Comparing the hemodynamic effects of acute intoxication with racemic bupiva-caine and with 50% enantiomeric excess mixture (S75:R25): an experimental study in dogs

LETTERS TO THE EDITOR

Comparing the hemodynamic effects of acute intoxication with racemic bupiva-caine and with 50% enantiomeric excess mixture (S75:R25). An experimental study in dogs

Dear Editor,

There was a need for a study that investigated the cardiocirculatory effects of the local anesthetic developed in Brazil ¹.

Since this agent is widely used in anesthesiology, it needed scientific support to explain its pharmacology, which should have been done in the pre-clinical phase. But this phase was not fully explored because this anesthetic derived from bupivacaine, whose properties are well known although, even after almost half a century, it is still being studied.

Note that this "modified bupivacaine" needs further laboratory investigation, because it probably has a unique pharmacological profile, to give support to anesthesiologists that use it looking for greater efficacy and safety in their practice.

However, despite the significance of this study ¹, a few observations, especially concerning the real story of this agent to defend our intellectual property, should be made.

1. The 75:25 enantiomeric mixture of bupivacaine is a "local anesthetic". But before one is appalled by my calling it so, it is necessary to explain why the denomination "local anesthetic". When racemic bupivacaine was separated, the isomer that was used, the left (S-) bupivacaine, or levobupivacaine, was considered a local anesthetic and as such has remained so. But that was possible because it happened in the northern hemisphere, more precisely in Cambridge, UK; 2. This study in dogs suppressed, if not misrepresented, the authorship of this local anesthetic: a) the pharmaceutical industry DID NOT synthesize this drug. It arose from the enantiomeric manipulation of the components of racemic bupivacaine. This report incurred in a conceptual error when, in the discussion, it mentioned that the industry synthesized the drug. In the pharmaceutical industrial process, synthesis refers to the production of a new molecule by means of fine chemistry. In reality, bupivacaine was synthesized in 1957 by the Swedish chemist Ekanstam from the pipecolylxylidine skeleton that gave rise to other agents. The distribution of the radicals attached to the skeleton determined the chiral condition, i.e., the optical isomer, forming two identical isomers with distinct pharmacologic profiles. Therefore, each enantiomer presents unique pharmacologic properties. Thus, R(+) bupivacaine has more affinity for cardiac ion channels and more motor blockade that its antipodal ²; b) based on this evidence, we performed a "laboratorial juggling act" and mixed the isomers in amounts that differ from racemic bupivacaine (S50:R50). This happened in 1989 in the Pharmacology Department of the Instituto de Ciências Médicas da Universidade de São Paulo, and is well documented, both scientifically an legally ³. But a formal agreement transferred the technology of the new enantiomeric compounds from the Universidade de São Paulo to the Industry that adopted and produced the compound (S75:R25) in industrial scale with raw materials bought abroad (chloridate of S(-) bupivacaine and chloridate of R(+) bupivacaine), which was commercialized after approval by ANVISA; 3) The conceptual impropriety that I argue here suggests that, although this study was well done (placing us on the same level as other large international research centers), it erred in not making a deeper literature search.

The results suggest that the enantiomeric mixture S75:R25 is more cardiotoxic than racemic bupivacaine (the data are explicit) but do not allow for a definitive conclusion. The lack of knowledge of the authors about the assays with the S75:R25 compound that preceded this study in dogs hampered the comparison between their results with those done in other species, raising controversy about the cardiotoxicity. As such, the discrepancies gave rise to the label "intriguing results" – a convenient observation taken from the Editorial ⁴. Consider this:

a) Trachez et al. ⁵ undertook a judicious study and demonstrated that the lethal dose for rats was: 39.9 mg.kg^-1 for S75: R25; 34.7 mg.kg^-1 for S(-); 16.2 mg.kg^-1 for R(+); and 18.4 mg.kg^-1 racemic bupivacaine. Therefore, it is necessary a higher dose of the S75:R25 mixture than racemic bupivacaine to kill the rats. Consequently, one can conclude that the former is less toxic. That study confirms our results ⁶, which was also done in vivo in rats, in which the hemodynamic parameters (mean arterial pressure and heart rate) suggest that S75:R25 causes less cardiac depression than the racemic compound and the pure (R+) bupivacaine. But its effects, concerning this depression, were THE SAME as S(-) bupivacaine (levobupivacaine). b) Contrary to what is stated in the discussion, it was not Gonçalves et al. ⁷ who indicated the need for the R(+) isomer to achieve a good motor blockade for surgical procedures. It was Mathias ⁸ in his study of levobupivacaine who said: "to be good, a local anesthetic has to be toxic". It was his conclusion when he was faced with the inefficient neuromuscular blockade of the epidural block with levobupivacaine (the pure S(-) isomer) in abdominal surgeries.

Thus, taking advantage of this bright and rational inference supported by the literature, we manipulated the isomeric components of bupivacaine with two objectives: toxicity and motor blockade. Reducing the proportion of the cardiotoxic component, R(+) bupivacaine, and increasing the proportion of S(-) bupivacaine, the resulting compound reduced the toxicity of racemic bupivacaine and corrected the ineffective neuromuscular blockade.

A "specific racemism" was then obtained, since it has two isomers in its composition. This concept of "specific racemism" has been suggested lately, although it does not have the classic meaning of racemism, of a 1:1 proportion of the isomeric forms. However, the new concept should be considered, in this era of stereoisomerism, where there might be other racemic changes.

Therefore, the enantiomeric mixture of bupivacaine results from changing the proportion of the isomers of racemic bupivacaine.

The cardiocirculatory parameters of the new compounds were studied in vivo, in rats, in the sciatic nerve preparation, analyzing the 3 local anesthetics: S75:R25, levobupivacaine, and racemic bupivacaine and the isomer R(+) bupivacaine ^3,6. These studies were corroborated by Tranches et al., who showed that the blocking potency of S75:R25 is 25% greater than that of S(-) bupivacaine (levobupivacaine), while the toxicity was significantly different from racemic bupivacaine.

It should be mentioned that the results of this study in dogs disagree from those reported in the literature. This controversy deserves further studies regarding: a) cardiac electro physiology; b) pharmacokinetics (there was no mention about the equipment used to inject the local anesthetics and the rate of the injection); c) reevaluation of the statistical analysis. That would elucidate the "intriguing result" that startled not only the authors but also the editorialist ^1,4. It is important to include the pure S(-) bupivacaine (levobupivacaine) in future studies, since it would confirm or weaken the hypothesis that there is "modulation in the connection of the enantiomers with their sites of action" ⁵.

However, the study of Udelsmann et al. ¹ deserves credit regarding the highly sophisticated methodology in large animals, although Kasten and Martin ⁹, renowned for their studies on the toxicity of bupivacaine, prefer to work with sheep due to their similarity with human beings regarding some physiological characteristics.

Finally, I congratulate the authors paraphrasing two great researchers, Mather and Chang ¹⁰: "the newer agents should be considered safer, but they should never be considered safe "

Sincerely,

Maria P. B. Simonetti, TSA, M.D.

Professor/Physician

Pharmacology Department

Instituto de Ciências Biomédicas

Universidade de São Paulo

REFERENCES

01. Uldelsmann A, Munhoz DC, Silva WA et al — Comparação entre efeitos hemodinâmicos da intoxicação aguda com bupivacaína racêmica e a mistura com excesso enantiomérico de 50% (s75:r25). Estudo experimental em cães. Rev Bras Anestesiol, 2006;56:4:391-401.

02. Vladimirov M, Nau C, Mok WM et al — Potency of bupivacaine stereoisomers tested in vitro and in vivo. Biochemical, electrophysiological, and neurobehavioral studies. Anesthesiology, 2000;93:744-755.

03. Simonetti MPB, Ferreira FM — Does the D-isomer of bupivacaine contribute to improvement of efficacy in neural block. Reg Anesth Pain Med, 1999;24:(3/Suppl):43.

04. Torres MLA — Toxicidade dos anestésicos locais: o debate continua! Rev Bras Anestesiol, 2006;56:339-342.

05. Trachez MM, Zapata-Sudo, Moreira OR et al — Motor nerve blockade potency and toxicity of non-racemic bupivacaine in rats. Acta Anaesthesiol Scand, 2005:49:66-71.

06. Simonetti MPB, Ferreira FMC, Ferreira Jr R et al — Is it worth manipulating the enantiomeric ratio of bupivacaine to improve the efficacy of the neural block with reduced cardiotoxicity? Inter Monitor, 1999;11: (Suppl):196.

07. Gonçalves RF, Lauretti GR, Mattos AL — Estudo comparativo entre bupivacaína a 0,5% e mistura enantiomérica de bupivacaína (S75:R25) em anestesia peridural. Rev Bras Anestesiol, 2003;53:169-175.

08. Mathias RS – Levobupi: uma nova opção de anestésico local com menor cardiotoxicidade. Rev Bras Anestesiol, 1997 ;47:(Supl22): CBA.

09. Kasten GW, Martin ST — Bupivacaine cardiovascular toxicity: comparison of treatment with bretylium and lidocaine. Anesth analg,.1985,64:911-916.

10. Mather LE, Chang DH — Cardiotoxicity with modern local anaesthetics: is there a safer choice? Drugs, 2001:61:333-342.

Reply

Dear Editor,

My dear colleague is right: the industry produced, distributed, and commercialized the drug. Its authorship was not the focus of our study; therefore, it was neither suppressed nor distorted. But, if this matter is object of a legal battle, lay people should keep a distance. Dr. Simonetti did present an interesting study on enantiomeric mixtures, whose summary is published in Regional Anesthesia and Pain Medicine, 1999;24(3/Suppl):43 and, for this reason, should be respected. This does not diminish our laboratory that really found "intriguing results"¹, but real results, which should be discussed. Gonçalves et al. ², in the discussion of their paper, indicated the possibility that the introduction of 25% of R-bupivacaine could improve the anesthetic profile of the drug. This does not go against what Mathias stated previously, but we did not have access to it. Our results were really the opposite of those reported in the literature, but one should be careful because similar works always used L-bupivacaine and not the enantiomeric mixture. But some recent reports ^3,4 indicated a greater cardiotoxicity of the pure levorotatory isomer in animals. The anesthetic was injected in 30 seconds, which was the standard duration, and the statistical analysis was done by the Serviço de Bioestatística da Câmara de Pesquisa da FCM – UNICAMP. Intrigued with our results, we did another study in pigs, due to their physiologic similarity with human beings concerning the cardiovascular system, and this time we used racemic bupivacaine, the enantiomeric mixture, and levobupivacaine. Those results were presented in the 52º Congresso Brasileiro de Anestesiologia, were included in the annals (CBA 163), and we hope will be published in the Revista Brasileira de Anestesiologia to contribute even more to the debate on local anesthetics.

Artur Udelsmann

FCM – UNICAMP

REFERENCES

01. Torres MLA — Toxicidade dos anestésicos locais: o debate continua. Rev Bras Anestesiol, 2006;56:339-342.

02. Gonçalves RF, Lauretti GR, Mattos AL — Estudo comparativo entre bupivacaína a 0,5% e mistura enantiomérica de bupivacaína (S75-R25) a 0,5% em anestesia peridural. Rev Bras Anestesiol, 2003;53:169-176.

03. Masuda R, Takeda S, Yoshii S et al. — Levobupivacaine exerts the most detrimental effect on the cardiovascular system among enantiomers of bupivacaine in anesthetized dogs Anesthesiology, 2004;101:(Suppl):A652

04. Jung CW, Lee KH, Choe YS et al. – Comparison of resuscitative effect of insulin between bupivacaine and levobupivacaine induced cardiovascular collapse in dogs. Anesthesiology, 2004; 101:(Suppl):A649

03. Simonetti MPB, Ferreira FM — Does the D-isomer of bupivacaine contribute to improvement of efficacy in neural block. Reg Anesth Pain Med, 1999;24:(3/Suppl):43.

Publication Dates

• Publication in this collection
  27 Nov 2006
• Date of issue
  Dec 2006