbital on the physiological changes, heart rate and ECG (electrocardiogram) parameters in the leopard frog, Rana pipiens. Loss of righting reflex (RR), loss of pain response (NR = nociceptor response) and recovery time were measured. Heart rate and ECG parameters were also tested before and during anesthesia. The time to loss of RR and NR decreased while recovery time markedly increased with the increasing concentration of MS-222. Benzocaine at 200 mg/l induced a rapid anesthesia, but all frogs needed resuscitation. Pentobarbital at 300 mg/l induced a slow anesthesia, however, all of the frogs also needed resuscitation. All anesthetics at the mentioned concentrations decreased heart rate significantly as well as altered the ECG parameters. All anesthetics prolonged the Q-T interval, and MS-222 at 800 mg/l and benzocaine at 200 mg/l were the most effective anesthetic concentrations in increasing the Q-T interval. Frogs anesthetized by benzocaine and pentobarbital and high concentrations of MS-222 required resuscitation due to hypoxia. Pentobarbital and benzocaine seem to be very effective compounds, but their safety margins are narrow because of ventilatory failure. Therefore, MS-222 at a concentration of 200 mg/l or less is highly recommended for leopard frogs because prolonged recovery, high mortality rate and significant ECG changes are observed with higher concentrations of MS-222.

PMID: 16129913 [PubMed - in process]

Inhibition of the A-type K+ channels of dorsal root ganglion neurons by the long-duration anesthetic butamben.

J Pharmacol Exp Ther. 2005 Sep;314(3):1177-86

Authors: Winkelman DL, Beck CL, Ypey DL, O'Leary ME

n-Butyl-p-aminobenzoate (BAB; butamben) is a long-duration anesthetic used for the treatment of chronic pain. Epidural administration of BAB is thought to reduce the electrical excitability of dorsal root nociceptor fibers by inhibiting voltage-gated ion channels. To further investigate this mechanism, we examined the effects of BAB on the potassium currents of acutely dissociated neurons from the rat dorsal root ganglion (DRG). These neurons express a rapidly inactivating A-type K(+) current (I(A)) that is resistant to tetraethylammonium (20 mM) but inhibited by 4-aminopyridine (5 mM). At low concentrations, BAB (< or =1 microM) selectively inhibited the I(A) component of DRG K(+) current. The voltage dependence of activation and inactivation, kinetics of recovery from inactivation, and the pharmacology of the DRG I(A) were similar to those of the Kv4 family of K(+) channels. Reverse transcription-polymerase chain reaction was used to establish that the messages encoding for all three of the mammalian Kv4 channel subunits (Kv4.1-Kv4.3) were present in the rat DRG. BAB produced a high-affinity, partial inhibition of heterologously expressed Kv4.2 channels (K(D) = 59 nM) but did not alter the kinetics or voltage sensitivity of gating. Substituting polar threonines for conserved hydrophobic residues of the S6 segment weakened BAB binding but did not alter the voltage-dependent gating of the Kv4.2 channel. At physiological pH, BAB is uncharged, suggesting that hydrophobic interactions may contribute to drug binding. The data support a mechanism in which BAB binds near the narrow cytoplasmic entrance of Kv4 channels and inhibits current by a pore blocking mechanism.

PMID: 15923341 [PubMed - indexed for MEDLINE]

The block of total and N-type calcium conductance in mouse sensory neurons by the local anesthetic n-butyl-p-aminobenzoate.

Anesth Analg. 2005 Jun;100(6):1674-9

Authors: Beekwilder JP, Winkelman DL, van Kempen GT, van den Berg RJ, Ypey DL

To contribute to the understanding of the mechanism underlying selective analgesia by epidural application of suspensions of the local anesthetic butamben (n-butyl-p-aminobenzoate; BAB), we investigated the effect of dissolved BAB on calcium channels in sensory neurons. Small-diameter dorsal root ganglion neurons from newborn mice were used to measure whole-cell barium or calcium currents through calcium channels upon voltage-clamp stimulation. BAB suppressed the voltage-step-evoked barium current of these cells in a concentration-dependent manner with a 50% inhibitory concentration of 207 +/- 14 microM (n = 40). A similar concentration dependency was found for the pharmacologically isolated N-type component of the whole-cell barium current. The time constants of inactivation and deactivation of the N-type current became smaller in the presence of BAB, thus suggesting that kinetic changes are involved in the inhibition of this current. BAB caused a similar inhibition of the total calcium current and its N-type component when these currents were evoked by command potentials with the shape of an action potential. This inhibition of calcium currents by BAB should be considered in the search for the mechanism of selective analgesia by epidural suspensions of this local anesthetic.

PMID: 15920194 [PubMed - indexed for MEDLINE]

Benzocaine: not dangerous enough?

Pediatrics. 2005 May;115(5):1452

Authors: Calello DP, Muller AA, Henretig FM, Osterhoudt KC

PMID: 15867086 [PubMed - indexed for MEDLINE]

The use of folk remedies among children in an urban black community: remedies for fever, colic, and teething.

Pediatrics. 2005 Mar;115(3):e297-304

Authors: Smitherman LC, Janisse J, Mathur A

BACKGROUND: Folk remedy use is universal, occurring in all cultures. Folk remedies have been and still are relied on in the black community. In this study, folk remedies refer to herbs, over-the-counter medications, and items traditionally used for cooking that are used to treat a variety of ailments. OBJECTIVE: To identify folk remedies used to treat fever, colic, and teething among black children in Detroit, Michigan. METHODS: Structured interviews were conducted with caregivers of healthy black children <2 years of age who were patients of the general pediatric clinic at Children's Hospital of Michigan. Descriptive analysis of the frequency distribution of the responses was performed. RESULTS: One hundred seven caregivers agreed to participate. All participants were familiar with the use of folk remedies. Most caregivers learned of these remedies from their mothers or grandmothers. Older parents were more likely to use folk remedies, but there was no difference in remedy use among different levels of maternal education. CONCLUSIONS: The knowledge and use of folk remedies were active in this black community. Their use seems to be cultural, rather than attributable to decreased access to health care. Physicians should be aware of these remedies, to educate families about remedies that may be harmful. Most remedies used pose no threat to health. In some cases, remedies may be blended with traditional medical treatments to ensure better patient compliance.

PMID: 15741355 [PubMed - indexed for MEDLINE]

Block of inactivation-deficient Na+ channels by local anesthetics in stably transfected mammalian cells: evidence for drug binding along the activation pathway.

J Gen Physiol. 2004 Dec;124(6):691-701

Authors: Wang SY, Mitchell J, Moczydlowski E, Wang GK

According to the classic modulated receptor hypothesis, local anesthetics (LAs) such as benzocaine and lidocaine bind preferentially to fast-inactivated Na(+) channels with higher affinities. However, an alternative view suggests that activation of Na(+) channels plays a crucial role in promoting high-affinity LA binding and that fast inactivation per se is not a prerequisite for LA preferential binding. We investigated the role of activation in LA action in inactivation-deficient rat muscle Na(+) channels (rNav1.4-L435W/L437C/A438W) expressed in stably transfected Hek293 cells. The 50% inhibitory concentrations (IC(50)) for the open-channel block at +30 mV by lidocaine and benzocaine were 20.9 +/- 3.3 microM (n = 5) and 81.7 +/- 10.6 microM (n = 5), respectively; both were comparable to inactivated-channel affinities. In comparison, IC(50) values for resting-channel block at -140 mV were >12-fold higher than those for open-channel block. With 300 microM benzocaine, rapid time-dependent block (tau approximately 0.8 ms) of inactivation-deficient Na(+) currents occurred at +30 mV, but such a rapid time-dependent block was not evident at -30 mV. The peak current at -30 mV, however, was reduced more severely than that at +30 mV. This phenomenon suggested that the LA block of intermediate closed states took place notably when channel activation was slow. Such closed-channel block also readily accounted for the LA-induced hyperpolarizing shift in the conventional steady-state inactivation measurement. Our data together illustrate that the Na(+) channel activation pathway, including most, if not all, transient intermediate closed states and the final open state, promotes high-affinity LA binding.

PMID: 15545401 [PubMed - indexed for MEDLINE]

Local anesthetics inhibit thromboxane A2 signaling in Xenopus oocytes and human k562 cells.

Anesth Analg. 2004 Sep;99(3):930-7, table of contents

Authors: H&#xF6;nemann CW, Hahnenkamp K, Podranski T, Strumper D, Hollmann MW, Durieux ME

Thromboxane A(2) (TXA(2)) has been proposed as a mediator of perioperative myocardial ischemia, vasoconstriction, and thrombosis. As these adverse events are minimized with epidural anesthesia, rather than general anesthesia, we hypothesized that local anesthetics would inhibit TXA(2)-receptor signaling. We used fluorometric determination of intracellular [Ca(2+)] in human K562 cells and 2-electrode voltage clamp measurements in Xenopus laevis oocytes expressing TXA(2) receptors. After 10-min incubation, lidocaine (IC(50): 1.02 +/- 0.2 x 10(-3) M), ropivacaine (IC(50): ropivacaine 6.3 +/- 0.9 x 10(-5) M), or bupivacaine (IC(50): 1.42 +/- 0.08 x 10(-7) M) inhibited TXA(2)-induced [Ca(2+)](i) in K562 cells. These data were confirmed in Xenopus oocytes recombinantly expressing TXA(2) receptors, with IC(50)s of bupivacaine 1.2 +/- 0.2 x 10(-5) M, R(+) ropivacaine 4.9 +/- 1.7 x 10(-4) M, S(-) ropivacaine 5.3 +/- 0.9 x 10(-5) M, and lidocaine 6.4 +/- 2.8 x 10(-4) M. Intracellular pathways activated by IP(3) and GTPgammaS were not significantly affected by the local anesthetics tested. QX314, a positively charged lidocaine analog, inhibited only if injected intracellularly (IC(50): 5.3 +/- 1.7 x 10(-4) M), indicating one local anesthetic target is most likely inside the cell. Benzocaine (largely uncharged) inhibited with an IC(50) of 8.7 +/- 1.8 x 10(-4) M. This suggests that some of the beneficial effects of regional anesthesia techniques might be due to direct interaction of local anesthetics with the functioning of membrane proteins.

PMID: 15333434 [PubMed - indexed for MEDLINE]

Methemoglobinemia: sudden dyspnea and oxyhemoglobin desaturation after esophagoduodenoscopy.

Respir Care. 2004 Aug;49(8):940-2

Authors: Lunenfeld E, Kane GC

PMID: 15271232 [PubMed - indexed for MEDLINE]

Management of earwax in primary care--postal survey of UK GPs and practice nurses.

Fam Pract. 2004 Aug;21(4):413-4

Authors: Coppin R, Wicke D, Mehta R, Little P

PMID: 15249529 [PubMed - indexed for MEDLINE]

Acute methemoglobinemia after endoscopy.

J Am Board Fam Pract. 2004 May-Jun;17(3):227-9

Authors: Bayard M, Farrow J, Tudiver F

PMID: 15226289 [PubMed - indexed for MEDLINE]

Reported adverse event cases of methemoglobinemia associated with benzocaine products.

Arch Intern Med. 2004 Jun 14;164(11):1192-6

Authors: Moore TJ, Walsh CS, Cohen MR

BACKGROUND: Methemoglobinemia (MHb) is characterized by abnormal levels of oxidized hemoglobin that cannot bind and transport oxygen. When induced by benzocaine anesthetic spray and other chemicals, it can result in cyanosis and life-threatening complications. METHODS: From 818 439 adverse event reports received by the US Food and Drug Administration from November 1997 through March 2002, we extracted every report for use of a benzocaine product. We classified each case by product type (eg, spray, gel, or solution), by whether MHb was involved, and by the dose given. RESULTS: Among 198 reported adverse events of all types associated with benzocaine, 132 cases (66.7%) involved definite or probable MHb. The MHb cases included 107 serious adverse events (81.1%) and 2 deaths (1.5%). In 123 cases (93.2%), the product was a spray; in 2 cases (1.5%), a benzocaine-containing lozenge; and 1 case, a gel. In the 69 cases that specified a dose, 37 (53.6%) indicated that a single spray was applied (approximately the recommended amount). CONCLUSIONS: Health professionals involved in endoscopy, intubation, bronchoscopy, or similar invasive procedures using benzocaine-containing sprays should know that (1) administration may cause MHb with potentially serious consequences, (2) identifying the reaction to benzocaine usually requires cooximetry (although it can be implied by symptoms), and (3) treatment involves immediate intravenous administration of 1 to 2 mg/kg of methylene blue.

PMID: 15197044 [PubMed - indexed for MEDLINE]

Effectiveness of 20% benzocaine as a topical anesthetic for intraoral injections.

Anesth Prog. 2003;50(4):159-63

Authors: Nusstein JM, Beck M

The use of topical anesthetics has been advocated prior to the administration of various types of anesthetic injections. Reported results have varied between studies. The purpose of this study was to compare the effectiveness of 20% benzocaine in reducing the pain of needle insertion during maxillary posterior and anterior infiltration and inferior alveolar nerve block injections. In this retrospective study, 1080 patients received 2336 injections using a 27-gauge needle. Topical anesthetic was applied prior to 720 of the injections. Patients rated pain of needle insertion using a 0-4 pain scale. Logistic regression analysis showed no differences in pain ratings between topical and no topical groups for the inferior alveolar nerve block and posterior maxillary infiltration injections. The use of topical anesthetic did reduce the pain of needle insertion with the maxillary anterior injections (P = .0041).

PMID: 14959903 [PubMed - indexed for MEDLINE]

Benzocaine-induced methemoglobinemia: a potentially fatal complication of transesophageal echocardiography.

Tex Heart Inst J. 2003;30(4):308-10

Authors: Sachdeva R, Pugeda JG, Casale LR, Meizlish JL, Zarich SW

We describe the cases of 2 patients who developed benzocaine-induced methemoglobinemia after the administration of benzocaine as premedication for transesophageal echocardiography. The use of intravenous methylene blue resolved the cyanosis in both patients. Physicians who perform procedures involving the application of topical anesthesia need to be aware of this side effect to prevent morbidity and mortality.

PMID: 14677742 [PubMed - indexed for MEDLINE]

Colorimetric determination of benzocaine, lignocaine and procaine hydrochlorides in pure form and in pharmaceutical formulations using p-benzoquinone.

Anal Sci. 2003 Oct;19(10):1457-9

Authors: Amin AS, el-Didamony AM

A simple, accurate and sensitive method for the microdetermination of benzocaine, lignocaine and procaine hydrochlorides in pure forms and in pharmaceutical formulations is described. The procedure is based on the reaction of those drugs in an aqueous acidic medium with p-benzoquinone to form charge-transfer complexes. The method has been used for the determination of 5.0-70, 5.0-60 and 5.0-90 microg ml(-1) of benzocaine, lignocaine HCl and procaine HCl, respectively. The complexes have apparent molar absorptivities of 1.70 x 10(3), 2.79 x 10(3) and 2.42 x 10(3) L mol(-1) cm(-1) and Sandell sensitivities of 9.72, 10.34 and 11.25 ng cm(-2), respectively. The proposed procedure of analysis is as accurate as the British Pharmacopoeial method (2003). The method was successfully used for the determination of those drugs in the presence of their degradation products, additives and excipients, which were normally encountered in pharmaceutical formulations.

PMID: 14596417 [PubMed - indexed for MEDLINE]

Analgesic synergy between topical morphine and butamben in mice.

Anesth Analg. 2003 Oct;97(4):1103-7, table of contents

Authors: Kolesnikov YA, Cristea M, Pasternak GW

Studies have revealed that lidocaine is an effective analgesic when applied topically to the tail of a mouse in the radiant heat tail-flick assay. In addition, the topical combination of lidocaine with morphine revealed synergistic interactions between the two drugs. In the current studies, we demonstrate that topical butamben, benzocaine, and bupivacaine are active in the radiant heat tail-flick assay. In this assay, topical lidocaine has a ceiling effect and displays a biphasic curve, with large doses markedly decreasing the responses almost to baseline levels. In contrast, butamben has an S-shape dose-dependent response in the assay and did not display a biphasic curve as seen with lidocaine, suggesting that topical butamben may have advantages over lidocaine. Both benzocaine and bupivacaine also showed dose-dependent analgesic activity in this model. Like lidocaine, butamben/morphine combinations displayed synergistic interactions. Indeed, the synergy appeared more prominent with a butamben/morphine combination. We also observed synergy between topical benzocaine and morphine. Although the bupivacaine/morphine combination was suggestive of synergy on isobolographic analysis, it did not achieve statistical significance. These studies indicate that a series of local anesthetics are all active topically in the radiant heat tail-flick assay in mice and that several interact synergistically with morphine. Of the local anesthetics tested, butamben seemed to have several pharmacological characteristics, alone and in combination with morphine, which suggest that it may be superior to the other local anesthetics. Together, these observations suggest that topical combinations of opioids and local anesthetics may prove clinically valuable. IMPLICATIONS: Topical administration of the opioid micro -agonist morphine and the sodium channel inhibitors butamben and benzocaine results in a synergistic interaction for antinociception in radiant heat tail-flick assay in mice, suggesting that the combination of these drugs will enhance rather than detract from the analgesia of either alone.

PMID: 14500165 [PubMed - indexed for MEDLINE]

Angioedema as a complication of upper endoscopy.

Ann Intern Med. 2003 Aug 5;139(3):W-W62

Authors: Lawrence C, Abdrabbo MK

PMID: 12899608 [PubMed - indexed for MEDLINE]

Should a mucoadhesive patch (DentiPatch) be used for gingival anesthesia in children?

Anesth Prog. 2002;49(1):3-8

Authors: Stecker SS, Swift JQ, Hodges JS, Erickson PR

A local anesthetic-impregnated mucosal adhesive patch (DentiPatch) was compared with topical anesthetic (Hurricaine Dry Handle Swab) for gingival anesthesia before rubber dam clamp placement in children. Twenty-eight children needing sealants on their posterior teeth were enrolled in this study. Topical anesthesia was provided using either the mucoadhesive patch (20% lidocaine) or topical anesthetic (20% benzocaine). Subjects were randomized using a split mouth model. Either the patch or topical anesthetic was applied to the gingiva for 5 minutes or 1 minute, respectively. Subjects used a visual analog scale to describe their pain during the procedure. Linear regression and mixed linear models were used for data analysis. The visual analog scale results (pain scores) showed no significant difference between treatments. The mean per-child patch-sticking fraction was 29.7%. Patch adherence to oral mucosa increased with age in girls (P = .0045), but not in boys. The DentiPatch is as effective as, although not superior to, the Hurricaine Dry Handle Swab for gingival anesthesia before rubber dam clamp placement in children. These study results would not support the use of the DentiPatch for gingival anesthesia in children because of poor adherence to oral mucosa and the extra time necessary to apply and retain the device.

PMID: 12779107 [PubMed - indexed for MEDLINE]

Thermodynamics of partitioning of benzocaine in some organic solvent/buffer and liposome systems.

Chem Pharm Bull (Tokyo). 2003 Mar;51(3):237-40

Authors: Avila CM, Mart&#xED;nez F

The thermodynamics of partitioning of benzocaine (BZC) were studied in octanol/buffer (ROH/W), isopropyl myristate/buffer (IPM/W), cyclohexane/buffer (CH/W), and dimyristoyl phosphatidylcholine (DMPC) and dipalmitoyl phosphatidylcholine (DPPC) liposome systems. In all cases the partition coefficients were greater than unity; therefore the free energies of transfer were negative, that is, the processes of transfer of BZC from aqueous media to organic systems were spontaneous. The partition coefficients were approximately three-fold higher in DMPC liposomes compared with the ROH/W system in the 30 degrees -40 degrees C temperature range. The enthalpies of transfer from aqueous media to ROH and IPM were negative, but positive for CH, while this property was negative for DMPC liposomes and positive for DPPC liposomes. The entropies of transfer were positive in almost all cases, except for DMPC. The results presented here confirm the lipophilic nature of BZC.

PMID: 12612403 [PubMed - indexed for MEDLINE]

Kv1.1 channels of dorsal root ganglion neurons are inhibited by n-butyl-p-aminobenzoate, a promising anesthetic for the treatment of chronic pain.

J Pharmacol Exp Ther. 2003 Feb;304(2):531-8

Authors: Beekwilder JP, O'Leary ME, van den Broek LP, van Kempen GT, Ypey DL, van den Berg RJ

In this study, we investigated the effects of the local anesthetic n-butyl-p-aminobenzoate (BAB) on the delayed rectifier potassium current of cultured dorsal root ganglion (DRG) neurons using the patch-clamp technique. The majority of the K(+) current of small DRG neurons rapidly activates and slowly inactivates at depolarized voltages. BAB inhibited the whole-cell K(+) current of these neurons with an IC(50) value of 228 microM. Dendrotoxin K (DTX(K)), a specific inhibitor of Kv1.1, reduced the DRG K(+) current at +20 mV by 34%, consistent with an important contribution of channels incorporating the Kv1.1 subunit to the delayed rectifier current. To further investigate the mechanism of BAB inhibition, we examined its effect on Kv1.1 channels heterologously expressed in mammalian tsA201 cells. BAB inhibits the Kv1.1 channels with an IC(50) value of 238 microM, similar to what was observed for the native DRG current. BAB accelerates the opening and closing of Kv1.1, but does not alter the midpoint of steady-state activation. BAB seems to inhibit Kv1.1 by stabilizing closed conformations of the channel. Coexpression with the Kv beta 1 subunit induces rapid inactivation and reduces the BAB sensitivity of Kv1.1. Comparison of the heterologously expressed Kv1.1 and native DRG currents indicates that the Kv beta 1 subunit does not modulate the gating of the DTX(K)-sensitive Kv1.1 channels of DRG neurons. Inhibition of the delayed rectifier current of these neurons may contribute to the long-duration anesthesia attained during the epidural administration of BAB.

PMID: 12538804 [PubMed - indexed for MEDLINE]

Local lymph node assay with non-radioisotope alternative endpoints.

J Toxicol Sci. 2002 Aug;27(3):205-18

Authors: Suda A, Yamashita M, Tabei M, Taguchi K, Vohr HW, Tsutsui N, Suzuki R, Kikuchi K, Sakaguchi K, Mochizuki K, Nakamura K

The local lymph node assay has recently been accepted by regulatory agencies as a stand-alone alternate method for predicting allergic contact dermatitis. To compare the sensitivity of non-radioisotope methods with that of the standard assay, we determined if these modified methods would affect evaluation of sensitization potency. For this reason, we used 2,4-dinitrochlorobenzene (DNCB) and benzocaine for different sensitizing criteria. Female CBA mice were treated for 3 days with a test compound or vehicle applied to each side of both ears. Bilateral auricular lymph node proliferative activity was assessed by the following endpoints with incorporation of 3H-methyl thymidine (3H-TdR), bromodeoxyuridine (BrdU) in vivo, and BrdU ex vivo, IL-2 production, and proliferating cell nuclear antigen (PCNA) expression. Ear thickness was also tested. The strong sensitizer DNCB was detectable by any of the non-radioisotope endpoints as well as by radioisotope-dependent standard assay. On the other hand, when evaluating the weak sensitizer benzocaine, significant changes were evident in BrdU incorporation ex vivo and in vivo, and IL-2 production. We believe that these non-radioisotope methods can assess allergic contact dermatitis caused by chemicals even in the laboratory, where it can be difficult to handle radioisotopes.

PMID: 12238144 [PubMed - indexed for MEDLINE]

Benzoate X receptors alpha and beta are pharmacologically distinct and do not function as xenobiotic receptors.

J Biol Chem. 2002 Nov 15;277(46):43691-7

Authors: Gr&#xFC;n F, Venkatesan RN, Tabb MM, Zhou C, Cao J, Hemmati D, Blumberg B

The Xenopus benzoate nuclear hormone receptors, BXRalpha and BXRbeta, share 82% identity within their ligand-binding domains and are classified as members of the NR1I2 subfamily that includes the mammalian steroid and xenobiotic receptor, SXR/PXR. Although alkyl benzoates have been identified as endogenous ligands, the exact role of the benzoate receptors in amphibian physiology has not been established. In this report, we show that BXRalpha and BXRbeta are pharmacologically distinct from each other: BXRalpha is more promiscuous than BXRbeta with respect to both ligand specificity and co-activator recruitment. BXRalpha can be transactivated by a number of benzoate derivatives including 4-amino-butylbenzoate (4-ABB), 4-hydroxy-butylbenzoate (4-HBB), 3-hydroxy ethyl benzoate (3-HEB), and benzyl benzoate, but only 4-HBB acts as an agonist for both receptors. Furthermore, BXRalpha-specific agonists such as 4-ABB, chlorpyrifos, and trifluralin act as antagonists on BXRbeta. BXRs are widely distributed in adult tissues but do not show any enrichment in liver and intestine, major sites of SXR/PXR expression that are critical in xenobiotic metabolism. Neither BXR shows the broad specificity toward steroids or xenobiotics exhibited by SXR/PXR. Therefore, we conclude that the BXRs are pharmacologically distinct from each other and unlikely to serve as xenobiotic sensors.

PMID: 12198127 [PubMed - indexed for MEDLINE]

Inhibition of tetrodotoxin (TTX)-resistant and TTX-sensitive neuronal Na(+) channels by the secretolytic ambroxol.

Mol Pharmacol. 2002 Sep;62(3):433-8

Authors: Weiser T, Wilson N

Ambroxol has a long history for the treatment of airway diseases because of its beneficial effects on surfactant synthesis and mucus-modifying properties. Some findings, however, point to an additional effect on neuronal signal transduction: ambroxol can suppress reflexes such as the cough or the corneal reflex. The airways and the cornea are innervated by C-fibers, which express voltage-gated Na(+) channels with and without sensitivity to tetrodotoxin (TTX). In this study, we performed voltage-clamp experiments to investigate whether ambroxol affects these channel types. In rat dorsal root ganglia, TTX-resistant Na(+) currents were suppressed in a concentration-dependent manner with IC(50) values of 35.2 and 22.5 microM for tonic and phasic block, respectively. Depolarizing prepulses increased the potency of ambroxol, and steady-state inhibition curves were shifted to more negative values. The inhibition was not frequency-dependent. TTX-sensitive currents were inhibited with lower potency (approximately 50% inhibition with 100 microM). Recombinant rat brain IIA channels in Chinese hamster ovary cells were blocked with IC(50) values of 111.5 and 57.6 microM for tonic and phasic block, respectively; in contrast to TTX-resistant channels the block was frequency-dependent. Thus, ambroxol indeed blocks neuronal voltage-gated Na(+) channels, and TTX-resistant channels in sensory neurons were more sensitive than TTX-sensitive. Compared with known local anesthetics (e.g., lidocaine or benzocaine), the potency for Na(+) channel block was relatively high. A recent clinical trial has further confirmed that ambroxol relieved pain and was beneficial in patients who suffered from sore throat.

PMID: 12181417 [PubMed - indexed for MEDLINE]

The role of fat and cholecystokinin in functional dyspepsia.

Gut. 2002 Jul;51 Suppl 1:i54-7

Authors: Fried M, Feinle C

The main factors involved in the pathophysiology of fat induced dyspepsia were investigated by reviewing a series of controlled double blind randomised studies which sought to determine the role of nutrient fat and the postprandial release of cholecystokinin (CCK) in the development of dyspeptic symptoms in healthy volunteers and in patients with functional dyspepsia. The studies showed that during distension of the stomach, lipids are a major trigger of dyspeptic symptoms such as nausea, bloating, pain, and fullness, and that they modulate upper gastrointestinal sensations and symptoms in a dose related fashion. CCK is a major mediator of the sensitisation of gastric perception by lipids in patients with functional dyspepsia as the CCK-A receptor antagonist dexloxiglumide markedly diminishes this effect. The studies provide important insights into the mechanisms underlying gastrointestinal perception in response to fat and the role of CCK in patients with functional dyspepsia.

PMID: 12077066 [PubMed - indexed for MEDLINE]

The antinociceptive and histologic effect of sciatic nerve blocks with 5% butamben suspension in rats.

Anesth Analg. 2002 Mar;94(3):711-6; table of contents

Authors: McCarthy RJ, Kerns JM, Nath HA, Shulman M, Ivankovich AD

Butamben, a lipophilic local anesthetic of the ester class, produces a differential nerve block of long duration. Epidural and peripheral nerve blocks with butamben, formulated as a 5%--10% suspension, result in prolonged analgesia without significant motor blockade. We evaluated the effect of butamben sciatic nerve block on antinociception using the rat paw formalin test, as well as withdrawal latencies to thermal stimulation, and assessed histologic changes in the nerve. After right sciatic nerve block with butamben 5% or saline, responses to intradermal injection of 5% formalin were recorded in randomly selected groups of 6 animals each on days 1, 2, 5, 10, 21, and 28. In an additional group of 8 thermal challenges to both hind paws were recorded at 1, 2, 5, 7, 10, 14, 17, 21, and 28 days after right sciatic butamben 5% blocks. Butamben injection decreased the formalin-induced flinches on days 2, 5, 10, 21 and 28 and decreased thermal challenges on days 1 through 17. Histologic changes were minimal. This study demonstrates a prolonged antinociceptive effect from butamben nerve block to both formalin-induced nociception and heat hyperalgesia, without an effect on gross motor function or histologic morphology. IMPLICATIONS: Butamben 5% nerve blocks produced a prolonged antinociceptive effect to formalin-induced nociception and heat hyperalgesia, without significant motor effect or evidence of substantial histologic changes.

PMID: 11867403 [PubMed - indexed for MEDLINE]

Evaluation of a transoral delivery system for topical anesthesia.

J Am Dent Assoc. 2001 Dec;132(12):1714-9

Authors: Carr MP, Horton JE

BACKGROUND: The development of bioadhesives has allowed for the creation of a novel transoral topical anesthesia delivery system used to alleviate pain by needlestick injections and select dental procedures. METHODS: Sixty subjects evaluated the effectiveness of a lidocaine-containing bioadhesive patch, or L-BP, to alleviate pain caused by needlesticks, or Ns, with or without injection, and with scaling and root planing, or Sc/RP, instrumentation. The authors topically administered a commonly used benzocaine-containing gel, or B-G, preparation to analogous sites for direct comparison. Subjects rated their degree of pain/discomfort using verbal pain score, or VPS, measurements. RESULTS: Paired t tests and signed ranked tests revealed that the subjects' perception of pain was significantly reduced after the application of L-BP with placebo (P < .01) for both Ns and Sc/RP but was not significantly reduced by B-G with placebo. L-BP also significantly reduced the subjects' perception of pain caused by Ns and Sc/RP when compared directly with B-G (P < .01). The resultant tissue anesthesia by L-BP significantly reduced pain to Ns with or without anesthetic injection using 25- and 27-gauge needles. However, Ns in conjunction with anesthetic injections generated significantly greater pain than that caused by Ns alone (P < .01). VPS score differences between 25- and 27-gauge needles were not found. CONCLUSIONS: This study found that a lidocaine-containing bioadhesive system delivering topical anesthesia was highly effective in alleviating pain/discomfort arising from Ns, with and without concomitant injection, and select Sc/RP procedures. CLINICAL IMPLICATIONS: A new topical delivery system that effectively anesthetizes oral tissues may prove highly useful in allaying patient anxieties about and fear of select dental procedures.

PMID: 11780993 [PubMed - indexed for MEDLINE]

Mathematical modeling of surface-active and non-surface-active drug transport in emulsion systems.

AAPS PharmSci. 2000;2(3):E31

Authors: Chidambaram N, Burgess DJ

Mathematical models were developed for the prediction of surface-active and non- surface-active drug transport in triphasic (oil, water, and micellar) emulsion systems as a function of micellar concentration. These models were evaluated by comparing experimental and simulated data. Fick's first law of diffusion with association of the surface-active or complexation nature of the drug with the surfactant was used to derive a transport model for surface-active drugs. This transport model assumes that the oil/water (O/W) partitioning process was fast compared with membrane transport and therefore drug transport was limited by the membrane. Consecutive rate equations were used to model transport of non-surface-active drugs in emulsion systems assuming that the O/W interface acts as a barrier to drug transport. Phenobarbital (PB) and barbital (B) were selected as surface-active model drugs. Phenylazoaniline (PAA) and benzocaine (BZ) were selected as non- surface-active model drugs. Transport studies at pH 7.0 were conducted using side-by-side diffusion cells and bulk equilibrium reverse dialysis bag techniques. According to the surface-active drug model, an increase in micellar concentration is expected to decrease drug-transport rates. Using the Microsoft EXCEL program, the non-surface-active drug model was fitted to the experimental data for the cumulative amount of the model drug that disappeared from the donor chamber. The oil/continuous phase partitioning rates (k1) and the membrane transport rates (k2) were estimated. The predicted data were consistent with the experimental data for both the surface-active and non- surface-active models.

PMID: 11741247 [PubMed - indexed for MEDLINE]

Effect of nonionic surfactant on transport of surface-active and non-surface-active model drugs and emulsion stability in triphasic systems.

AAPS PharmSci. 2000;2(3):E30

Authors: Chidambaram N, Burgess DJ

The effect of surfactant concentration on transport kinetics in emulsions using surface-active (phenobarbital, barbital) and non- surface-active (phenylazoaniline, benzocaine) model drugs is determined. Mineral oil was chosen as the oil phase and the nonionic surfactant polyoxyethylene-10-oleyl-ether (Brij 97) was chosen as the emulsifier. Model drug transport in the triphasic systems was investigated using side-by-side diffusion cells mounted with hydrophilic dialysis membranes (molecular weight cutoffs 1 kd and 50 kd) and a novel bulk equilibrium reverse dialysis bag technique. Emulsion stability was determined by droplet size analysis as a function of time, temperature, and the presence of model drugs, using photon correlation spectroscopy. Mineral oil/water (O/W) partition coefficients and aqueous solubilities were determined in the presence of surfactant. The transport rates of model drugs in emulsions increased with an increase in Brij 97 micellar concentrations up to 1.0% wt/vol and then decreased at higher surfactant concentrations. The transport profiles of the model drugs appeared to be governed by model drug O/W partition coefficient values and by micellar shape changes at higher surfactant concentrations. Total transport rates of phenobarbital and barbital were faster than those of phenylazoaniline and benzocaine. Excess surfactant affected the transport rates of the model drugs in the emulsions depending on drug surface activity and lipophilicity.

PMID: 11741246 [PubMed - indexed for MEDLINE]

Effect of cationic surfactant on transport of surface-active and non-surface-active model drugs and emulsion stability in triphasic systems.

AAPS PharmSci. 2000;2(3):E28

Authors: Chidambaram N, Burgess DJ

A study was carried out to determine the effect of excess surfactant on transport kinetics in emulsions, using surface-active (phenobarbital, barbital) and non-surface-active (phenylazoaniline, benzocaine) model drugs (pH 7.0). Mineral oil was chosen as the oil phase, and the ionic surfactant cetyltrimethylammonium bromide (CTAB) was chosen as the emulsifier. The effect of nonionic surfactant Brij 97 on transport kinetics of these model drugs were determined by authors elsewhere. Model drug transport in the triphasic systems was investigated using side-by-side diffusion cells mounted with hydrophilic dialysis membranes (molecular weight cutoffs 1 kD and 50 kD) and a novel bulk equilibrium reverse dialysis bag technique. Emulsion stability was determined by droplet size analysis as a function of time, temperature, and the presence of model drugs using photon correlation spectroscopy. Mineral oil/water partition coefficients and aqueous solubilities were determined in the presence of surfactant. The droplet size of the CTAB-stabilized emulsion system is bigger than that of the Brij 97-stabilized system because of the relatively less dense interfacial packing of the cationic surfactant. CTAB forms a complex with the model drugs because of ionic interaction between CTAB and the aromatic and azo groups of the model drugs. This complexation is expected to increase emulsion stability and affect model drug transport kinetics. The transport rates of model drugs in emulsions increased with increases in CTAB micellar concentrations up to 0.5% w/v and then decreased at higher surfactant concentrations. Total transport rates of phenobarbital and barbital were faster than those of phenylazoaniline and benzocaine. Excess surfactant affected the transport rates of the model drugs in the emulsions depending on drug surface activity and lipophilicity. The transport profiles of the model drugs appeared to be governed by model drug oil/water partition coefficient values and by micellar shape changes at higher surfactant concentrations.

PMID: 11741244 [PubMed - indexed for MEDLINE]

A novel in vitro release method for submicron sized dispersed systems.

AAPS PharmSci. 1999;1(3):E11

Authors: Chidambaram N, Burgess DJ

Sink conditions are often violated when using conventional release methods for dispersed systems. A novel reverse dialysis bag method was designed to overcome this problem. Model drug transport rates from submicron emulsions obtained using the conventional diffusion cell method and this novel method were compared. In the side-by-side diffusion cell method, emulsions were placed in the donor chamber and surfactant/buffer solutions in the receiver chamber. In the novel dialysis bag method, emulsions were diluted infinitely in the donor phase and surfactant/buffer solutions were placed in the receiver phase (dialysis bags). Slow release rates and linear release profiles were obtained using the side-by-side diffusion cell method apparently due to limited model drug solubility in the donor chamber resulting in violation of sink conditions. Biphasic release profiles were obtained using the dialysis bag method apparently due to an initial rapid release of free and micellar solubilized model drug from the donor to the receiver chambers followed by slow release from the oil droplets. Using both release methods, an initial increase and latter decrease in release rates were observed with increase in surfactant concentration. The initial increase was considered to be due to a decrease in the model drug oil-in-water partition coefficients and the subsequent decrease in release rates was due to micellar shape change (spheres to rods) causing a decrease in diffusion rates. Sink conditions were violated using the side-by-side diffusion cell method but were maintained in the dialysis bag method since emulsions were diluted infinitely in the donor phase.

PMID: 11741207 [PubMed - indexed for MEDLINE]

Inhibition of m3 muscarinic acetylcholine receptors by local anaesthetics.

Br J Pharmacol. 2001 May;133(1):207-16

Authors: Hollmann MW, Ritter CH, Henle P, de Klaver M, Kamatchi GL, Durieux ME

1. Muscarinic m1 receptors are inhibited by local anaesthetics (LA) at nM concentrations. To elucidate in more detail the site(s) of LA interaction, we compared these findings with LA effects on m3 muscarinic receptors. 2. We expressed receptors in Xenopus oocytes. Using two-electrode voltage clamp, we measured the effects of lidocaine, QX314 (permanently charged) and benzocaine (permanently uncharged) on Ca(2+)-activated Cl(-)-currents (I(Cl(Ca))), elicited by acetyl-beta-methylcholine bromide (MCh). We also characterized the interaction of lidocaine with [(3)H]-quinuclydinyl benzylate ([(3)H]-QNB) binding to m3 receptors. Antisense-injection was used to determine the role of specific G-protein alpha subunits in mediating the inhibitory effects of LA. Using chimeric receptor constructs we investigated which domains of the muscarinic receptors contribute to the binding site for LA. 3. Lidocaine inhibited m3-signalling in a concentration-dependent, reversible, non-competitive manner with an IC(50) of 370 nM, approximately 21 fold higher than the IC(50) (18 nM) reported for m1 receptors. Intracellular inhibition of both signalling pathways by LA was similar, and dependent on the G(q)- protein alpha subunit. In contrast to results reported for the m1 receptor, the m3 receptor lacks the major extracellular binding site for charged LA. The N-terminus and third extracellular loop of the m1 muscarinic receptor molecule were identified as requirements to obtain extracellular inhibition by charged LA.

PMID: 11325812 [PubMed - indexed for MEDLINE]

Contact dermatitis in students practicing sports: incidence of rubber sensitisation.

Br J Sports Med. 2001 Apr;35(2):100-2

Authors: Ventura MT, Dagnello M, Matino MG, Di Corato R, Giuliano G, Tursi A

BACKGROUND: Over the last few years, changes in cutaneous homoeostasis resulting from sports activities have been reported. In particular, alterations in sweating mechanisms, the hydrolipid barrier, and surface bacterial flora, together with exposure to atmospheric conditions and the need to use medicaments, detergents, and other topical substances, predispose subjects to allergic contact dermatitis. OBJECTIVE: To evaluate the incidence of allergic contact dermatitis in a group of young people practising sports activities. METHODS: Patch tests were performed to confirm the diagnosis of irritant or allergic dermatitis; in addition, the radioallergoabsorbent test (RAST) to latex was evaluated in the group studied. RESULTS: Allergic contact dermatitis caused by thiourams (23.3%) and mercaptobenzothiazole (20.9%) was prevalent. Other haptens, such as benzocaine and nickel, which are contained in clothing, equipment, topical medicaments, and creams used for massage, were also allergenic. In two cases, RAST positivity to latex was registered. CONCLUSIONS:-The results suggest that close contact with sports equipment may increase the incidence of allergic contact dermatitis. Students practising certain sports may have "professional" allergic contact dermatitis to additives used in the production of rubber.

PMID: 11273970 [PubMed - indexed for MEDLINE]

Canister tip orientation and residual volume have significant impact on the dose of benzocaine delivered by Hurricaine spray.

Anesth Analg. 2001 Feb;92(2):379-83

Authors: Khorasani A, Candido KD, Ghaleb AH, Saatee S, Appavu SK

Delivered quantities of 20% benzocaine spray (Hurricaine; Beutlich L.P. Pharmaceuticals, Waukegan, IL) are estimated by counting the number of sprays or the spraying time. Because Hurricaine spray supplies a continuous (albeit nonmetered) stream of benzocaine, neither method addresses delivered dose. We hypothesized that dose per time is a function of canister content and orientation. Thirty full canisters of Hurricaine were placed into three equal orientations (upright, inverted, or horizontal). Extrapolating from a full canister, four different estimates of benzocaine residual volume were determined before spraying out the contents (80%, 60%, 40%, and 20% full). Each canister was then sprayed for 10-s intervals, and the quantity delivered was calculated and compared statistically. Upright canisters 100% full emitted more benzocaine than canisters with residual volume 20% full (190 +/- 10 vs 172 +/- 10 mg/s). Inverted canisters emitted significantly less benzocaine from 100% full to residual volume 20% full (188 +/- 14 vs 70 +/- 10 mg/s). Oriented horizontally, two full canisters emitted <76 mg/s benzocaine, contrasted with the remaining eight in that group (186 +/- 20 mg/s). We conclude that the benzocaine (Hurricaine) sprayed in milligrams per second depends on canister content and orientation. When residual volumes diminish, there is a reduction in spraying volume per time. This diminution occurs progressively from larger to smaller residual volumes with canisters oriented horizontally, inverted, or upright. Arbitrary documentation of spraying time bears no relationship to dose delivered. Perhaps affixing an atomization device to a graduated syringe filled with benzocaine will help increase accuracy and precision in dosing.

PMID: 11159236 [PubMed - indexed for MEDLINE]

Placement of the esophageal Doppler ultrasound monitor probe in awake patients.

Chest. 2001 Jan;119(1):319

Authors: Atlas G, Mort T

PMID: 11157636 [PubMed - indexed for MEDLINE]

Modulation of gastric distension-induced sensations by small intestinal receptors.

Am J Physiol Gastrointest Liver Physiol. 2001 Jan;280(1):G51-7

Authors: Feinle C, Grundy D, Fried M

Duodenal lipid exacerbates gastrointestinal sensations during gastric distension. Using luminal application of the local anesthetic benzocaine, we investigated the role of intestinal receptors in the induction of these sensations. Nine healthy subjects were studied on five occasions, during which isotonic saline or 20% lipid (2 kcal/min), combined with (duodenal or jejunal) 0.75% benzocaine or vehicle at 2.5 ml/min, was infused intraduodenally before and during gastric distension. Intragastric pressures and volumes, gastrointestinal sensations, and plasma CCK levels were determined. Duodenal lipid combined with vehicle increased gastric volume (in ml: saline, -10 +/- 18; lipid/vehicle, 237 +/- 30) and plasma CCK [mean levels (pmol/l): saline, 2.0 +/- 0. 2; lipid/vehicle, 8.0 +/- 1.6] and, during distensions, induced nausea (scores: saline, 3 +/- 2: lipid/vehicle, 58 +/- 19) and decreased pressures at which fullness and discomfort occurred. Duodenal but not jejunal benzocaine attenuated the effect of lipid on gastric volume, plasma CCK, and nausea during distension (135 +/- 38 and 216 +/- 40 ml, 4.6 +/- 0.6 pmol/l and not assessed, and 37 +/- 12 and 64 +/- 21 for lipid + duodenal benzocaine and lipid + jejunal benzocaine, respectively) and on pressures for sensations. In conclusion, intestinal receptors modulate gastrointestinal sensations associated with duodenal lipid and gastric distension. There is also the potential for local neural mechanisms to regulate CCK release and thereby reduce afferent activation indirectly.

PMID: 11123197 [PubMed - indexed for MEDLINE]

Selective block of late Na(+) current by local anaesthetics in rat large sensory neurones.

Br J Pharmacol. 2000 Apr;129(8):1617-26

Authors: Baker MD

The actions of lignocaine and benzocaine on transient and late Na(+) current generated by large diameter (> or =50 microm) adult rat dorsal root ganglion neurones, were studied using patch-clamp techniques. Both drugs blocked whole-cell late Na(+) current in a concentration-dependent manner. At 200 ms following the onset of a clamp step from -110 to -40 mV, the apparent K for block of late Na(+) current by lignocaine was 57.8+/-15 microM (mean+/-s.e.mean, n = 4). The value for benzocaine was 24.9+/-3.3 microM, (mean+/-s.e. mean, n = 3). The effect of lignocaine on transient current, in randomly selected neurones, appeared variable (n = 8, half-block from approximately 50 to 400 microM). Half-block by benzocaine was not attained, but both whole-cell (n = 11) and patch data suggested a high apparent K,>250 microM. Transient current always remained after late current was blocked. The voltage-dependence of residual late current steady-state inactivation was not shifted by 20 microM benzocaine (n = 3), whereas 200 microM benzocaine shifted the voltage-dependence of transient current steady-state inactivation by -18.7+/-5.9 mV (mean+/-s.e.mean, n = 4). In current-clamp, benzocaine (250 microM) could block subthreshold, voltage-dependent inward current, increasing the threshold for eliciting action potentials, without preventing their generation (n = 2). Block of late Na(+) current by systemic local anaesthetic may play a part in preventing ectopic impulse generation in sensory neurones.

PMID: 10780966 [PubMed - indexed for MEDLINE]

Benzocaine-induced methemoglobinemia.

Anesth Analg. 2000 Feb;90(2):369-71

Authors: Nguyen ST, Cabrales RE, Bashour CA, Rosenberger TE, Michener JA, Yared JP, Starr NJ

PMID: 10648323 [PubMed - indexed for MEDLINE]

The long-term effect of epidural administration of butamben suspension on nerve injury-induced allodynia in rats.

Anesth Analg. 1999 Oct;89(4):989-94

Authors: Mitchell VA, White DM, Cousins MJ

Although local anesthetics can, in some situations, alleviate neuropathic pain, currently available preparations are short-acting and nonselective, producing, for example, motor dysfunction. Clinical studies report that a novel suspension preparation of butamben has the advantage of a prolonged duration of action, and it can be used epidurally, without impairment of motor function. In this behavioral study, we investigated the effect of the epidural administration of a 5% butamben suspension on nerve injury-induced allodynia. Behavioral studies were performed using an established animal model of neuropathic pain, which involves a partial ligation of the sciatic nerve. Nociceptive thresholds to mechanical stimulation were determined by the paw withdrawal method. The allodynia to mechanical stimulation induced by partial nerve ligation was significantly attenuated by daily injections, for 5 days, of 10 microL of butamben suspension. The analgesia lasted at least 7 days after the final injection. Daily injections of 10 microL of vehicle, for 5 days, had no significant effect on allodynia. During the period of daily injections, both the butamben and vehicle treated rats had temporary impairment of motor coordination compared with untreated controls. Motor function recovered after the final injection. Neither daily injections of butamben for 2 or 3 days, nor smaller volumes for 5 days (2.5-5 microL), had a long-lasting effect. We conclude that repeated epidural administration of butamben suspension for several days provides long-lasting analgesia in rats with nerve injury-induced allodynia to mechanical stimulation. IMPLICATIONS: In this animal behavioral study, using rats with nerve injury-induced pain, we examined the possible long-term analgesic effects of epidural administration of a suspension of the local anesthetic, butamben. We found that multiple doses for several days were required to provide a prolonged analgesia.

PMID: 10512277 [PubMed - indexed for MEDLINE]

Local anesthetic anchoring to cardiac sodium channels. Implications into tissue-selective drug targeting.

Circ Res. 1999 Jul 9;85(1):88-98

Authors: Li RA, Tsushima RG, Himmeldirk K, Dime DS, Backx PH

Local anesthetics inhibit Na+ channels in a variety of tissues, leading to potentially serious side effects when used clinically. We have created a series of novel local anesthetics by connecting benzocaine (BZ) to the sulfhydryl-reactive group methanethiosulfonate (MTS) via variable-length polyethylether linkers (L) (MTS-LX-BZ [X represents 0, 3, 6, or 9]). The application of MTS-LX-BZ agents modified native rat cardiac as well as heterologously expressed human heart (hH1) and rat skeletal muscle (rSkM1) Na+ channels in a manner resembling that of free BZ. Like BZ, the effects of MTS-LX-BZ on rSkM1 channels were completely reversible. In contrast, MTS-LX-BZ modification of heart and mutant rSkM1 channels, containing a pore cysteine at the equivalent location as cardiac Na+ channels (ie, Y401C), persisted after drug washout unless treated with DTT, which suggests anchoring to the pore via a disulfide bond. Anchored MTS-LX-BZ competitively reduced the affinity of cardiac Na+ channels for lidocaine but had minimal effects on mutant channels with disrupted local anesthetic modification properties. These results establish that anchored MTS-LX-BZ compounds interact with the local anesthetic binding site (LABS). Variation in the linker length altered the potency of channel modification by the anchored drugs, thus providing information on the spatial relationship between the anchoring site and the LABS. Our observations demonstrate that local anesthetics can be anchored to the extracellular pore cysteine in cardiac Na+ channels and dynamically interact with the intracellular LABS. These results suggest that nonselective agents, such as local anesthetics, might be made more selective by linking these agents to target-specific anchors.

PMID: 10400914 [PubMed - indexed for MEDLINE]