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Analgesia was tested at 5 minutes intervals by gently clasping the temporal conjunctiva 5 mm away from the limbus, with a pair of nontoothed forceps, similar to the method reported by Linn and Vey (18). The subjects’ responses were graded by scoring from 0-2: Grade 0 (score = 0) was given when the response was "painful", Grade 1 (score = 1) when there was "no pain but subject felt it or complained of slight discomfort", and Grade 2 (score = 2) when no pain was felt by subject with no discomfort at all; thus a maximum score of 2 was obtainable from any study eye. Other ocular side effects like itching, irritation, foreign body sensation, grittiness, watering, pain, eyeache or headache, diminution of vision, persistent congestion, chemosis, lid oedema and corneal epithelial defects were especially asked for and ruled out using slit lamp biomicroscopy and fluorescein staining. Visual acuity, and pupillary size and reactions were noted, and intraocular pressure (IOP) was measured by non-contact tonometer (without any necessity of topical anaesthesia). Systemic side effects like drowsiness, change in mood and dizziness if any, along with pulse rate and blood pressure or any respiratory or neurological difficulties were also noted. Statistical analysis Observations
were recorded according to code of drug and entered into Excel
software. One-way analysis of variance (ANOVA) was applied
to detect the statistically significant differences between
the mean values. In case of significant difference shown by
ANOVA, post-analysis variance (i.e. multiple range test) was
applied to detect the statistically significant difference on
various pairs of group means (21). The analysis was done using
STATA 6.0 intercooled version package. After the analysis was
performed, vials were decoded and results were accordingly interpreted. RESULTSSubjects of all the groups were age and sex matched. Both objective and subjective criteria were tabulated for grading the subject responses to tactile sensation. The objective criteria were primarily used for scoring and the subjective responses were utilized to decide the score only in equivocal situations. A subject's request to repeat the test was interpreted as 'no score' and graded accordingly. In our study the onset of anaesthesia was quickest with 4% lignocaine in DW followed by 0.5% centbucridine in DW and then by 1% in DW (Table II). With 1% centbucridine, the peak achievement and peak duration surface anaesthesia and also its maintenance for the longest period were supported by its highest score for depth of anaesthesia as well as depth of analgesia the corresponding values for 0.5% centbucridine in DW were lower, followed finally by 4% lignocaine in DW (Table II), with differences being statistically significant (P<0.001). Burning sensations were noted with all three drug solutions, the period of burning being longest (over 2 minutes) for 1% centbucridine drops in DW (Table II). No other ocular and systemic side effects were noted with any of these drug solutions on single drop instillations.
The testing for the effect of any anaesthetic agent calls for a safe, objective and standardized method in clinical situations which can give reproducible results. Anaesthesiometers have disadvantages of stimulation of pain receptors along with the touch receptors and the fact that their higher stimulus strength can cause corneal epithelial abrasions, thus obviating its use in clinical situations (17, 22). Therefore, cotton wisp was used as a suitable and adequate stimulus to test corneal and conjunctival tactile sensations, and subject responses were graded rather than grading the stimulus. The non-contrasting background rendered the cotton wisp less noticeable, and bringing in the stimulus from a non-seeing to a seeing area further helped. The qualities of an ideal ocular surface anaesthetic agent (so important for many ophthalmic procedures), include : good epithelial penetration good potency, satisfactory onset of action, short latent period, no secondary effect on pupillary size and intraocular pressure, no tissue allergic reaction, no systemic toxicity, no inhibition of healing process, good solubility in water and saline, a pH close to that of tears, easy sterilization, chemical stability in solution, and preferably low cost (18, 23, 24). At present no drug fulfils all these diverse criteria, indicating the need of a continuous search in this regard. Lignocaine hydrochloride used as a control drug in this study is the most commonly used anaesthetic drug in this part of the world. However, more so in the West, lignocaine is not the favoured drug especially for topical anaesthesia, and side effects including fatal reactions had been reported from its injectable use (3). Secondly, though onset of lignocaine maybe quicker, it has a relatively shorter duration of action maybe because of its intrinsic vasodilator activity (25). Centbucridine, a quinoline derivative anaesthetic agent, has been found to have potent anaesthetic activity (5-17). It has been tried by subarachnoid (11), intravenous regional (13), as well as for infiltration anaesthesia (14-17) including our earlier study (16), and proved to have good anaesthetic activity with wide margin of safety. It has again been demonstrated that action of injectable centbucridine was concentration dependent, a higher concentration giving more anaesthetic activity (15). It was shown that centbucridine was 4-5 times more potent than lignocaine dose to dose. Though various experimental and clinical studies including topical anaesthesia (6) have been conducted on centbucridine, to the best of our knowledge, no study as ours has been carried out earlier to evaluate its comparative efficacy in different strengths by using single drop topical application to evaluate different parameters (Table II). We observed that, centbucridine's topical anaesthetic action was also concentration dependent, i.e. centbucridine 1% showed maximum peak as well as duration of anaesthetic and analgesic activities. Another interesting result of our study was that, with centbucridine in both the concentrations (0.5% and 1%), longer durations of anaesthesia (Table II) were obtained as compared to 4% lignocaine (which is the latter's usual strength used to obtain ocular surface anaesthesia in clinical ophthalmic settings). The increased duration of anaesthetic action of centbucridine may be of greater value in clinical and operative ophthalmology, where more time may be required in modern day procedures and microtechniques. Centbucridine in higher concentration (1%) produces temporary burning sensations for a slightly longer period as compared to 0.5% centbucridine and 4% lignocaine hydrochloride - however, this did not reduce the clinical applicability or efficacy of 1% as well as 0.5% centbucridine, and no other serious side effects like corneal epithelial defect were observed from either of these. Our study was the initial step to evaluate different clinicopharmacological parameters of topical centbucridine as compared to lignocaine by single drop application. We are in the process of further analyses including multiple drop studies and comparison of effectivity of centbucridine using different vehicles and pH values, so that along with our earlier proven efficacy of this newer agent as an infiltration anaesthetic (16), centbucridine with its greater potency and wide safety margins can be then considered both for topical and injectable use in ophthalmic and all other surgeries. ACKNOWLEDGEMENTS The study was supported by a research grant from the All India
Institute of Medical Sciences (AIIMS) New Delhi, India. We are grateful to Mrs. S. Jhingan,
Pharmacist for preparing centbucridine and lignocaine eye drops
and Mr. Alok K. Ravi for help in preparing the manuscript. 1. de Jong RH, Wagman IH. Physiological mechanism of peripheral nerve block by local anaesthetics. Anaesthesiology 1963; 24: 684-727. 2. Noble DS, Pierce GFM. Allergy to Lignocaine. The Lancet 1961; 2: 1436. 3. Deacock AR de C, Simson WT. Fatal reactions to lignocaine. Anaesthesia 1964; 19: 217-221. 4. Central Drug Research Institute Monograph on "Summary of available pharmacological, toxicological and clinical data on 4-N-Butylamino1,2,3,4-Tetrahydroacridine hydrochloride (Centbucridine : compound 64-124) A new local anaesthetic" September 1975, P.1,14,38. CDRI, Lucknow, India. 5. Patnaik GK, Rastogi SN, Anand N, Dhawan BN. Evaluation of local anaesthetic activity of 4-N-Butylamino-1,2,3,4-Tetrahydroacridine Hydrochloride (Centbucridine) A 4-substituted polymethylenequinoline. Ind J Expt Biol 1982; 20: 327-329. 6. Gupta PP, Tangri AN, Saxena RC, Dhawan BN. Clinical Pharmacology studies of 4-N-Butylamino-1,2,3,4-Tetrahydroacridine Hydrochloride (Centbucridine) A new local anaesthetic agent. Ind J Expt Biol 1982; 20: 344-346. 7. Patnaik GK, Dhawan BN. Pharmacological study of 4-N-Butylamino-1,2,3,4-Tetrahydroacridine Hydrochloride (Centbucridine) A new local anaesthetic agent. Ind J Expt Biol 1982; 20: 330- 333. 8. Nityanand S, Sethi N, Srivastava GN, Roy AK, Mukherjee SK. Chronic toxicity studies on 4-N-Butylamino- 1,2,3,4 - Tetrahydroacridine Hydrochloride (Centbucridine) A new local anaesthetic agent. Ind J Expt Biol 1982; 20: 334-336. 9. Sethi N, Mukherjee SK. Teratogenic studies on -N-Butylamino- 1,2,3,4 - Tetrahydroacridine Hydrochloride (Centbucridine) A new local anaesthetic agent. Ind J Expt Biol 1982; 20: 337- 338. 10. Gupta PP, Nityanand S, Shipstone AC, Dhawan BN. Experimental evaluation of potential neurotoxicity of 4-N-Butylamino-1,2,3,4-Tetrahydroacridine Hydrochloride (Centbucridine) A new local anaesthetic agent. Ind J Expt Biol 1982; 20: 339- 343. 11. Suri YV, Shinghal AP, Phadke VK, Rajauria SS, Singh D, Gupta PP et al. Double blind study on centbucridine for subarachnoid and extradural anaesthesia. Ind J Med Res 1982; 76: 875-881. 12. Samsi AB, Bhalerao RA, Shah SC, Mody BB, Paul T, Satoskar RS. Evaluation of centbucridine as a local anaesthetic. Anesth Analg 1983; 62: 109-111. 13. Suri YV, Patnaik GK, Nayak BC, Gupta PP, Singh D, Dhawan BN. Evaluation of centbucridine for intravenous regional anaesthesia. Ind J Med Res 1983;77:722-727. 14. Dhir SP, Sharma PL, Jain IS, Zafrulla KM. Comparative double blind clinical trial of centbucridine and lignocaine hydrochloride in ocular surgery. Bull PGI (Chandigarh, India) 1977; 11(4): 163-165. 15. Gupta PP, Asthana OP, Dhawan BN, Goel R, Shukla KN. Clinical evaluation of centbucridine in ophthalmic surgery. Ind J Med Res 1985; 81: 230- 233. 16. Beri S, Biswas NR, Shende DR, Das GK, Pandey RM, Ghose S. Injectable centbucridine and lidocaine hydrochloride for intraocular surgery. Ophthalmic Surg Lasers 1997; 28: 1027-1029. 17. Vacharajani GN, Parikh N, Paul T, Satoskar RS. A comparative study of centbucridine and lidocaine in dental extraction. Int J Clin Pharm Res 1983; III(4): 251-255. 18. Linn JG Jr, Vey EK. Topical anesthesia in ophthalmology. Am J Ophthalmol 1955; 40: 697- 704. 19. Duke-Elder S. The examination of the eye. In System of Ophthalmology, Vol VII : The Foundations of Ophthalmology, St. Louis, CV Mosby 1962; Ch XIII: 244. 20. Boozan CW, Cohen IJ. Ophthaine : A new topical anesthetic for the eye. Am J Ophthalmol 1953; 36: 1619-1621. 21. Daly LE, Bourke GJ, McGilvay J. Analysis of variance and multiple range test. In : Interpretation and Uses of Medical Statistics. Fourth Edition, Blackwell Scientific Publications, UK, 1991; 139-156. 22. Bolerg AJ. Experience in clinical examination of corneal sensitivity and the nasolacriinal reflex after retrobulbar anaesthesia. Br J Ophthalmol 1955; 39:705-726. 23. Jerry JW. Topical anesthetic for the eye. A comparative study. South Med J 1955; 48: 770-777. 24. Bryant JA. Local and topical anesthetic in ophthalmology. Survey Ophthalmol 1969; 13(5): 263-283. 25. Stoelting RK. Local anaesthetics. In : Pharmacology and Physiology in Anaesthetic practice. Second edition, St Louis, JB Lippincott 1991; 131-150. |
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