The Systemic Toxicity of Equipotent Proxymetacaine, Oxybuprocaine, and Bupivacaine During Continuous Intravenous Infusion in Rats

Hung, Ching Hsia; Liu, Kuo Sheng; Shao, Dong; Cheng, Kuang Hung; Chen, Yu Chung; Chen, Yu Wen

doi:10.1213/ane.0b013e3181bf6acf

Cited by 23 publications

(19 citation statements)

References 16 publications

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“…Subcutaneous injections of drugs were administered as reported previously. 5,6,15 Briefly, the drugs, which were dissolved in normal saline 0.6 mL, were injected subcutaneously in non-anesthetized rats using a 30-G needle on the dorsal surface of the thoracolumbar region. The back of each rat was divided into left and right parts, either of which received one drug injection with a washout period of one week.…”

Section: Part I -Infiltrative Cutaneous Anesthesiamentioning

confidence: 99%

“…The cutaneous anesthetic effects of the drugs were evaluated using the cutaneous trunci muscle reflex, which is characterized by the reflex movement of the skin over the back produced by twitches of the lateral thoracispinal muscle in response to local dorsal cutaneous stimulation. 5,6,15 A No.15 von Frey filament (Somedic Sales AB, Stockholm, Sweden) affixed with the cut end of an 18-G needle was used to produce the standardized nociceptive stimulus (19 ± 1 g). Six pinpricks (at six different points within each wheal) with a frequency of 0.5-1 Hz were used in each testing.…”

Section: Part I -Infiltrative Cutaneous Anesthesiamentioning

confidence: 99%

“…The drug duration of action was defined as the time from drug injection (i.e., time = 0) to full recovery (no analgesic effect or 0% PE recorded). 5,6,15 After subcutaneously injecting the rats with four different doses of each drug (n = 8 for each dose of each drug), cutaneous anesthesia was plotted against time. The lower doses were tested first, and then larger doses were given until comparable doses of each drug were obtained.…”

Section: Part I -Infiltrative Cutaneous Anesthesiamentioning

confidence: 99%

“…The catheter was cut with 5 cm protruding from the skin, and it was then sealed by heating it with a match and compressing it with a hemostat. 15,16 The animal's trachea was then intubated (PE 200), and its lungs were ventilated mechanically (Small Animal Ventilator Model 683, Harvard Apparatus, Holliston, MA, USA) at 50 breathsÁmin -1 with a tidal volume of 8 mLÁkg -1 and a positive end expiratory pressure at 5 cmH 2 O. After cutting into the rat's chest at the third intercostal space to expose the heart, a small section (1 cm long) of the ascending aorta was freed from connective tissue.…”

Section: Part II -Cardiovascular and Neurological Effectsmentioning

confidence: 99%

“…A Transonic Flowprobe (Transonic Systems Inc, Ithaca, NY, USA) was implanted around the root of the ascending aorta, and the connecting wire was tunnelled subcutaneously and exited the skin at the midline in the posterior area of the head. 15,17 Next, the chest was closed and the endotracheal tube was removed after implanting the Transonic Flowprobe. The rat's temperature was maintained via an electric blanket until the rat recovered from anesthesia.…”

Section: Part II -Cardiovascular and Neurological Effectsmentioning

confidence: 99%

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Systemic dextromethorphan and dextrorphan are less toxic in rats than bupivacaine at equianesthetic doses

Chen

Wang

Liu

et al. 2010

Can J Anesth/J Can Anesth

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Purpose Dextrorphan, a major metabolite of dextromethorphan, produces the duration of spinal and cutaneous anesthesia similar to bupivacaine. The purpose of this study was to test the central nervous system and cardiovascular toxicity of bupivacaine, dextromethorphan, and dextrorphan. Methods First, dose-response curves for dextromethorphan, dextrorphan, and bupivacaine (n = 8 at each testing point) were determined for cutaneous analgesia on the rat back, and equipotent doses were calculated. Next, during continuous intravenous infusion of equipotent doses of bupivacaine, dextromethorphan, and dextrorphan (n = 8 in each group), we observed the time to seizure, apnea, and complete cardiac arrest. A saline group (n = 7) was used for comparison. Mean arterial blood pressure (MAP), heart rate (HR), stroke volume (SV), and cardiac output (CO) were also monitored. Results Bupivacaine, dextromethorphan, and dextrorphan produced dose-dependent cutaneous anesthesia. A longer duration of equipotent infusion doses was required to produce seizures in the dextromethorphan group (10.6 ± 1.3 min) than in the bupivacaine group (7.6 ± 2.1 min) (P = 0.005). Dextrorphan did not produce any seizures. Compared with bupivacaine, time to apnea and complete cardiac arrest was longer with dextrorphan (P \ 0.001) and with dextromethorphan (P = 0.001). Cardiovascular collapse, defined as a decline in MAP, HR, CO, and SV, was slower in the dextromethorphan and dextrorphan groups than in the bupivacaine group (P \ 0.001 for both comparisons). Conclusion At equipotent doses for local anesthesia, dextromethorphan and dextrorphan were less likely than bupivacaine to induce central nervous system and cardiovascular toxicity. RésuméObjectif Le dextrorphane, un me´tabolite majeur du dextrome´thorphane, produit une anesthe´sie rachidienne et cutane´e d'une dure´e similaire a`la bupivacaı¨ne. L'objectif de cette e´tude consistait a`e´valuer la toxicite´de la bupivacaı¨ne, du dextrome´thorphane et du dextrorphane sur le syste`me nerveux central et le syste`me cardiovasculaire. Méthode Tout d'abord, les courbes dose-re´ponse du dextrome´thorphane, du dextrorphane et de la bupivacaı¨ne (n = 8 pour chaque essai) ont e´te´de´termine´es pour l'analge´sie cutane´e sur le dos du rat, et des doses Y.W. Chen and Y.C. Chen contributed equally to this study.

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Section: Part I -Infiltrative Cutaneous Anesthesiamentioning

confidence: 99%

Section: Part I -Infiltrative Cutaneous Anesthesiamentioning

confidence: 99%

Section: Part I -Infiltrative Cutaneous Anesthesiamentioning

confidence: 99%

Section: Part II -Cardiovascular and Neurological Effectsmentioning

confidence: 99%

Section: Part II -Cardiovascular and Neurological Effectsmentioning

confidence: 99%

See 3 more Smart Citations

Systemic dextromethorphan and dextrorphan are less toxic in rats than bupivacaine at equianesthetic doses

Chen

Wang

Liu

et al. 2010

Can J Anesth/J Can Anesth

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Ultrasound-Guided Bilateral Transversus Abdominis Plane (US-TAP) Block for Postoperative Analgesia After Breast Reconstruction by Deep Intra Epigastric Perforator (DIEP) Flap

Hivelin

Wyniecki

Plaud

et al. 2016

Breast Reconstruction

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Fine mapping of candidate effector genes for heart rate

Ramírez,

van Duijvenboden,

Young

et al. 2024

Hum. Genet.

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An elevated resting heart rate (RHR) is associated with increased cardiovascular mortality. Genome-wide association studies (GWAS) have identified > 350 loci. Uniquely, in this study we applied genetic fine-mapping leveraging tissue specific chromatin segmentation and colocalization analyses to identify causal variants and candidate effector genes for RHR. We used RHR GWAS summary statistics from 388,237 individuals of European ancestry from UK Biobank and performed fine mapping using publicly available genomic annotation datasets. High-confidence causal variants (accounting for > 75% posterior probability) were identified, and we collated candidate effector genes using a multi-omics approach that combined evidence from colocalisation with molecular quantitative trait loci (QTLs), and long-range chromatin interaction analyses. Finally, we performed druggability analyses to investigate drug repurposing opportunities. The fine mapping pipeline indicated 442 distinct RHR signals. For 90 signals, a single variant was identified as a high-confidence causal variant, of which 22 were annotated as missense. In trait-relevant tissues, 39 signals colocalised with cis-expression QTLs (eQTLs), 3 with cis-protein QTLs (pQTLs), and 75 had promoter interactions via Hi-C. In total, 262 candidate genes were highlighted (79% had promoter interactions, 15% had a colocalised eQTL, 8% had a missense variant and 1% had a colocalised pQTL), and, for the first time, enrichment in nervous system pathways. Druggability analyses highlighted ACHE, CALCRL, MYT1 and TDP1 as potential targets. Our genetic fine-mapping pipeline prioritised 262 candidate genes for RHR that warrant further investigation in functional studies, and we provide potential therapeutic targets to reduce RHR and cardiovascular mortality.

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The Systemic Toxicity of Equipotent Proxymetacaine, Oxybuprocaine, and Bupivacaine During Continuous Intravenous Infusion in Rats

Abstract: Oxybuprocaine and proxymetacaine were more potent at producing cutaneous anesthesia but were less potent than bupivacaine at producing central nervous system and cardiovascular toxicity.

Cited by 23 publications

References 16 publications

Systemic dextromethorphan and dextrorphan are less toxic in rats than bupivacaine at equianesthetic doses

Systemic dextromethorphan and dextrorphan are less toxic in rats than bupivacaine at equianesthetic doses

Ultrasound-Guided Bilateral Transversus Abdominis Plane (US-TAP) Block for Postoperative Analgesia After Breast Reconstruction by Deep Intra Epigastric Perforator (DIEP) Flap

Fine mapping of candidate effector genes for heart rate

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