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Antihistaminic activity of carane derivatives in isolated guinea pig ileum
Pharmacological Reports 2009, 61, 12111215 ISSN 1734-1140
Copyright © 2009 by Institute of Pharmacology Polish Academy of Sciences
Short communication
Antihistaminic activity of carane derivatives in isolated guinea pig ileum Tadeusz Librowski, Karolina Pytka, Marcin Szaleniec Department of Pharmacodynamics, Jagiellonian University, Medical College, Faculty of Pharmacy, Medyczna 9, PL 30-688 Kraków, Poland Correspondence: Tadeusz Librowski, e-mail: [email protected]
Abstract: Local anesthetics (LAs) inhibit membrane depolarization by reducing sodium and potassium conductance, and subsequent displacement of calcium ions from binding sites seems to occur. Histamine release appears to be a secretory process in which calcium couples the stimulus to the exocytosis of histamine-containing granules. Furthermore, LAs are structurally similar to histamine H -receptor antagonists. Thus, LAs can be considered antihistaminic drugs. Previous pharmacological investigations have shown strong local anesthetic, anti-inflammatory and analgesic activity of the carane derivative KP-23. As it has previously been demonstrated that KP-23R,S and its R,S-diasteroisomers have an inhibitory effect on guinea pig ileum contractions, the aim of the present study was to determine and compare the antihistaminic effects of KP-23R,S and its individual isomers KP-23R and KP-23S on isolated guinea pig ileum. Key words: carane derivatives, diastereoisomers, lidocaine, propranolol, guinea pig ileum, antihistaminic activity
Introduction Local anesthetics (LAs) are drugs that reversibly interrupt pain impulses in a specific region of the body by direct interaction with voltage-gated Na2+ channels without a loss in patient consciousness. In addition to the most prominent and well-defined function mentioned above, numerous studies have shown LAs to also exhibit anti-inflammatory, anti-arrhythmic, analgesic, anticonvulsant, antifungal and antibacterial activities [1, 3, 6, 8, 9, 11, 14, 25]. The structure of LAs resembles the structure of histamine H1-receptor antagonists, suggesting that LAs may influence histamine release. Several studies have shown that lidocaine used at a concentration lower
than that used in infiltration anesthesia inhibits histamine release from mast cells [16]. Moreover, low concentrations of lidocaine (LID) or mepivacaine inhibit histamine release from activated mast cells, and the effect is more intense when the pH is more alkaline [28]. Recent studies suggest that both intravenous and inhaled lidocaine inhibit bronchial contraction caused by histamine [10], although only a few studies have demonstrated that LID causes bronchial contraction [12]. Chirality is a fundamental property of biologic systems. Drug-receptor interaction has always been recognized to be stereoselective. Stereoisomers have identical sets of atoms that are configured in the same positions but are arranged differently spatially. Therefore, to elicit a particular effect, a receptor must bind Pharmacological Reports, 2009, 61, 12111215
1211
with a specific ligand whose atoms are orientated in space so as to suit the stereospecific structure of the receptor [26]. In addition to the biochemical aspect of stereoselectivity, there is increasing awareness of its clinical importance. Although physicochemically identical in an achiral environment, stereoisomers can exhibit quantitative and qualitative differences in the pharmacologic actions they elicit. Thus, stereoisomers of a drug may act differently or exhibit untoward side effects. For example, recent studies have shown that S(–)-bupivacaine exhibits a lower neuro- and cardiotoxicty and is longer lasting than the R(+)-enantiomer [4]. Similarly, the S-prilocaine enantiomer acts longer and stronger than R-prilocaine [30]. Even though there are many available LAs, their activity time is not satisfactorily long and they often result in untoward side effects. Hence, the search for a long-lasting, safer LA is the goal of many research studies. Recent studies have shown that the derivative of propranolol and carane, KP-23 (the main component of the Pinus sylvestris essential oil) [27], is a potent LA with strong and long-lasting activity [5, 19, 21]. The aim of the present study was to determine and compare the antihistaminic effects of KP-23R,S and its isomers KP-23R and KP-23S on isolated guinea pig ileum. As a reference, the drugs LID, propranolol (PRP) and its isomers were used.
Materials and Methods
((S)propranololum hydrochloricum, Fluka, Austria), and PRP R ((R)propranololum hydrochloricum, Fluka, Austria) were dissolved in distilled water. Isolated guinea pig ileum
Male and female guinea pigs were sacrificed by cervical dislocation. The ileum was immediately removed and cut into approximately 2.5-cm segments. Segments were placed in a carbogen-aerated organ bath (37oC) containing buffer (120 μM NaCl, 5.6 μM KCl, 2.2 M MgCl2, 2.4 M CaCl2, 19 μM NaHCO3 and 10 μM glucose). One end of the ileal segment was attached to the transducer (FDT10-A), and the resting tension was adjusted to a load of 0.5 g. All samples were allowed to equilibrate for at least 30 min before contractions were measured. After the 30 min incubation, 107 M histamine was added to the buffer and the contraction of the ileum was recorded. Next, the ileum was washed twice with buffer and the compound under investigation was added to the buffer for 15 min. Finally, another 107 M histamine was added and the change in ileum contraction strength was recorded. The contractions were recorded using computer software (MP35 Data Acquisition Unit). Statistical analysis
The data are expressed as mean ± SEM. Differences between treatments and controls were examined for statistical significance using a paired t-test, where a p value of less than 0.05 denotes a statistically significant difference.
Animals
Male and female guinea pigs (300–450 g) were used in the experiment. The animals were housed and fed in a laboratory kept at constant temperature of 22°C under standard conditions (12:12 h light-dark cycle, standard pellet diet, water ad libitum). Treatment of laboratory animals in the present study was in accordance with the respective Polish and European regulations and was approved by the Local Ethics Committee. Drugs
KP-23, KP-23R and KP-23S [22], LID (lignocainum hydrochloricum, Polfa, Poland), (±)-PRP (R,S; propranololum hydrochloricum, Fluka, USA) PRP S
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Pharmacological Reports, 2009, 61, 12111215
Results KP-23R used at a 104 M concentration significantly decreased the strength of ileum contraction by 22.2% (Fig. 1A). In contrast, 106 M concentrations of KP-23R increased the strength by 16.9%. Similarly, PRP R used at a concentration of 104 M decreased (by 25.9%) while 106 M concentrations increased (17.8%) the strength of ileum contraction (Fig. 1A). Likewise, KP-23S used at 104 M decreased the strength of ileum contraction by 33.1% (Fig. 1B). In contrast to KP-23R, the KP-23S did not affect the contractions at a concentration of 106 M. Similar to
Antihistaminic activity of carane derivatives Tadeusz Librowski et al.
A
contraction by 28.9% and 36.8%, respectively (Fig. 1C). At a concentration of 10`$ M neither agent had an affect on histamine-induced contractions of guinea pig ileum (Fig 1C). LID at a concentration of 10`" M increased the strength of ileum contractions induced by histamine by 20.3%, while no effect was observed at a concentration of 10`$ M (Fig. 1C).
Discussion
B
C
Fig. 1. The effect of KP-23R and propranolol R (PRP R) ( A), KP-23S and propranolol S (PRP S) (B), KP-23R,S, lidocaine (LID) and propranolol R,S (PRP R,S) (C) on histamine-induced contraction in
guinea pig ileum. Results are expressed as mean ± SEM of 8 samples per group. * p < 0.05, ** p < 0.01 vs. Histamine-induced contraction
KP diastereoisomers, 10`" M of PRP S significantly decreased the strength of ileum contraction by 43.0% (Fig. 1B), while concentrations remained unaffected at 10`$ M of PRP S (Fig. 1B). KP-23R,S and PRP R,S used at 10`" M concentrations significantly decreased the strength of ileum
Guinea pig ileum is commonly used to define whether a potential drug has an antihistaminic effect [18]. As mentioned previously, the structure of LAs is similar to the structure of histamine H -receptor antagonists. Furthermore, recent data indicate that LAs also have antihistaminic properties [16, 21], and that antihistamine agents exhibit analgesic and anti-inflammatory activity [24, 29]. Studies in guinea pig ileum demonstrate that LAs behave similarly to histamine H -receptor antagonists [15]. Because KP-23R,S and its isomers showed stronger local aesthetic activity than LID [5, 20, 21], we sought to define the antihistaminic effects of KP-23R and KP-23S enantiomers. KP-23R,S and its R,S-diastereoisomers did not induce late-type contact allergy and abolished spontaneous contractile activity of rabbit ileum [21]. In agreement with these findings, the present study demonstrates that application of KP-23RS as well as KP-23R and KP-23S at a concentration of 10`" M decreases the strength of contraction of guinea pig ileum induced by histamine. The same effect was observed after treatment at the same concentration with PRP R,S, PRP R and PRP S but not LID. Similarly, PRP, one of the components of betathiazid, had a diminished effect on the contraction of guinea pig ileum induced by histamine [17]. Since KP-23 is a PRP derivative, the above-mentioned findings are in agreement with results obtained in this study. Interestingly, lower concentrations of KP-23 R caused the opposite effect, i.e., they increased the strength of contractions of guinea pig ileum induced by histamine. The same effect was also observed for PRP (present data). PRP has been shown to intensify the action of histamine in various other tests (e.g. histamine-induced bronchoconstriction) in addition to the present data [2, 23]. Recent data indicate that LID can either enhance [12, 13] or decrease the strength of
Pharmacological Reports, 2009, 61, 12111215
1213
bronchi or trachea contraction induced by histamine [7, 10]. Our results are in agreement with these findings. The mechanism by which KP exerts its antihistaminic effects remains unknown. This, in addition to the observations that lower concentrations have opposing effects necessitates the need for further studies. Nevertheless, this is the first demonstration that KP-23 compounds possess antihistaminic properties in addition to their canonical anesthetic activity [19].
References: 1. Aydin ON, Eyigor M, Aydin N: Antimicrobial activity of ropivacaine and other local anaesthetics. Eur J Anaesthesiol, 2001, 18, 687–694. 2. Bhatt PA, Makwana D: Comparative influence of propranolol and verapamil on glycemic control and histamine sensitivity associated with L-thyroxine-induced hyperthyroidism – an experimental study. Fundam Clin Pharmacol, 2008, 22, 53–59. 3. Cassuto J, Sinclair R, Bonderovic M: Anti-inflammatory properties of local anesthetics and their present and potential clinical implications. Acta Anaesthesiol Scand, 2006, 50, 265–282. 4. Cox CR, Faccenda KA, Gilhooly C, Bannister J, Scott NB, Morrison LM: Extradural S(–)-bupivacaine: comparison with racemic R,S-bupivacaine. Br J Anaesth, 1998, 80, 289–293. 5. Czarnecki R, Czerwiñska K, Grochowska K, Grochowski J, Librowski T, Serda T: Molecular structure and antiaggregating activity of a potent local anaesthetic (–)-4-[2-hydroxy-3-(n-isopropylamino)-propoxyimino]cis-carane. Arzneimittel-Forsh, 1992, 42, 1279–1283. 6. De Iuliis A, Zanatta L, Vincenti E, Galzigna L: Differences of ropivacaine and bupivacaine relevant to antiinflammatory activity, platelet aggregation and antioxidant activity in vitro. Farmaco, 2001, 56, 153–157. 7. Downes H, Loehning RW: Local anesthetic contracture and relaxation of airway smooth muscle. Anesthesiology, 1977, 47, 430–436. 8. Frey HH: On the anticonvulsant activity of local anaesthetics. Acta Pharmacol Toxicol (Copenh), 1962, 19, 205–211. 9. Goodman EJ, Jacobs MR, Bajaksouzian S, Windau AR, Dagirmanjian JP: Clinically significant concentrations of local anesthetics inhibit Staphylococcus aureus in vitro. Int J Obstet Anesth, 2002, 11, 95 – 99. 10. Groeben H, Peters J: Lidocaine exerts its effect on induced bronchospasm by mitigating reflexes, rather than by attenuation of smooth muscle contraction. Acta Anaesthesiol Scand, 2007, 51, 359 – 364. 11. Hellström-Westas L, Westgren U, Rosén I, Svenningsen NW: Lidocaine for treatment of severe seizures in newborn infants. I. Clinical effects and cerebral electrical activity monitoring. Acta Paediatr Scand, 1988, 77, 79–84.
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12. Hirota K, Hashimoto Y, Sato T, Yoshioka H, Kudo T, Ishihara H, Matsuki A: I.v. lidocaine worsens histamineinduced bronchoconstriction in dogs. Br J Anaesth, 1999, 82, 87–89. 13. Hirota K, Hashimoto Y, Sato T, Yoshioka H, Kudo T, Matsuki A, Lambert DG: Bronchoconstrictive and relaxant effects of lidocaine on the airway in dogs. Crit Care Med, 2001, 29, 1040–1044. 14. Hollmann MW, Durieux ME: Local anesthetics and the inflammatory response: a new therapeutic indication? Anesthesiology, 2000, 93, 858–875. 15. Horio S, Nagare T, Ishida Y, Moritoki H: Interaction of local anaesthetics with histamine H receptors in guineapig ileum. J Pharm Pharmacol, 1997, 49, 715–720. 16. Kazimierczak W, Peret M, Maœliñski C: The action of local anaesthetics on histamine release. Biochem Pharmacol, 1976, 25, 1747–1750. 17. Künneke M, Lorenz W, Duda D, Künkel D, Schunack W: Unknown effects of clinically used drugs as bias in clinical trials: antihistaminergic activity of the antihypertensive fixed-dose combination Betathiazid. Agents Actions, 1994, 41, 131–133. 18. Larsson AK, Fumagalli F, DiGennaro A, Andersson M, Lundberg J, Edenius C, Govoni M et al.: A new class of nitric oxide-releasing derivatives of cetirizine; pharmacological profile in vascular and airway smooth muscle preparations. Br J Pharmacol, 2007, 151, 35–44. 19. Librowski T, Czarnecki R, Lochyñski S, Fr¹ckowiak B, Pasenkiewicz-Gierula M, Grochowski J, Serda P: Comparative investigations of hydroxyamine carane derivative and its R,S-diastereoisomers with strong local anesthetic activity. Pol J Pharmacol, 2001, 53, 535–539. 20. Librowski T, Czarnecki R, Lochyñski S, Fr¹ckowiak B, Pasenkiewicz-Gierula M, Grochowski J, Serda P: Local anaesthetic activity of new hydroxyamine carane derivative and its R,S-diastereoisomers. Molecular and Physiological Aspects of Regulatory Processes of the Organism, Ed. Lach H, Wydawnictwo Naukowe AP Kraków, Kraków 2000, 260–261. 21. Librowski T: Analgesic and anti-inflammatory activity of stereoisomers of carane derivatives in rodent test. Pharmacol Rep, 2005, 57, 802–810. 22. Lochyñski S, Fr¹ckowiak B, Librowski T, Czarnecki R, Grochowski J, Serda P, Pasenkiewicz-Gierula M: Stereochemistry of terpene derivatives. Part 3: Hydrolytic kinetic resolution as a convenient approach to chiral aminohydroxyiminocaranes with local anaesthetic activity. Tetrahedron Asymmetry, 2002, 13, 873–878. 23. Ney UM: Propranolol-induced airway hyperreactivity in guinea-pigs. Br J Pharmacol, 1983, 79, 1003–1009. 24. Panaszek B, Liebhart J: Sources of actions and efficacy of antiallergic drugs. Pharmacol Rep, 2007, 59, 111–122. 25. Pina-Vaz C, Rodrigues AG, Sansonetty F, Martinez-DeOliveira J, Fonseca AF, Mårdh PA: Antifungal activity of local anesthetics against Candida species. Infect Dis Obstet Gynecol, 2000, 8, 124–137. 26. Pluta J, Haznar D, Cha³on M: Stereoisomerism of drugs. Part 1. Importance in pharmacology. (Polish) Farm Pol, 2002, 58, 987–992. 27. Siemieniuk A, Sza³kowska-P¹gowska H, Lochyñski S, Pi¹tkowski K, Filipek B, Krupiñska J, Czarnecki R et al.:
Antihistaminic activity of carane derivatives Tadeusz Librowski et al.
Synthesis and some pharmacological properties of 1,2amino ethers with natural monoterpene structures. Pol J Pharmacol Pharm, 1992, 44, 187–200. 28. Suzuki T, Ohishi K, Kida J, Uchida M: Influence of pH on the inhibitory effects of local anesthetics on histamine release induced from rat mast cells by concanavalin A and compound 48/80. Eur J Pharmacol, 1984, 98, 347–355. 29. Tamaddonfard E, Khalilzadeh E, Hamzeh-Gooshchi N, Seiednejhad-Yamchi S: Central effect of histamine in
a rat model of acute trigeminal pain. Pharmacol Rep, 2008, 60, 219–224. 30. Van der Meer AD, Burm AG, Stienstra R, van Kleef JW, Vletter AA, Olieman W: Pharmacokinetics of prilocaine after intravenous administration in volunteers: enantioselectivity. Anesthesiology, 1999, 90, 988–992.
Received:
May 14, 2009; in revised form: November 17, 2009.
Pharmacological Reports, 2009, 61, 12111215
1215
Copyright © 2009 by Institute of Pharmacology Polish Academy of Sciences
Short communication
Antihistaminic activity of carane derivatives in isolated guinea pig ileum Tadeusz Librowski, Karolina Pytka, Marcin Szaleniec Department of Pharmacodynamics, Jagiellonian University, Medical College, Faculty of Pharmacy, Medyczna 9, PL 30-688 Kraków, Poland Correspondence: Tadeusz Librowski, e-mail: [email protected]
Abstract: Local anesthetics (LAs) inhibit membrane depolarization by reducing sodium and potassium conductance, and subsequent displacement of calcium ions from binding sites seems to occur. Histamine release appears to be a secretory process in which calcium couples the stimulus to the exocytosis of histamine-containing granules. Furthermore, LAs are structurally similar to histamine H -receptor antagonists. Thus, LAs can be considered antihistaminic drugs. Previous pharmacological investigations have shown strong local anesthetic, anti-inflammatory and analgesic activity of the carane derivative KP-23. As it has previously been demonstrated that KP-23R,S and its R,S-diasteroisomers have an inhibitory effect on guinea pig ileum contractions, the aim of the present study was to determine and compare the antihistaminic effects of KP-23R,S and its individual isomers KP-23R and KP-23S on isolated guinea pig ileum. Key words: carane derivatives, diastereoisomers, lidocaine, propranolol, guinea pig ileum, antihistaminic activity
Introduction Local anesthetics (LAs) are drugs that reversibly interrupt pain impulses in a specific region of the body by direct interaction with voltage-gated Na2+ channels without a loss in patient consciousness. In addition to the most prominent and well-defined function mentioned above, numerous studies have shown LAs to also exhibit anti-inflammatory, anti-arrhythmic, analgesic, anticonvulsant, antifungal and antibacterial activities [1, 3, 6, 8, 9, 11, 14, 25]. The structure of LAs resembles the structure of histamine H1-receptor antagonists, suggesting that LAs may influence histamine release. Several studies have shown that lidocaine used at a concentration lower
than that used in infiltration anesthesia inhibits histamine release from mast cells [16]. Moreover, low concentrations of lidocaine (LID) or mepivacaine inhibit histamine release from activated mast cells, and the effect is more intense when the pH is more alkaline [28]. Recent studies suggest that both intravenous and inhaled lidocaine inhibit bronchial contraction caused by histamine [10], although only a few studies have demonstrated that LID causes bronchial contraction [12]. Chirality is a fundamental property of biologic systems. Drug-receptor interaction has always been recognized to be stereoselective. Stereoisomers have identical sets of atoms that are configured in the same positions but are arranged differently spatially. Therefore, to elicit a particular effect, a receptor must bind Pharmacological Reports, 2009, 61, 12111215
1211
with a specific ligand whose atoms are orientated in space so as to suit the stereospecific structure of the receptor [26]. In addition to the biochemical aspect of stereoselectivity, there is increasing awareness of its clinical importance. Although physicochemically identical in an achiral environment, stereoisomers can exhibit quantitative and qualitative differences in the pharmacologic actions they elicit. Thus, stereoisomers of a drug may act differently or exhibit untoward side effects. For example, recent studies have shown that S(–)-bupivacaine exhibits a lower neuro- and cardiotoxicty and is longer lasting than the R(+)-enantiomer [4]. Similarly, the S-prilocaine enantiomer acts longer and stronger than R-prilocaine [30]. Even though there are many available LAs, their activity time is not satisfactorily long and they often result in untoward side effects. Hence, the search for a long-lasting, safer LA is the goal of many research studies. Recent studies have shown that the derivative of propranolol and carane, KP-23 (the main component of the Pinus sylvestris essential oil) [27], is a potent LA with strong and long-lasting activity [5, 19, 21]. The aim of the present study was to determine and compare the antihistaminic effects of KP-23R,S and its isomers KP-23R and KP-23S on isolated guinea pig ileum. As a reference, the drugs LID, propranolol (PRP) and its isomers were used.
Materials and Methods
((S)propranololum hydrochloricum, Fluka, Austria), and PRP R ((R)propranololum hydrochloricum, Fluka, Austria) were dissolved in distilled water. Isolated guinea pig ileum
Male and female guinea pigs were sacrificed by cervical dislocation. The ileum was immediately removed and cut into approximately 2.5-cm segments. Segments were placed in a carbogen-aerated organ bath (37oC) containing buffer (120 μM NaCl, 5.6 μM KCl, 2.2 M MgCl2, 2.4 M CaCl2, 19 μM NaHCO3 and 10 μM glucose). One end of the ileal segment was attached to the transducer (FDT10-A), and the resting tension was adjusted to a load of 0.5 g. All samples were allowed to equilibrate for at least 30 min before contractions were measured. After the 30 min incubation, 107 M histamine was added to the buffer and the contraction of the ileum was recorded. Next, the ileum was washed twice with buffer and the compound under investigation was added to the buffer for 15 min. Finally, another 107 M histamine was added and the change in ileum contraction strength was recorded. The contractions were recorded using computer software (MP35 Data Acquisition Unit). Statistical analysis
The data are expressed as mean ± SEM. Differences between treatments and controls were examined for statistical significance using a paired t-test, where a p value of less than 0.05 denotes a statistically significant difference.
Animals
Male and female guinea pigs (300–450 g) were used in the experiment. The animals were housed and fed in a laboratory kept at constant temperature of 22°C under standard conditions (12:12 h light-dark cycle, standard pellet diet, water ad libitum). Treatment of laboratory animals in the present study was in accordance with the respective Polish and European regulations and was approved by the Local Ethics Committee. Drugs
KP-23, KP-23R and KP-23S [22], LID (lignocainum hydrochloricum, Polfa, Poland), (±)-PRP (R,S; propranololum hydrochloricum, Fluka, USA) PRP S
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Pharmacological Reports, 2009, 61, 12111215
Results KP-23R used at a 104 M concentration significantly decreased the strength of ileum contraction by 22.2% (Fig. 1A). In contrast, 106 M concentrations of KP-23R increased the strength by 16.9%. Similarly, PRP R used at a concentration of 104 M decreased (by 25.9%) while 106 M concentrations increased (17.8%) the strength of ileum contraction (Fig. 1A). Likewise, KP-23S used at 104 M decreased the strength of ileum contraction by 33.1% (Fig. 1B). In contrast to KP-23R, the KP-23S did not affect the contractions at a concentration of 106 M. Similar to
Antihistaminic activity of carane derivatives Tadeusz Librowski et al.
A
contraction by 28.9% and 36.8%, respectively (Fig. 1C). At a concentration of 10`$ M neither agent had an affect on histamine-induced contractions of guinea pig ileum (Fig 1C). LID at a concentration of 10`" M increased the strength of ileum contractions induced by histamine by 20.3%, while no effect was observed at a concentration of 10`$ M (Fig. 1C).
Discussion
B
C
Fig. 1. The effect of KP-23R and propranolol R (PRP R) ( A), KP-23S and propranolol S (PRP S) (B), KP-23R,S, lidocaine (LID) and propranolol R,S (PRP R,S) (C) on histamine-induced contraction in
guinea pig ileum. Results are expressed as mean ± SEM of 8 samples per group. * p < 0.05, ** p < 0.01 vs. Histamine-induced contraction
KP diastereoisomers, 10`" M of PRP S significantly decreased the strength of ileum contraction by 43.0% (Fig. 1B), while concentrations remained unaffected at 10`$ M of PRP S (Fig. 1B). KP-23R,S and PRP R,S used at 10`" M concentrations significantly decreased the strength of ileum
Guinea pig ileum is commonly used to define whether a potential drug has an antihistaminic effect [18]. As mentioned previously, the structure of LAs is similar to the structure of histamine H -receptor antagonists. Furthermore, recent data indicate that LAs also have antihistaminic properties [16, 21], and that antihistamine agents exhibit analgesic and anti-inflammatory activity [24, 29]. Studies in guinea pig ileum demonstrate that LAs behave similarly to histamine H -receptor antagonists [15]. Because KP-23R,S and its isomers showed stronger local aesthetic activity than LID [5, 20, 21], we sought to define the antihistaminic effects of KP-23R and KP-23S enantiomers. KP-23R,S and its R,S-diastereoisomers did not induce late-type contact allergy and abolished spontaneous contractile activity of rabbit ileum [21]. In agreement with these findings, the present study demonstrates that application of KP-23RS as well as KP-23R and KP-23S at a concentration of 10`" M decreases the strength of contraction of guinea pig ileum induced by histamine. The same effect was observed after treatment at the same concentration with PRP R,S, PRP R and PRP S but not LID. Similarly, PRP, one of the components of betathiazid, had a diminished effect on the contraction of guinea pig ileum induced by histamine [17]. Since KP-23 is a PRP derivative, the above-mentioned findings are in agreement with results obtained in this study. Interestingly, lower concentrations of KP-23 R caused the opposite effect, i.e., they increased the strength of contractions of guinea pig ileum induced by histamine. The same effect was also observed for PRP (present data). PRP has been shown to intensify the action of histamine in various other tests (e.g. histamine-induced bronchoconstriction) in addition to the present data [2, 23]. Recent data indicate that LID can either enhance [12, 13] or decrease the strength of
Pharmacological Reports, 2009, 61, 12111215
1213
bronchi or trachea contraction induced by histamine [7, 10]. Our results are in agreement with these findings. The mechanism by which KP exerts its antihistaminic effects remains unknown. This, in addition to the observations that lower concentrations have opposing effects necessitates the need for further studies. Nevertheless, this is the first demonstration that KP-23 compounds possess antihistaminic properties in addition to their canonical anesthetic activity [19].
References: 1. Aydin ON, Eyigor M, Aydin N: Antimicrobial activity of ropivacaine and other local anaesthetics. Eur J Anaesthesiol, 2001, 18, 687–694. 2. Bhatt PA, Makwana D: Comparative influence of propranolol and verapamil on glycemic control and histamine sensitivity associated with L-thyroxine-induced hyperthyroidism – an experimental study. Fundam Clin Pharmacol, 2008, 22, 53–59. 3. Cassuto J, Sinclair R, Bonderovic M: Anti-inflammatory properties of local anesthetics and their present and potential clinical implications. Acta Anaesthesiol Scand, 2006, 50, 265–282. 4. Cox CR, Faccenda KA, Gilhooly C, Bannister J, Scott NB, Morrison LM: Extradural S(–)-bupivacaine: comparison with racemic R,S-bupivacaine. Br J Anaesth, 1998, 80, 289–293. 5. Czarnecki R, Czerwiñska K, Grochowska K, Grochowski J, Librowski T, Serda T: Molecular structure and antiaggregating activity of a potent local anaesthetic (–)-4-[2-hydroxy-3-(n-isopropylamino)-propoxyimino]cis-carane. Arzneimittel-Forsh, 1992, 42, 1279–1283. 6. De Iuliis A, Zanatta L, Vincenti E, Galzigna L: Differences of ropivacaine and bupivacaine relevant to antiinflammatory activity, platelet aggregation and antioxidant activity in vitro. Farmaco, 2001, 56, 153–157. 7. Downes H, Loehning RW: Local anesthetic contracture and relaxation of airway smooth muscle. Anesthesiology, 1977, 47, 430–436. 8. Frey HH: On the anticonvulsant activity of local anaesthetics. Acta Pharmacol Toxicol (Copenh), 1962, 19, 205–211. 9. Goodman EJ, Jacobs MR, Bajaksouzian S, Windau AR, Dagirmanjian JP: Clinically significant concentrations of local anesthetics inhibit Staphylococcus aureus in vitro. Int J Obstet Anesth, 2002, 11, 95 – 99. 10. Groeben H, Peters J: Lidocaine exerts its effect on induced bronchospasm by mitigating reflexes, rather than by attenuation of smooth muscle contraction. Acta Anaesthesiol Scand, 2007, 51, 359 – 364. 11. Hellström-Westas L, Westgren U, Rosén I, Svenningsen NW: Lidocaine for treatment of severe seizures in newborn infants. I. Clinical effects and cerebral electrical activity monitoring. Acta Paediatr Scand, 1988, 77, 79–84.
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May 14, 2009; in revised form: November 17, 2009.
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