The First Etherization in England: New Research Regarding the Identity of the First Patient, Miss Lonsdale.

On December 19, 1846, at the London home of Francis Boott, dentist James Robinson administered the vapor of diethyl ether to a young female patient named Miss Lonsdale. This was the earliest known attempt in England to provide painless operating conditions for a dental extraction, and it was successful. Many authors have since written much about Boott and Robinson, but scarcely anything is known about Miss Lonsdale. In contemporaneous accounts of the event, Robinson referred to his patient as a "young person" and a "young lady"; Boott, however, named her, suggesting that she was publicly recognizable. Our initial attempt to identify Miss Lonsdale was based on genealogical, United Kingdom Census, and other public records, using selection criteria based on age, name recognition, familial relationships, and London addresses. This produced 7 possible candidates from publicly recognizable families, though none was notable in her own right. Our second attempt was based primarily on contemporaneous newspaper records, among which were published 2 private letters in which Boott referred to Robinson's patient as a "girl." We found that "Miss Lonsdale" was the publicly recognizable name of 2 young stage-performing sisters, Adeline Lonsdale, a danseuse, and Annie Lonsdale, an actor-comedienne. Both subsequently emigrated to the United States where they were well-known stage performers. Accordingly, we suggest that both are highly probable candidates for that etherized patient, with the younger sister Adeline then more publicly recognizable. However, no records were found that directly associated any of the Miss Lonsdale candidates with that first dental anesthetic in England.

William T. G. Morton's English Patent for Etherization: Patently Pointless?

Boston dentist William T. G. Morton secured a provisional English patent for etherization in December 1846. The full patent specification was submitted 6 months later, and the patent was sealed on June 18, 1847. The enrolled copies of the provisional and full patents, which are held in The National Archives, London, have not been previously documented in the anesthesia literature. We review the communications between Boston and London regarding the patent for etherization, the possibility that preliminary discussions and trials of etherization may have been conducted in London before the earliest known application of the discovery for a dental extraction on December 19, 1846, and the role of the American lawyer James Augustus Dorr, who was Morton's agent in the United Kingdom.

When Regional Anesthesia Met Pharmacokinetics.

Pharmacokinetics of Local Anaesthetic Agents. By Tucker GT, Mather LE. Br J Anaesth 1975; 47(suppl 1):213-24 Information derived from measurements of blood concentrations of local anaesthetics can be extended by the application of pharmacokinetic analysis. A better understanding of quantitative aspects of the disposition and absorption of these drugs should assist the anaesthetist in deciding the optimal agent and dosage for regional block techniques.

Anaesthetic or "Antiaesthetic" or "Antaesthetic"? Correspondence From Andrew Buchanan, MD, to James Simpson, MD, Concerning a Name for the Agents Producing Insensibility.

In November 1847, James Young Simpson, MD, of Edinburgh, Scotland, applied the word anaesthesia to the state of narcotism and insensibility produced by the inhaled vapors of sulfuric ether and chloroform, along with the word anaesthetic as an adjective to denote that state and as a generic term for agents capable of inducing the state of insensibility. In March 1848, Andrew Buchanan, MD, of Glasgow, Scotland, penned a letter to Simpson to suggest a more semantically precise word, the spelling of which is not clear in Buchanan's letter. We do not know whether Simpson replied to Buchanan. Simpson continued using the words anaesthesia and anaesthetic in his publications.

(Re)introducing medicinal cannabis.

• After considering extensive scientific and medical evidence, a New South Wales Legislative Council multiparty committee recommended that medicinal cannabis should lawfully be made available for selected-use pharmacotherapy. • The evidence indicates that cannabis has genuine medicinal utility in patients with certain neuropathic conditions, with acceptable levels of risk from mostly mild side effects. • The potential medical benefits of cannabis pharmacotherapy have largely been overlooked, with research and society's attention, in most parts of the world, being directed towards the hazards of its recreational use. • The NSW Government has since dismissed the unanimous and compassionate recommendations of their committee.

The acute toxicity of local anesthetics.

IMPORTANCE OF THE FIELD: Systemic toxicity, usually from overdose or intravascular dose, is feared because it mainly affects the heart and brain, and may be acutely life-threatening. AREAS COVERED IN THIS REVIEW: Pharmacological studies of local anesthetic toxicity have largely been reviewed primarily relating to the evaluation of ropivacaine and levobupivacaine during the past decade. This review/opinion focuses more on the principles and concepts underlying the main models used, from chemical pharmacological and pharmacokinetic perspectives. WHAT THE READER WILL GAIN: Research models required to produce pivotal toxicity data are discussed. The potencies for neural blockade and systemic toxicity are associated across virtually all models, with some deviations through molecular stereochemistry. These models show that all local anesthetics can produce direct cardiovascular system toxicity and CNS excitotoxicity that may further affect the cardiovascular system response. Whereas the longer-acting local anesthetics are more likely to cause cardiac death by malignant arrhythmias, the shorter-acting agents are more likely to cause cardiac contraction failure. In most models, equi-anesthetic doses of ropivacaine and levobupivacaine are less likely to produce serious toxicity than bupivacaine. TAKE HOME MESSAGE: Of the various models, this reviewer favors a whole-body large animal preparation because of the comprehensive data collection possible. The conscious sheep preparation has contributed more than any other, and may be regarded as the de facto 'standard' experimental model for concurrent study of local anesthetic toxicity ± pharmacokinetics, using experimental designs that can reproduce the toxicity seen in clinical accidents.

Safety of combined use of local anesthetic infiltration and reinfusion drains in total knee arthroplasty.

Injection of local anesthetic during total knee arthroplasty (TKA) has been shown to aid postoperative pain relief. Reinfusion drains have also proven useful in decreasing allogenic blood transfusion. Combined use carries the risk of reinfusion of local anesthetic from drainage bag. We examined plasma ropivacaine concentrations from 20 patients undergoing TKA, who were treated with these 2 techniques. Samples were taken from a dedicated venous cannula and from the reinfusion drainage bag. The average amount of ropivacaine reinfused was 1.9 mg, a fraction of the injected dose (150 mg), and venous plasma concentrations reached peaks of 0.5 to 1.5 microg/mL, well below demonstrated levels of toxicity. Patients tolerated the treatment well, with no adverse outcomes. This study demonstrates the safety of combining these 2 techniques in TKA.

The effects of general anesthesia on whole body and regional pharmacokinetics of local anesthetics at toxic doses.

BACKGROUND: Local anesthetic toxicity is often studied experimentally in anesthetized subjects, but clinical toxicity usually occurs in conscious patients. In this study, we determined the influence of general anesthesia on the pharmacokinetics of six local anesthetics administered i.v. at approximately the highest recommended doses. METHODS: Chronically instrumented ewes (approximately 45-50 kg, n = 18) were infused over 3 min with (base doses as HCl salts) bupivacaine (100 mg), levobupivacaine (125 mg), ropivacaine (150 mg), lidocaine (350 mg), mepivacaine (350 mg), or prilocaine (350 mg), on separate occasions when conscious and halothane anesthetized. Serial arterial, heart, and brain venous blood drug concentrations were measured by achiral/chiral high-performance liquid chromatography, as relevant. Whole body pharmacokinetics were assessed by noncompartmental analysis; heart and brain pharmacokinetics were assessed by mass balance. Drug blood binding, in the absence and presence of halothane, was assessed by equilibrium dialysis in vitro. RESULTS: Blood local anesthetic concentrations were doubled with anesthesia because of decreased whole body distribution and clearance (respectively, to 33% and 52% of values when conscious). Heart and brain net drug uptake were greater under anesthesia, reflecting slower efflux from both regions. Clearances of R-bupivacaine > S-bupivacaine and R-prilocaine > S-prilocaine, but, mepivacaine clearance was not enantioselective. Halothane did not influence blood binding of the local anesthetics. CONCLUSIONS: General anesthesia significantly changed whole body and regional pharmacokinetics of each local anesthetic as well as the systemic effects. General anesthesia is thus an important but frequently overlooked factor in studies of local anesthetic toxicity.

The effects of general anesthesia on the central nervous and cardiovascular system toxicity of local anesthetics.

BACKGROUND: Local anesthetic toxicity is often studied experimentally in acutely prepared, anesthetized laboratory animals. We determined the influence of halothane/O(2) anesthesia on cardiovascular and central nervous system (CNS) toxic responses to six amide-type local anesthetics administered i.v.. METHODS: Behavioral, cardiovascular, and pharmacokinetic responses were determined in previously instrumented ewes (approximately 45-50 kg, n = 18), on separate occasions when conscious and anesthetized, to bupivacaine (100 mg), levobupivacaine (125 mg), ropivacaine (150 mg), lidocaine (350 mg), mepivacaine (350 mg), prilocaine (350 mg), and saline (control) infused i.v. over 3 min. RESULTS: The local anesthetics caused convulsions in conscious sheep, but no overt CNS effects in anesthetized sheep. Negative inotropy and slight bradycardia without changes in arterial blood pressure occurred initially in conscious sheep, followed by positive inotropy, tachycardia, and hypertension at the abrupt onset of CNS excitotoxicity, along with widening of QRS complexes. Fatal cardiac arrhythmias occurred in, respectively, 3 of 11, 2 of 12, and 2 of 13 conscious sheep infused with bupivacaine, levobupivacaine, and ropivacaine; in 1 of 9 with prilocaine, electromechanical dissociation (followed by polymorphic ventricular tachycardia) caused death. In anesthetized sheep, cardiovascular depression, preexisting from the general anesthesia, was exacerbated by all local anesthetics, and increased QRS width was prolonged; concurrent blood local anesthetic concentrations were doubled. Nevertheless, all anesthetized animals survived. CONCLUSIONS: General anesthesia produced physiological perturbations, exacerbated local anesthetic-induced cardiovascular depression, and changed the pharmacokinetics of toxic doses of local anesthetics. However, cardiovascular fatalities from local anesthetics occurred only in conscious animals.

Enhancement of cisplatin efficacy by thalidomide in a 9L rat gliosarcoma model.

With the aim of improving the treatment of glioblastoma multiforme, we investigated the potential of thalidomide to enhance the effectiveness of cisplatin chemotherapy in a rat glioma model. Female F344 rats were implanted with 9L gliosarcoma tumors either intracranially or subcutaneously and treated with 1 mg/kg cisplatin injected i.p. or with 1% thalidomide in the food or with these treatments combined. Cisplatin in combination with thalidomide significantly reduced both the subcutaneous tumor volume at 30 days to 22 +/- 5% (mean +/- SEM, P < 0.001) and the intracranial tumor volume at 18 days to 44 +/- 15% (P < 0.05) of that with cisplatin alone. Thalidomide selectively increased the cisplatin concentration 10-fold in intracranial tumors (P < 0.05) and 2-fold in the subcutaneous tumors (P < 0.05) without increasing its concentration in major organs including brain and kidney. Cisplatin combined with thalidomide caused a significant decrease in vascular endothelial growth factor (VEGF) levels by 73% in intracranial tumors (P < 0.05) and by 50% in subcutaneous tumors (P < 0.05) and caused the level of active hepatic growth factor (a-HGF) to double in both the subcutaneous and intracranial tumors (P < 0.05), suggesting this treatment altered the vasculature in these tumors. We conclude the increased efficacy of cisplatin in the presence of thalidomide was due to the selective increase in cisplatin concentration within the tumors and speculate that this is the result of thalidomide or the cisplatin/thalidomide combination, selectively altering the tumor vasculature. Based on the selective effects of thalidomide on tumor cisplatin concentrations and the resulting increase in efficacy, thalidomide may also increase the efficacy of other drugs that are presently considered ineffective against glioma.

Studies with ketamine and alfentanil following Freund's complete adjuvant-induced inflammation in rats.

1. N-Methyl-D-aspartate (NMDA) receptor antagonists suppress inflammatory hyperalgesia and the development of acute opioid tolerance. They may also enhance opioid-induced antinociception, while suppressing postopioid-induced hyperalgesia and opioid-enhanced inflammatory hyperalgesia. 2. The non-competitive NMDA receptor antagonist, ketamine, is a racemic chiral drug; its individual enantiomers have differing affinities for the NMDA receptor. The anaesthetic and antinociceptive potencies of (S)-ketamine are 1.5- and threefold higher, respectively, than those of (R)-ketamine in laboratory rodents. 3. The present study investigated the effects of racemic ketamine and enantiopure (S)-ketamine on inflammatory hyperalgesia in rats, 5 days after intraplantar injection of Freund's complete adjuvant (FCA) into one hind paw. First, racemic or (S)-ketamine was administered alone; second, racemic or (S)-ketamine was administered 30 min after initiation of i.v. infusions of the micro-opioid agonist, alfentanil. 4. Area under the curve (AUC) values for Von Frey paw withdrawal threshold (PWT) versus time curves were significantly increased (P < 0.05) for both inflamed and non-inflamed hind paws by racemic and (S)-ketamine (5 & 10 mg/kg, s.c.). Similarly, AUC values for reduction of hind paw volume versus time were significantly increased (P < 0.05) by racemic and (S)-ketamine (10 mg/kg, s.c.). 5. Alfentanil infusions significantly increased PWT in both hind paws, but neither racemic nor (S)-ketamine (5 mg/kg, s.c.) administered 30 min after initiation of alfentanil infusion produced further increases in PWT. 6. Racemic and (S)-ketamine produced antinociceptive effects in both hind paws, but an antihyperalgesic effect per se was not apparent. Additionally, there was a possible anti-inflammatory effect of both drugs in the inflamed hind paw. These findings complement previous studies in which non-competitive NMDA receptor antagonists suppressed behavioural hyperalgesia. 7. However, racemic and (S)-ketamine did not further enhance alfentanil's antinociceptive effects, although they appeared to prolong alfentanil's antinociceptive effects in the non-inflamed hind paw. These findings suggest that factors such as time-course, frequency and the mode of administration of NMDA receptor antagonists, in addition to the type of antinociceptive model (i.e. inflammatory compared with acute) and the nociceptive testing procedure (i.e. noxious mechanical compared with low threshold stimuli) may influence their effects on opioid-induced antinociception.

Enantioselectivity of thalidomide serum and tissue concentrations in a rat glioma model and effects of combination treatment with cisplatin and BCNU.

Thalidomide is currently under evaluation as an anti-angiogenic agent in cancer treatment, alone and in combination with cytotoxic agents. Thalidomide is a racemate with known pharmacologic and pharmacokinetic enantioselectivity. In a previous study with thalidomide combination chemotherapy, we found evidence of anti-tumour synergy. In this study, we examined whether the synergy involved altered pharmacokinetics of thalidomide enantiomers. Adult female F344 rats were implanted with 9L gliosarcoma tumours intracranially, subcutaneously (flank), or both. Effectiveness of oral thalidomide alone, and with intraperitoneal BCNU or cisplatin combination chemotherapy, was assessed after several weeks treatment. Presumed pseudo steady-state serum, tumour and other tissues, collected after treatment, were assayed for R- and S-thalidomide by chiral HPLC. Both serum and tissue concentrations of R-thalidomide were 40-50% greater than those of S-thalidomide. Co-administration of BCNU or cisplatin with thalidomide did not alter the concentration enantioselectivity. Poor correlation of concentration with subcutaneous anti-tumour effect was found for individual treatments, and with all treatments for intracranial tumours. The consistency of the enantiomer concentration ratios across treatments strongly suggests that the favourable antitumour outcomes from interactions between thalidomide and the cytotoxic agents BCNU and cisplatin did not have altered enantioselectivity of thalidomide pharmacokinetics as their basis.

Thalidomide enantiomers: determination in biological samples by HPLC and vancomycin-CSP.

Thalidomide is a racemate with potentially different pharmacokinetics and pharmacodynamics of the component (+)-(R)- and (-)-(S)-thalidomide enantiomers. As part of a project on the adjunctive effects of thalidomide and cytotoxic agents, a method for the chiral separation and quantitation of thalidomide was developed and validated. Thalidomide in relevant serum and tissue homogenate samples was stabilized by buffering with an equal volume of citrate-phosphate buffer (pH 2, 0.2M), and stored at -80 degrees C pending assay. The thalidomide enantiomers, extracted from the samples with diethyl ether, were well separated on a chiral HPLC column of vancomycin stationary phase and a mobile phase of 14% acetonitrile in 20 mM ammonium formate adjusted to pH 5.4; their concentrations were determined with phenacetin as internal standard at 220 nm detection. Over a thalidomide concentration range of 0.1-20 microg/ml, assay precision was 1-5% (CV) for both enantiomers, and calibration curves were linear with all correlation coefficients being >0.99. The estimated limit of quantification for both enantiomers was 0.05 microg/ml with 0.2-0.6 ml serum samples. Thalidomide in rat and human serum, acidified and stored as described above, was found to be chemically and chirally stable over 1 year. The method has been successfully applied to serum samples from human patients undergoing thalidomide treatment for mesothelioma, and to serum, blood and tissue samples from a laboratory rodent model using transplanted 9l gliosarcoma. Enantioselectivity in thalidomide pharmacokinetics has been found, thereby reinforcing the need for considering the relevance of chirality in thalidomide pharmacology.

Acute toxicity of local anesthetics: underlying pharmacokinetic and pharmacodynamic concepts.

The risk of accidental intravascular injection and consequent acute toxicity is ever-present with most neural blockade techniques. The severity of cardiovascular and central nervous system (respectively, CVS and CNS) toxicity is directly related to the local anesthetic potency, dose, and rate of administration. Nonetheless, although the anesthetic potency of ropivacaine and levobupivacaine is similar to that of bupivacaine, at usual clinical doses, ropivacaine and levobupivacaine are less likely than bupivacaine to cause convulsions or lethal dysrhythmias. Signs of CNS stimulation, ranging from tremors to convulsions and perhaps cardiac dysrhythmias, can be described in terms of a chaos-derived state change in which the local anesthetic appears to act as an initiator. Both CNS and CVS effects are rather poorly correlated with arterial drug concentrations but better correlated with concentrations in the respective regional venous drainage. Lung uptake reduces the maximum drug concentration by approximately 40%. Prolonging intravenous administration from 1 to 3 minutes results in a similar decrease in maximum concentration. This is an underlying tenet of dose fractionation, but the main advantage of dose fractionation is that the anesthesiologist is able to cease administration with less of the dose given if signs or symptoms of toxicity occur. Overall, it appears that the gains in safety from ropivacaine and levobupivacaine are due more to favorable pharmacodynamic enantioselectivity than to pharmacokinetic factors. This essay presents some pharmacokinetic aspects relevant to acute toxicity of local anesthetics, mainly using data from the authors' studies in a sheep model of simulated accidental intravenous administration.