1426
In other areas of medicine the potential of fractal analysis has been recognised but few data have been produced. The self-similar structure of the intestinal absorptive surface, from mucosal folds down to microvilli, has been described ;6 fractal analysis could display structural changes associated with malabsorption. The similarity between computergenerated fractal structures and skin lesions has been noted," and in pathology fractal analysis may allow quantification of complex images such as nuclear shape or texture2l and microbial growth patterns.22 What are the limitations of fractal geometry?23,24 Since fractal analysis is essentially mathematical, as with all mathematical models there must be a close link with the biological event if the model is to be useful. Relating the fractal dimension of an arterial tree to a diffusion-limited aggregation process may be a useful analogy, but it does not imply complete understanding of the process of angiogenesis. Natural objects are often self-similar over no more than three or four levels of recursion, so the scales at which the fractal dimension is calculated must be selected accordingly; many of the methods of fractal analysis require confirmation by further research. Nevertheless, the concept of fractal geometry is likely to prove very productive in areas of medicine where Euclidean geometry fails.25 With the availability of high-speed computers and high-resolution graphical displays we can now see that the iteration of very simple formulae can produce infinitely complex structures3,4-perhaps the infinitely complex forms of nature will be revealed as repetitions of simple formulae after all. 1. Mandelbrot BB. The fractal geometry of nature. New York: Freeman, 1983. 2. Mandelbrot BB. How long is the coast of Britain? Statistical selfsimilarity and fractional dimension. Science 1967; 156: 636-38. 3. Peitgen H-O, Richter PH. The beauty of fractals: images of complex
4.
dynamical systems. Berlin: Springer-Verlag, 1986. Barnsley MF, Devaney RL, Mandelbrot BB, Peitgen H-O, Saupe D, Voss RF. The science of fractal images. New York: Springer-Verlag,
5.
Bassingthwaighte JB, van Beek JHGM. Lightning and the heart: fractal
6.
Goldberger AL, Rigney DR, West BJ. Chaos and fractals in human physiology. Sci Am 1990; 46: 42-49. Goldberger AL, West BJ. Fractals in physiology and medicine. Yale J
1988. behaviour in cardiac function. Proc IEEE 1988; 76: 693-99.
7.
Biol Med 1987; 60: 421-35. 8. James TN. The spectrum of diseases of small coronary arteries and their physiologic consequences. JACC 1990; 15: 763-74. 9. Bassingthwaighte JB, van Beek JHGM, King RB. Fractal branchings: the basis of myocardial flow heterogeneities? Ann N Y Acad Sci 1990; 591: 392-401. 10. Goldberger AL. Fractal electrodynamics of the heartbeat. Ann N Y Acad Sci 1990; 591: 402-09. 11. Denton TA, Diamond GA, Helfant RH, Khan S, Karaguezian H. Fascinating rhythm: a primer on chaos theory and its application to cardiology. Am Heart J 1990; 120: 1419-40. 12. Goldberger AL, Rigney DR, Mietus J, Antman EM, Greenwald S. Nonlinear dynamics in sudden cardiac death syndrome: heartrate oscillations and bifurcations. Experientia 1988; 44: 983-87. 13. West BJ, Goldberger AL. Physiology in fractal dimensions. Am Sci 1987; 75: 354-65. 14. Lefevre J. Teleonomical optimization of a fractal model of the pulmonary arterial bed. J Theor Biol 1983; 102: 225-48. 15. Glenny RW, Robertson HT. Fractal properties of pulmonary blood flow: characterization of spatial heterogeneity. J Appl Physiol 1990; 69: 532-45.
16. Mainster MA. The fractal properties of retinal vessels: embryological and clinical implications. Eye 1990; 4: 235-41. 17. Kuklinski WS, Chandra K, Ruttirmann UE, Webber RL. Application of fractal texture analysis to segmentation of dental radiographs. Proc SPIE 1989; 1092: 111-17. 18. Caldwell CB, Stapleton SJ, Holdsworth DW, et al. Characterization of mammographic parenchyma) pattern by fractal dimension. Phys Med Biol 1990; 35: 235-47. 19. Nelson TR. Fractals: physiologic complexity, scaling and opportunities for imaging. Invest Radiol 1990; 25: 1140-48. 20. Goldsmith LA. Chaos: to see a world in a grain of sand and heaven in a wild flower. Arch Dermatol 1990; 126: 1159-60. 21. MacAulay C, Palcic B. Fractal texture features based on optical density surface area: use in image analysis of cervical cells. Anal Quant Cytol Histol 1990; 12: 394-98. 22. Obert M, Pfeifer P, Sernetz M. Microbial growth patterns described by fractal geometry. J Bacteriol 1990; 172: 1180-85. 23. Holmes P. How attractive is chaos? Nonlinear models in neurobiology. Ann N Y Acad Sci 1990; 591: 301-02. 24. McNamee JE. Introduction to fractals in biomedical research. Ann Biomed Engineering 1990; 18: 109-10. 25. Bassingthwaighte JB. Physiological heterogeneity: fractals link determinism and randomness in structures and functions. News Physiol Sci 1988; 3: 5-10.
Celiprolol: theory and practice Noting the
diverse actions of sympathomimetic amines in various tissues, Ahlquist1 suggested in 1948 that adrenoreceptors might be divided into a and 0. Less than twenty years later (3 receptors were subtyped into (31 and i2, and subsequently a receptors
reclassified. Development of clinically useful agents to antagonise these receptors was likewise swift: there are now over thirty P-blockers that are antagonists at both (31 and (3Z adrenoreceptors in the heart. Although these drugs-eg, propranolol- are widely used in hypertension and angina, they also block 0,-receptors in bronchial smooth muscle, predisposing to bronchoconstriction, and in liver and skeletal muscle, thereby inhibiting carbohydrate and lipid metabolism. Furthermore, most of these drugs will increase total peripheral vascular resistance by inhibiting &bgr;2-mediated arterial vasodilatation. Thus, non-specific (3-blockers are contraindicated in patients with asthma, obstructive airways disease, or peripheral vascular disease. Second generation P-blockers such as atenolol, acebutolol, and metoprolol are relatively selective for &bgr;l adrenoreceptors; consequently, they do not attenuate vasodilatation induced the by circulating catecholamines to the same extent as their predecessors and they are less likely to produce bronchoconstriction. Third generation (3-blockers have additional properties such as vasodilatation and even less tendency to cause bronchoconstriction. Like carvedilol combines non-selective labetalol, P-blockade with oq-blockade, the vasodilator effects of r11-blockade counteract the raised peripheral resistance induced by (3-blockade. Carvedilol is available in Germany and Belgium. In September this year celiprolol was launched in the UK. This racemic mixture is a hydrophilic &bgr;l-selective adrenoreceptor antagonist with mild (3Z agonist and weak vasodilator properties.2 It is licensed were
1427
in mild to moderate hypertension and promoted as the only available vasodilating cardioselective p-blocker. In Ireland, where it was launched in 1989, it now accounts for about 10% of the 0-blocker market. Is this astonishing rise in for
use
popularity justified? The (31 selectivity of celiprolol has been established in several in-vitro studies: (a) the drug is as selective as atenolol but 3-4 times more potent;3 (b) it is far more selective but less potent than propranolol ;4 and (c) it seems to have weak 0,-agonist properties and consequently has modestly positive inotropic and chronotropic actions.25 Because of the numerous (32 receptors in the vasculature, celiprolol would
therefore be expected to reduce arteriolar resistance and increase blood flow. Many studies support this contentionz but it remains uncertain whether the observed effect is solely due to (3z stimulation: Milne and Buckley2 suggest that other mechanisms must be
important because vasodilatation is observed in the kidney, where (32 receptors are scarce. There is little evidence that the drug exerts any substantial a-antagonism and there are no membrane stabilising local anaesthetic effects. Do these in-vitro properties confer any therapeutic advantages over the older (3-blockers in the management of hypertension? In terms of antihypertensive efficacy celiprolol is similar to the usual doses of propranolol and atenolol but it does not seem to depress resting cardiac output or heart rate; celiprolol reduces peripheral vascular resistance whereas conventional p-blockers do the opposite. Reductions in supine pressure can be ascribed to vasodilatation. Small studies suggest that celiprolol can substantially lower the exercise-induced rise in blood pressure. Other claims include no deleterious and possibly even favourable alteration in lipid and lipoprotein profiles, and no influence on carbohydrate metabolism. We do not know whether such surrogate end-points are important. With respect to tolerability, information from eighteen trials of celiprolol with a total of 1900 patients has been pooled.Z9For overall incidence of adverse events, celiprolol did not differ from placebo; the incidence of fatigue and dizziness was similar to that with propranolol or atenolol, and headache was as common as with propranolol. Celiprolol produces less clinically significant bradycardia. A few patients have received celiprolol and atenolol or propranolol in some trials and there is a suggestion that celiprolol was preferred. So, in terms of antihypertensive efficacy, celiprolol, for all its third-generation developments, differs little from its ancestors. The 0,-agonist properties suggest that theoretically it could be a bronchodilator and some data support this idea. In the few asthmatic patients in whom it has been tried, celiprolol caused little bronchoconstriction and, unlike propranolol, the drug does not impair bronchodilatation induced by aminophylline or terbutaline.5,1O However, there have
already been reports of asthma developing in hypertensive patients treated with celiprolol" and the data sheet recommends that it should not be used in patients with reversible airways disease. The theoretical attractions of celiprolol have not yet been borne out in clinical practice. 1. Ahlquist RP. A study of adrenoreceptors. Am J Physiol. 1948;
153:
586-600. 2. Milne RJ,
Buckley M. Celiprolol-an updated review of its pharmacodynamic and pharmacokinetic properties, and therapeutic efficacy in cardiovascular disease. Drugs 1991; 41: 941-69. 3. Anon. SCRIP Sept 13, 1991 (no 1651): 23. 4. Molinoff PB.&agr;-adrenergic receptor subtypes properties distribution and regulation. Drugs 1984; 28 (suppl 2): 1-15. 5. Riddell JG, Shanks RG, Brogden RN. Celiprolol: a preliminary review of its pharmacodynamic and pharmacokinetic properties and its therapeutic use in hypertension and angina pectoris. Drugs 1987; 34: 438-58. 6. Frishman
WH, Flamenbaum W, Schoenberger J, et al. Celiprolol in systemic hypertension. Am J Cardiol 1989; 63: 839-42. 7. Abe H, Kaneko Y, Omae T, Kobubu T, Iimura O. Clinical evaluation of celiprolol hydrochloride (NBP-582) on essential hypertension. Double-blind ground comparative study vs propranolol hydrochloride. Rinsho Iyaku 1989; 5: 105-59. 8. McInnes GI, McLenachan JM, Henderson H, Herrick AL, Dargie HJ. Celiprolol and verapamil in the treatment of essential hypertension. Am Heart J 1988; 116: 1437-38. 9. Lamon KD. Clinical safety and efficacy of celiprolol. Am Heart J 1991; 121: 683-87.
or
Matthys H, Doshan HD, Ruhle KH, Applin WJ, Braig H, Pohl M. Bronchosparing properties of celiprolol, a new &bgr;1, &agr;2-blocker in propranolol-sensitive asthmatic patients. J Cardiovascular Pharmacol 1986; 8 (suppl 4): 40-42. 11. Waal-Manning HJ, Simpson FO. Safety of celiprolol in hypertensives with chronic obstructive respiratory disease. NZ Med J 1990; 103: 10.
222.
Antisensibility: progress and prospects Use of DNA and RNA sequences to suppress the activity of genes in various cell systems and organisms has lately aroused considerable interest. One outcome of this approach would be a better understanding of the role of the suppressed gene in a particular biological process. However, the aim in some studies has been to target key genes (oncogenes) in the aetiology of cancer1 or in the viral genome—eg, in human immunodeficiency virus following infection. This technique might then lead to new treatments. The idea is that base sequences in the DNA or the messenger RNA-sense sequences-are targeted by complementary antisense sequences; the resulting hybrid sequence will thereby prevent gene activity either at the DNA or at the RNA level. In view of the base-pairing rules of the genetic code (adenine with thymine, guanine with cytosine), selection of the correct number of bases in a sequence should lead to formation of a unique hybrid. Such a process seems to occur naturally in prokaryotes and possibly in eukaryotes. For example, some bacterial genes use
antisense messages to regulate gene expression. There are various methods for introducing the antisense molecules into cells--eg, by microinjection, by in-situ production from plasmids or retrovirus vectors,
or
by feeding through the medium. When
In other areas of medicine the potential of fractal analysis has been recognised but few data have been produced. The self-similar structure of the intestinal absorptive surface, from mucosal folds down to microvilli, has been described ;6 fractal analysis could display structural changes associated with malabsorption. The similarity between computergenerated fractal structures and skin lesions has been noted," and in pathology fractal analysis may allow quantification of complex images such as nuclear shape or texture2l and microbial growth patterns.22 What are the limitations of fractal geometry?23,24 Since fractal analysis is essentially mathematical, as with all mathematical models there must be a close link with the biological event if the model is to be useful. Relating the fractal dimension of an arterial tree to a diffusion-limited aggregation process may be a useful analogy, but it does not imply complete understanding of the process of angiogenesis. Natural objects are often self-similar over no more than three or four levels of recursion, so the scales at which the fractal dimension is calculated must be selected accordingly; many of the methods of fractal analysis require confirmation by further research. Nevertheless, the concept of fractal geometry is likely to prove very productive in areas of medicine where Euclidean geometry fails.25 With the availability of high-speed computers and high-resolution graphical displays we can now see that the iteration of very simple formulae can produce infinitely complex structures3,4-perhaps the infinitely complex forms of nature will be revealed as repetitions of simple formulae after all. 1. Mandelbrot BB. The fractal geometry of nature. New York: Freeman, 1983. 2. Mandelbrot BB. How long is the coast of Britain? Statistical selfsimilarity and fractional dimension. Science 1967; 156: 636-38. 3. Peitgen H-O, Richter PH. The beauty of fractals: images of complex
4.
dynamical systems. Berlin: Springer-Verlag, 1986. Barnsley MF, Devaney RL, Mandelbrot BB, Peitgen H-O, Saupe D, Voss RF. The science of fractal images. New York: Springer-Verlag,
5.
Bassingthwaighte JB, van Beek JHGM. Lightning and the heart: fractal
6.
Goldberger AL, Rigney DR, West BJ. Chaos and fractals in human physiology. Sci Am 1990; 46: 42-49. Goldberger AL, West BJ. Fractals in physiology and medicine. Yale J
1988. behaviour in cardiac function. Proc IEEE 1988; 76: 693-99.
7.
Biol Med 1987; 60: 421-35. 8. James TN. The spectrum of diseases of small coronary arteries and their physiologic consequences. JACC 1990; 15: 763-74. 9. Bassingthwaighte JB, van Beek JHGM, King RB. Fractal branchings: the basis of myocardial flow heterogeneities? Ann N Y Acad Sci 1990; 591: 392-401. 10. Goldberger AL. Fractal electrodynamics of the heartbeat. Ann N Y Acad Sci 1990; 591: 402-09. 11. Denton TA, Diamond GA, Helfant RH, Khan S, Karaguezian H. Fascinating rhythm: a primer on chaos theory and its application to cardiology. Am Heart J 1990; 120: 1419-40. 12. Goldberger AL, Rigney DR, Mietus J, Antman EM, Greenwald S. Nonlinear dynamics in sudden cardiac death syndrome: heartrate oscillations and bifurcations. Experientia 1988; 44: 983-87. 13. West BJ, Goldberger AL. Physiology in fractal dimensions. Am Sci 1987; 75: 354-65. 14. Lefevre J. Teleonomical optimization of a fractal model of the pulmonary arterial bed. J Theor Biol 1983; 102: 225-48. 15. Glenny RW, Robertson HT. Fractal properties of pulmonary blood flow: characterization of spatial heterogeneity. J Appl Physiol 1990; 69: 532-45.
16. Mainster MA. The fractal properties of retinal vessels: embryological and clinical implications. Eye 1990; 4: 235-41. 17. Kuklinski WS, Chandra K, Ruttirmann UE, Webber RL. Application of fractal texture analysis to segmentation of dental radiographs. Proc SPIE 1989; 1092: 111-17. 18. Caldwell CB, Stapleton SJ, Holdsworth DW, et al. Characterization of mammographic parenchyma) pattern by fractal dimension. Phys Med Biol 1990; 35: 235-47. 19. Nelson TR. Fractals: physiologic complexity, scaling and opportunities for imaging. Invest Radiol 1990; 25: 1140-48. 20. Goldsmith LA. Chaos: to see a world in a grain of sand and heaven in a wild flower. Arch Dermatol 1990; 126: 1159-60. 21. MacAulay C, Palcic B. Fractal texture features based on optical density surface area: use in image analysis of cervical cells. Anal Quant Cytol Histol 1990; 12: 394-98. 22. Obert M, Pfeifer P, Sernetz M. Microbial growth patterns described by fractal geometry. J Bacteriol 1990; 172: 1180-85. 23. Holmes P. How attractive is chaos? Nonlinear models in neurobiology. Ann N Y Acad Sci 1990; 591: 301-02. 24. McNamee JE. Introduction to fractals in biomedical research. Ann Biomed Engineering 1990; 18: 109-10. 25. Bassingthwaighte JB. Physiological heterogeneity: fractals link determinism and randomness in structures and functions. News Physiol Sci 1988; 3: 5-10.
Celiprolol: theory and practice Noting the
diverse actions of sympathomimetic amines in various tissues, Ahlquist1 suggested in 1948 that adrenoreceptors might be divided into a and 0. Less than twenty years later (3 receptors were subtyped into (31 and i2, and subsequently a receptors
reclassified. Development of clinically useful agents to antagonise these receptors was likewise swift: there are now over thirty P-blockers that are antagonists at both (31 and (3Z adrenoreceptors in the heart. Although these drugs-eg, propranolol- are widely used in hypertension and angina, they also block 0,-receptors in bronchial smooth muscle, predisposing to bronchoconstriction, and in liver and skeletal muscle, thereby inhibiting carbohydrate and lipid metabolism. Furthermore, most of these drugs will increase total peripheral vascular resistance by inhibiting &bgr;2-mediated arterial vasodilatation. Thus, non-specific (3-blockers are contraindicated in patients with asthma, obstructive airways disease, or peripheral vascular disease. Second generation P-blockers such as atenolol, acebutolol, and metoprolol are relatively selective for &bgr;l adrenoreceptors; consequently, they do not attenuate vasodilatation induced the by circulating catecholamines to the same extent as their predecessors and they are less likely to produce bronchoconstriction. Third generation (3-blockers have additional properties such as vasodilatation and even less tendency to cause bronchoconstriction. Like carvedilol combines non-selective labetalol, P-blockade with oq-blockade, the vasodilator effects of r11-blockade counteract the raised peripheral resistance induced by (3-blockade. Carvedilol is available in Germany and Belgium. In September this year celiprolol was launched in the UK. This racemic mixture is a hydrophilic &bgr;l-selective adrenoreceptor antagonist with mild (3Z agonist and weak vasodilator properties.2 It is licensed were
1427
in mild to moderate hypertension and promoted as the only available vasodilating cardioselective p-blocker. In Ireland, where it was launched in 1989, it now accounts for about 10% of the 0-blocker market. Is this astonishing rise in for
use
popularity justified? The (31 selectivity of celiprolol has been established in several in-vitro studies: (a) the drug is as selective as atenolol but 3-4 times more potent;3 (b) it is far more selective but less potent than propranolol ;4 and (c) it seems to have weak 0,-agonist properties and consequently has modestly positive inotropic and chronotropic actions.25 Because of the numerous (32 receptors in the vasculature, celiprolol would
therefore be expected to reduce arteriolar resistance and increase blood flow. Many studies support this contentionz but it remains uncertain whether the observed effect is solely due to (3z stimulation: Milne and Buckley2 suggest that other mechanisms must be
important because vasodilatation is observed in the kidney, where (32 receptors are scarce. There is little evidence that the drug exerts any substantial a-antagonism and there are no membrane stabilising local anaesthetic effects. Do these in-vitro properties confer any therapeutic advantages over the older (3-blockers in the management of hypertension? In terms of antihypertensive efficacy celiprolol is similar to the usual doses of propranolol and atenolol but it does not seem to depress resting cardiac output or heart rate; celiprolol reduces peripheral vascular resistance whereas conventional p-blockers do the opposite. Reductions in supine pressure can be ascribed to vasodilatation. Small studies suggest that celiprolol can substantially lower the exercise-induced rise in blood pressure. Other claims include no deleterious and possibly even favourable alteration in lipid and lipoprotein profiles, and no influence on carbohydrate metabolism. We do not know whether such surrogate end-points are important. With respect to tolerability, information from eighteen trials of celiprolol with a total of 1900 patients has been pooled.Z9For overall incidence of adverse events, celiprolol did not differ from placebo; the incidence of fatigue and dizziness was similar to that with propranolol or atenolol, and headache was as common as with propranolol. Celiprolol produces less clinically significant bradycardia. A few patients have received celiprolol and atenolol or propranolol in some trials and there is a suggestion that celiprolol was preferred. So, in terms of antihypertensive efficacy, celiprolol, for all its third-generation developments, differs little from its ancestors. The 0,-agonist properties suggest that theoretically it could be a bronchodilator and some data support this idea. In the few asthmatic patients in whom it has been tried, celiprolol caused little bronchoconstriction and, unlike propranolol, the drug does not impair bronchodilatation induced by aminophylline or terbutaline.5,1O However, there have
already been reports of asthma developing in hypertensive patients treated with celiprolol" and the data sheet recommends that it should not be used in patients with reversible airways disease. The theoretical attractions of celiprolol have not yet been borne out in clinical practice. 1. Ahlquist RP. A study of adrenoreceptors. Am J Physiol. 1948;
153:
586-600. 2. Milne RJ,
Buckley M. Celiprolol-an updated review of its pharmacodynamic and pharmacokinetic properties, and therapeutic efficacy in cardiovascular disease. Drugs 1991; 41: 941-69. 3. Anon. SCRIP Sept 13, 1991 (no 1651): 23. 4. Molinoff PB.&agr;-adrenergic receptor subtypes properties distribution and regulation. Drugs 1984; 28 (suppl 2): 1-15. 5. Riddell JG, Shanks RG, Brogden RN. Celiprolol: a preliminary review of its pharmacodynamic and pharmacokinetic properties and its therapeutic use in hypertension and angina pectoris. Drugs 1987; 34: 438-58. 6. Frishman
WH, Flamenbaum W, Schoenberger J, et al. Celiprolol in systemic hypertension. Am J Cardiol 1989; 63: 839-42. 7. Abe H, Kaneko Y, Omae T, Kobubu T, Iimura O. Clinical evaluation of celiprolol hydrochloride (NBP-582) on essential hypertension. Double-blind ground comparative study vs propranolol hydrochloride. Rinsho Iyaku 1989; 5: 105-59. 8. McInnes GI, McLenachan JM, Henderson H, Herrick AL, Dargie HJ. Celiprolol and verapamil in the treatment of essential hypertension. Am Heart J 1988; 116: 1437-38. 9. Lamon KD. Clinical safety and efficacy of celiprolol. Am Heart J 1991; 121: 683-87.
or
Matthys H, Doshan HD, Ruhle KH, Applin WJ, Braig H, Pohl M. Bronchosparing properties of celiprolol, a new &bgr;1, &agr;2-blocker in propranolol-sensitive asthmatic patients. J Cardiovascular Pharmacol 1986; 8 (suppl 4): 40-42. 11. Waal-Manning HJ, Simpson FO. Safety of celiprolol in hypertensives with chronic obstructive respiratory disease. NZ Med J 1990; 103: 10.
222.
Antisensibility: progress and prospects Use of DNA and RNA sequences to suppress the activity of genes in various cell systems and organisms has lately aroused considerable interest. One outcome of this approach would be a better understanding of the role of the suppressed gene in a particular biological process. However, the aim in some studies has been to target key genes (oncogenes) in the aetiology of cancer1 or in the viral genome—eg, in human immunodeficiency virus following infection. This technique might then lead to new treatments. The idea is that base sequences in the DNA or the messenger RNA-sense sequences-are targeted by complementary antisense sequences; the resulting hybrid sequence will thereby prevent gene activity either at the DNA or at the RNA level. In view of the base-pairing rules of the genetic code (adenine with thymine, guanine with cytosine), selection of the correct number of bases in a sequence should lead to formation of a unique hybrid. Such a process seems to occur naturally in prokaryotes and possibly in eukaryotes. For example, some bacterial genes use
antisense messages to regulate gene expression. There are various methods for introducing the antisense molecules into cells--eg, by microinjection, by in-situ production from plasmids or retrovirus vectors,
or
by feeding through the medium. When
