1508
6.
Findlay IN, MacLeod K, Ford M, Gillen G, Elliott AT, Dargie HJ. Treatment of angina with nifedipine and atenolol: efficacy and effect on‘ cardiac function. Br Heart J 1986; 55: 240-45. 7. Parmley WW, Nesto RW, Singh BN, Deanfield J, Gottlieb SO. Attenuation of the circadian patterns of myocardial ischemia with nifedipine GITS in patients with chronic stable angina. N-CAP Study
Group. JACC 1992; 19: 1380-89. 8. TIBET Study Group. Total Ischemic Burden European Trial (TIBET): effect of treatment on exercise and Holter ECG in angina. Circulation 1992; 86: no 4, I-713 abstr: 28-39. 9. Krakoff LR, Bravo EL, Tuck ML, Friedman CP, and the Modem Approach to the Treatment of Hypertension (MATH) Study Group. Am J Hypertens 1990; 3: 318S-25S. 10. Houston MC, Olafsson L, Burger MC. Effects of nifedipine GITS and atenolol monotherapy on serum lipids, blood pressure, heart rate, and weight in mild to moderate hypertension. Angiology 1991; 42: 681-90. 11. DiPiro JT. Controlling drug effects through improved oral formulations. The pharmacokinetics of the prazosin gastrointestinal therapeutic systems. Am J Med 1989; 87: 31S-35S. 12. Tantucci C, Bruni B, Dottorini ML, et al. Comparative evaluation of cardioselectivity of metoprolol OROS and atenolol: a double blind, placebo controlled crossover study. Am Heart J 1990; 120: 467-72.
Botulinum toxin Botulinum toxin type A (BtA) is one of seve] immunologically distinct neurotoxins produced b: the bacterium Clostridium botulinum. Injection of ; small amount of the toxin into a muscle selectivel; weakens it by irreversibly blocking the release o
acetylcholine at the neuromuscular junction. Muscle injected atrophy and become weak over 2-20 day
so
2-4 months as new terminal axor form and restore transmission.1 sprouts BtA was first used in human beings in 1979 to treai strabismus2 and is now recognised as a safe anc effective symptomatic therapy for hemifacial spasm blepharospasm, cervical dystonia (torticollis), jawclosing oromandibular dystonia, and adductoi laryngeal dysphonia.3 In lateral rectus palsy and acquired esotropia BtA is useful in preoperative assessment and may be curative.4 In dysthyroid myopathy with strabismus5 the toxin can reduce prism correction and help to buy time before definitive surgery. BtA has been tried in many other conditions characterised by relative overactivity of a few muscles. The list includes orofacial dyskinesia, abductor laryngeal dysphonia, limb dystonias such as writer’s and musician’s cramp, movement disorders such as voice and head tremor, oscillopsia, bruxism, tics, focal cramps, and spasticity, and urinary and anal sphincter dysfunction.6Spontaneous fluctuations in severity of disease and crude rating scales make benefit difficult to evaluate and there is a significant placebo response.7 Moreover, many of the reported successes come from open or small studies. The temporary nature of BtA-induced paralysis is useful because side-effects are transient, and sometimes temporary weakness is all that is required. For example, induction of a temporary protective ptosis by injection of levator palpebrae superioris can be used to avoid surgical tarsorrhaphy. However, in most conditions, a long-term effect is wanted and this calls for repeated injections. Injection techniques have not been standardised. In and
recover over
muscles for injection are identified by clinical assessment of pain, muscle hypertrophy, and abnormal activity and posture. This approach may be adequate, but electromyography sometimes reveals muscle activity that is not clinically apparent. Finetuning of muscle selection with electromyography may be beneficial8 and theoretically could also reduce the dose or frequency of injections. In some disorders electromyography is essential for accurate placement of toxin in the selected muscles. Short-term side-effects are mostly minor and well tolerated, spread of toxin causing weakness of nearby muscles and local autonomic dysfunction. The main danger comes with injections around the neck, which can occasionally cause dysphagia and aspiration of fluid into the lungs. Systemic spread of toxin has been detected by electromyography9 but this does not lead to clinically detectable generalised weakness with standard doses of BtA. A few patients have experienced a flu-like illness or brachial neuritis which suggests an acute immune response. 10 These events do not preclude further injections. Although serious long-term side-effects have not been noted, doctors should remain vigilant, especially since there are no animal toxicity studies with repeated injections. There is little agreement about an assay for the three preparations of the toxin-haemagglutinin complex and there is a 3-5-fold difference in potency between them. Relative potencies may change according to the condition treated, perhaps because the preparations disperse differently in tissues, and "effective" doses vary between centres. This lack of standardisation is most centres
clearly unsatisfactory. The best long-term treatment strategy is uncertain. Most patients continue to respond even after 5-10 years and 20-30 treatments, although symptoms are seldom abolished and adjuvant conventional should not be withheld. In some cases of loss of efficacy toxin neutralising antibodies can be detected. We do not know whether one preparation is more antigenic than another, or whether dose or frequency of treatment is an important factor.66 Other serotypes of botulinum toxin that do not cross-react have been investigated. Type F has already proved effective in patients with torticollis who have become resistant to BtA and who have antitoxin antibodies.l1 Although the toxin moiety itself is known to be antigenic, toxin neutralising antibodies could also arise from other parts of the BtA-haemagglutinin complex, so a different preparation of BtA might be worth trying. A purer form of BtA would allow us to explore this possibility. treatment
1. Alderson
K, Holds JB, Anderson RL. Botulinum-induced alteration of nerve-muscle interactions in the human orbicularis oculi following treatment for blepharospasm. Neurology 1991; 41: 1800-05. 2. Scott AB. Botulinum toxin injections into extra ocular muscles as an alternative to strabismus surgery. Ophthalmology 1980; 87: 1044-49. 3. Therapeutics and Technology Subcommittee of the American Academy of Neurology. Assessment: the clinical usefulness of botulinum toxin-A in treating neurologic disorders. Neurology 1990; 40: 1332-36 4. Riordan-Ever P, Lee JP. Management of VIth nerve palsy avoiding unnecessary surgery. Eye 1992; 6: 386-90.
1509
Lyons CJ, Vickers SF, Lee JP. Botulinum toxin therapy in dysthyroid strabismus. Eye 1990; 4: 538-40. 6. Oates JA, Wood AJJ. Therapeutic uses of botulinum toxin. N Engl J Med 5.
1991; 324: 1186-94. 7. Moore AP, Blumhardt LD. Double blind study of botulinum toxin A in torticollis (with one year follow up). J Neurol Neurosurg Psychiatry 1991; 54: 813-16. 8. Comella CL, Buchman AS, Tanner CM, Brown-Toms NC, Goetz CG. Botulinum toxin injection for spasmodic torticollis: increased
magnitude of benefit with electromyographic assistance. Neurology 1992; 42: 878-82.
Lange D J, Brin MF, Warner CL, Fahn S, Lovelace RE. Distant effects of local injection of botulinum toxin. Muscle Nerve 1987; 10: 552-55. 10. Glanzman RL, Gelb DJ, Drury I, Bromberg MB, Truong DD. Brachial plexopathy after botulinum toxin injection. Neurology 1990; 40: 1143. 11. Ludlow CL, Hallett M, Rhew K, et al. Therapeutic use of type F botulinum toxin. N Engl J Med 1992; 326: 349-50. 9.
Mechanical coronary atherectomy Percutaneous transluminal coronary angioplasty (PTCA) has three main limitations (a) unsuccessful or inadequate balloon dilatation in 10-20% of patients; (b); acute vessel closure in 4-7%; and (c) restenosis in 25-50%. To overcome these drawbacks, balloon technology has been improved, intracoronary stents have been introduced, and in an attempt to "debulk" lesions effectively and safely, laser technology and mechanical atherectomy or ablative devices have been developed. Three catheter-mounted mechanical devices are available, although two are still investigational. For directional coronary atherectomy (DCA), a rigid metal cylinder with a 10 mm long window over about a quarter of its circumferencesis inserted into a coronary artery over a standard guide wire. The window is positioned against the atheromatous plaque; inflation of a balloon on the opposite side of the device under low pressure stabilises the window against the lesion, and then a cup-shaped circumferential blade, rotating at 2000 rpm, is advanced along the cylinder, excising the atheroma and pushing it into the nose cone. Usually DCA alone produces a satisfactory angiographic result, but adjunctive balloon PTCA may be required. The primary success rate of DCA is 80-98%, depending on the type of lesion,6-9 with about equal efficacy in native vessels, restenosis lesions, and grafts, although distal embolisation of graft atheroma may occur.1O Because of its size and rigidity, the device is most suited to bulky eccentric lesions in proximal straight segments of coronary arteries. There is a 1-4% acute closure rate. Hopes that the excellent angiographic appearances achieved with DCA would be associated with low restenosis rates have not been realised, but the rate is below 25% for the largest arteries." Although the reported success and complication rates are generally no different from those of PTCA, use of DCA has largely been restricted to complex lesions, unstable syndromes, or acute complications of PTCA. There is some evidence of a lower acute complication rate with DCA.12,13 The two techniques are being compared in several trials—eg, CAVEAT (coronary angioplasty
excisional atherectomy trial) I and II and the Canadian Coronary Atherectomy Trial. Initial results of CAVEAT reported at the American Heart versus
Association Meeting in New Orleans last month showed an 8% higher procedural success rate with better DCA, postprocedural angiographic and an lower restenosis 8-9% 6-month appearances, rate.
In percutaneous transluminal coronary rotational ablation ("rotablation") a small burr is mounted on a narrow drive shaft which tracks along a fine guide wire.14,15 The front face of the burr is studded with diamond microchips (30-50 ). Driven by compressed air, the burr rotates at 140 000-190 000 rpm. Atheromatous plaque protruding into the lumen is emulsified into small particles (generally less than 10 pm) which pass through the coronary microcirculation and are subsequently picked up by the reticuloendothelial system. With larger burr sizes, the fragments can be larger and can cause distal microembolisation. This complication may account for the non-Q-wave infarct rate of 1-6%, which rises to 19% in diffuse disease;16.17 one recommendation is to start with a small burr and work up. Because of the limited size of the burrs (1-0-2-5 mm), the final angiographic result may not be ideal, and adjunctive balloon PTCA is often necessary. Success rates of rotablation in complex lesions are now 90-95%.’ Overall acute closure rate is 2-8%,16,17,20,21 related to thrombus, dissection, or spasm. As with DCA, this device has not had a major impact on restenosis rates. The most likely application will be for specific lesions that are not suitable for either PTCA or DCA--eg, calcific lesions, those resistant to standard PTCA, and those in tortuous vessels. With the transluminal extraction endarterectomy catheter (TEC) the device likewise tracks along a standard guide wire. Two blades form the sides of what would otherwise be a conical tip, which rotates at 750 rpm and excised debris is aspirated through the central channel. 22 The primary success rate exceeds 90%.23 The device has been used in graft lesions and after thrombus aspiration in patients with unstable syndromes. As with rotablation, adjunctive PTCA is often necessary. Can we say that one device is conspicuously better than the others? No: these devices are complementary to PTCA and to each other; all three are 30-100% more expensive than standard balloons. DCA for clinically stable patients is about one-third more expensive overall than standard PTCA.24 These costs might be offset in the long-term if the devices reduce acute complication and restenosis rates. Mechanical atherectomy is not trouble free: coronary perforation is an occasional hazard.25 In most patients deemed suitable for coronary intervention PTCA will remain the best option. Proximal eccentric
lesions
be best treated with DCA; calcific, resistant, or tortuous lesions by rotablation; and graft or thrombotic lesions with TEC. In addition, DCA
might
6.
Findlay IN, MacLeod K, Ford M, Gillen G, Elliott AT, Dargie HJ. Treatment of angina with nifedipine and atenolol: efficacy and effect on‘ cardiac function. Br Heart J 1986; 55: 240-45. 7. Parmley WW, Nesto RW, Singh BN, Deanfield J, Gottlieb SO. Attenuation of the circadian patterns of myocardial ischemia with nifedipine GITS in patients with chronic stable angina. N-CAP Study
Group. JACC 1992; 19: 1380-89. 8. TIBET Study Group. Total Ischemic Burden European Trial (TIBET): effect of treatment on exercise and Holter ECG in angina. Circulation 1992; 86: no 4, I-713 abstr: 28-39. 9. Krakoff LR, Bravo EL, Tuck ML, Friedman CP, and the Modem Approach to the Treatment of Hypertension (MATH) Study Group. Am J Hypertens 1990; 3: 318S-25S. 10. Houston MC, Olafsson L, Burger MC. Effects of nifedipine GITS and atenolol monotherapy on serum lipids, blood pressure, heart rate, and weight in mild to moderate hypertension. Angiology 1991; 42: 681-90. 11. DiPiro JT. Controlling drug effects through improved oral formulations. The pharmacokinetics of the prazosin gastrointestinal therapeutic systems. Am J Med 1989; 87: 31S-35S. 12. Tantucci C, Bruni B, Dottorini ML, et al. Comparative evaluation of cardioselectivity of metoprolol OROS and atenolol: a double blind, placebo controlled crossover study. Am Heart J 1990; 120: 467-72.
Botulinum toxin Botulinum toxin type A (BtA) is one of seve] immunologically distinct neurotoxins produced b: the bacterium Clostridium botulinum. Injection of ; small amount of the toxin into a muscle selectivel; weakens it by irreversibly blocking the release o
acetylcholine at the neuromuscular junction. Muscle injected atrophy and become weak over 2-20 day
so
2-4 months as new terminal axor form and restore transmission.1 sprouts BtA was first used in human beings in 1979 to treai strabismus2 and is now recognised as a safe anc effective symptomatic therapy for hemifacial spasm blepharospasm, cervical dystonia (torticollis), jawclosing oromandibular dystonia, and adductoi laryngeal dysphonia.3 In lateral rectus palsy and acquired esotropia BtA is useful in preoperative assessment and may be curative.4 In dysthyroid myopathy with strabismus5 the toxin can reduce prism correction and help to buy time before definitive surgery. BtA has been tried in many other conditions characterised by relative overactivity of a few muscles. The list includes orofacial dyskinesia, abductor laryngeal dysphonia, limb dystonias such as writer’s and musician’s cramp, movement disorders such as voice and head tremor, oscillopsia, bruxism, tics, focal cramps, and spasticity, and urinary and anal sphincter dysfunction.6Spontaneous fluctuations in severity of disease and crude rating scales make benefit difficult to evaluate and there is a significant placebo response.7 Moreover, many of the reported successes come from open or small studies. The temporary nature of BtA-induced paralysis is useful because side-effects are transient, and sometimes temporary weakness is all that is required. For example, induction of a temporary protective ptosis by injection of levator palpebrae superioris can be used to avoid surgical tarsorrhaphy. However, in most conditions, a long-term effect is wanted and this calls for repeated injections. Injection techniques have not been standardised. In and
recover over
muscles for injection are identified by clinical assessment of pain, muscle hypertrophy, and abnormal activity and posture. This approach may be adequate, but electromyography sometimes reveals muscle activity that is not clinically apparent. Finetuning of muscle selection with electromyography may be beneficial8 and theoretically could also reduce the dose or frequency of injections. In some disorders electromyography is essential for accurate placement of toxin in the selected muscles. Short-term side-effects are mostly minor and well tolerated, spread of toxin causing weakness of nearby muscles and local autonomic dysfunction. The main danger comes with injections around the neck, which can occasionally cause dysphagia and aspiration of fluid into the lungs. Systemic spread of toxin has been detected by electromyography9 but this does not lead to clinically detectable generalised weakness with standard doses of BtA. A few patients have experienced a flu-like illness or brachial neuritis which suggests an acute immune response. 10 These events do not preclude further injections. Although serious long-term side-effects have not been noted, doctors should remain vigilant, especially since there are no animal toxicity studies with repeated injections. There is little agreement about an assay for the three preparations of the toxin-haemagglutinin complex and there is a 3-5-fold difference in potency between them. Relative potencies may change according to the condition treated, perhaps because the preparations disperse differently in tissues, and "effective" doses vary between centres. This lack of standardisation is most centres
clearly unsatisfactory. The best long-term treatment strategy is uncertain. Most patients continue to respond even after 5-10 years and 20-30 treatments, although symptoms are seldom abolished and adjuvant conventional should not be withheld. In some cases of loss of efficacy toxin neutralising antibodies can be detected. We do not know whether one preparation is more antigenic than another, or whether dose or frequency of treatment is an important factor.66 Other serotypes of botulinum toxin that do not cross-react have been investigated. Type F has already proved effective in patients with torticollis who have become resistant to BtA and who have antitoxin antibodies.l1 Although the toxin moiety itself is known to be antigenic, toxin neutralising antibodies could also arise from other parts of the BtA-haemagglutinin complex, so a different preparation of BtA might be worth trying. A purer form of BtA would allow us to explore this possibility. treatment
1. Alderson
K, Holds JB, Anderson RL. Botulinum-induced alteration of nerve-muscle interactions in the human orbicularis oculi following treatment for blepharospasm. Neurology 1991; 41: 1800-05. 2. Scott AB. Botulinum toxin injections into extra ocular muscles as an alternative to strabismus surgery. Ophthalmology 1980; 87: 1044-49. 3. Therapeutics and Technology Subcommittee of the American Academy of Neurology. Assessment: the clinical usefulness of botulinum toxin-A in treating neurologic disorders. Neurology 1990; 40: 1332-36 4. Riordan-Ever P, Lee JP. Management of VIth nerve palsy avoiding unnecessary surgery. Eye 1992; 6: 386-90.
1509
Lyons CJ, Vickers SF, Lee JP. Botulinum toxin therapy in dysthyroid strabismus. Eye 1990; 4: 538-40. 6. Oates JA, Wood AJJ. Therapeutic uses of botulinum toxin. N Engl J Med 5.
1991; 324: 1186-94. 7. Moore AP, Blumhardt LD. Double blind study of botulinum toxin A in torticollis (with one year follow up). J Neurol Neurosurg Psychiatry 1991; 54: 813-16. 8. Comella CL, Buchman AS, Tanner CM, Brown-Toms NC, Goetz CG. Botulinum toxin injection for spasmodic torticollis: increased
magnitude of benefit with electromyographic assistance. Neurology 1992; 42: 878-82.
Lange D J, Brin MF, Warner CL, Fahn S, Lovelace RE. Distant effects of local injection of botulinum toxin. Muscle Nerve 1987; 10: 552-55. 10. Glanzman RL, Gelb DJ, Drury I, Bromberg MB, Truong DD. Brachial plexopathy after botulinum toxin injection. Neurology 1990; 40: 1143. 11. Ludlow CL, Hallett M, Rhew K, et al. Therapeutic use of type F botulinum toxin. N Engl J Med 1992; 326: 349-50. 9.
Mechanical coronary atherectomy Percutaneous transluminal coronary angioplasty (PTCA) has three main limitations (a) unsuccessful or inadequate balloon dilatation in 10-20% of patients; (b); acute vessel closure in 4-7%; and (c) restenosis in 25-50%. To overcome these drawbacks, balloon technology has been improved, intracoronary stents have been introduced, and in an attempt to "debulk" lesions effectively and safely, laser technology and mechanical atherectomy or ablative devices have been developed. Three catheter-mounted mechanical devices are available, although two are still investigational. For directional coronary atherectomy (DCA), a rigid metal cylinder with a 10 mm long window over about a quarter of its circumferencesis inserted into a coronary artery over a standard guide wire. The window is positioned against the atheromatous plaque; inflation of a balloon on the opposite side of the device under low pressure stabilises the window against the lesion, and then a cup-shaped circumferential blade, rotating at 2000 rpm, is advanced along the cylinder, excising the atheroma and pushing it into the nose cone. Usually DCA alone produces a satisfactory angiographic result, but adjunctive balloon PTCA may be required. The primary success rate of DCA is 80-98%, depending on the type of lesion,6-9 with about equal efficacy in native vessels, restenosis lesions, and grafts, although distal embolisation of graft atheroma may occur.1O Because of its size and rigidity, the device is most suited to bulky eccentric lesions in proximal straight segments of coronary arteries. There is a 1-4% acute closure rate. Hopes that the excellent angiographic appearances achieved with DCA would be associated with low restenosis rates have not been realised, but the rate is below 25% for the largest arteries." Although the reported success and complication rates are generally no different from those of PTCA, use of DCA has largely been restricted to complex lesions, unstable syndromes, or acute complications of PTCA. There is some evidence of a lower acute complication rate with DCA.12,13 The two techniques are being compared in several trials—eg, CAVEAT (coronary angioplasty
excisional atherectomy trial) I and II and the Canadian Coronary Atherectomy Trial. Initial results of CAVEAT reported at the American Heart versus
Association Meeting in New Orleans last month showed an 8% higher procedural success rate with better DCA, postprocedural angiographic and an lower restenosis 8-9% 6-month appearances, rate.
In percutaneous transluminal coronary rotational ablation ("rotablation") a small burr is mounted on a narrow drive shaft which tracks along a fine guide wire.14,15 The front face of the burr is studded with diamond microchips (30-50 ). Driven by compressed air, the burr rotates at 140 000-190 000 rpm. Atheromatous plaque protruding into the lumen is emulsified into small particles (generally less than 10 pm) which pass through the coronary microcirculation and are subsequently picked up by the reticuloendothelial system. With larger burr sizes, the fragments can be larger and can cause distal microembolisation. This complication may account for the non-Q-wave infarct rate of 1-6%, which rises to 19% in diffuse disease;16.17 one recommendation is to start with a small burr and work up. Because of the limited size of the burrs (1-0-2-5 mm), the final angiographic result may not be ideal, and adjunctive balloon PTCA is often necessary. Success rates of rotablation in complex lesions are now 90-95%.’ Overall acute closure rate is 2-8%,16,17,20,21 related to thrombus, dissection, or spasm. As with DCA, this device has not had a major impact on restenosis rates. The most likely application will be for specific lesions that are not suitable for either PTCA or DCA--eg, calcific lesions, those resistant to standard PTCA, and those in tortuous vessels. With the transluminal extraction endarterectomy catheter (TEC) the device likewise tracks along a standard guide wire. Two blades form the sides of what would otherwise be a conical tip, which rotates at 750 rpm and excised debris is aspirated through the central channel. 22 The primary success rate exceeds 90%.23 The device has been used in graft lesions and after thrombus aspiration in patients with unstable syndromes. As with rotablation, adjunctive PTCA is often necessary. Can we say that one device is conspicuously better than the others? No: these devices are complementary to PTCA and to each other; all three are 30-100% more expensive than standard balloons. DCA for clinically stable patients is about one-third more expensive overall than standard PTCA.24 These costs might be offset in the long-term if the devices reduce acute complication and restenosis rates. Mechanical atherectomy is not trouble free: coronary perforation is an occasional hazard.25 In most patients deemed suitable for coronary intervention PTCA will remain the best option. Proximal eccentric
lesions
be best treated with DCA; calcific, resistant, or tortuous lesions by rotablation; and graft or thrombotic lesions with TEC. In addition, DCA
might
