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A NEW MUSCLE RELAXANT
561
Annotations MUSCLE RELAXANT MuscLE relaxants have so far been used mainly in anaesthesia, where a short duration of action and the need for parenteral injection are not disadvantages. A new preparation, zoxazolamine (2-amino-5-chlorobenzoxazole), is active by mouth and has a relatively long action.l-3 It’seems to act centrally and to depress the subcortical and spinal polysynaptic pathways. It has essentially no action on the monosynaptic arcs, motor nerves, myoneural junctions, or striated muscle. Zoxazolamine thus resembles mephenesin rather than the peripheral neuromuscular blocking agents such as tubocurarine or suxamethonium. Given to animals, zoxazolamine can produce a flaccid paralysis lasting several hours without a significant change in consciousness, blood-pressure, or respiration. Repeated daily, oral doses in rats and dogs produced no cumulative or toxic effects. This new drug has been used in the treatment of spasticity caused by neurological disorders, and some preliminary reports have appealed. 4-6 Many conditions have been studied and the results have been variable. Clinical observation and electromyographic studies have confirmed that zoxazolamine is a mild muscle relaxant in some spastic states ; but its action varies from case to case and even in the same patient at different times. Unfortunately reduction of spasticity. does not necessarily mean improved voluntary control of limb movements, and it is often achieved at the expense of reduced muscle strength. A diminution in muscle tone has been noted, chiefly in patients with spinal-cord lesions ; and this has been associated with abolition of uncontrolled mass flexion movements and considerable subjectiveimprovement. The benefit in patients with spasticity of cortical origin and in paralysis agitans has been inconsistent and indefinite. The drug has also been used in patients with muscular stiffness and aching due to rheumatic diseases.7 Side-effects have not been unduly troublesome with doses up to 0-5 g. four times a day. The commonest have been nausea, vomiting, epigastric discomfort, and dizziness. Fever and transient skin rashes have occasionally been noted. No blood abnormalities have been A NEW
recorded. doubt that zoxazolamine has pharmacothat make it Chief amongst these are its effectiveness by mouth, duration of action, and low toxicity. But the benefit to be achieved by its use in spastic and rheumatic states cannot yet be assessed. Zoxazolamine can do nothing to the underlying disease, but by reducing spasticity it may aid physiotherapy and reablement. Conditions such as disseminated sclerosis and rheumatoid arthritis are notoriously variable in their course and this makes assessment of the drug difficult and it seems itself to be rather irregular in its behaviour after oral doses. No further conclusions can be drawn on the evidence we have seen so far. There is
no
logical properties as a muscle relaxant suitable for long-continued administration.
MENTAL DEFECT AND HYPSARRHYTHMIA Prof. R. S. Illingworth 8 has described twelve children in whom severe dementia and convulsive disorders developed rapidly between the ages of four and eight months. The striking feature was an abrupt change in social responsiveness ; motor and manipulative develop1. Marsh, D. F. Fed. Proc. 1955, 14, 366. 2. Kamijo, K., Koelle, G. B. Proc. Soc. exp.
Biol., N.Y. 1955, 88,
565. 3. Funderburk, W. H., Woodcock, R. T. Fed. Proc. 1955, 14, 341. 4. Amols, W. J. Amer. med. Ass. 1956, 160, 742. 5. Abrahamsen, E. H., Baird, H. W. Ibid, p. 749. 6. Rodriguez-Gomez, M., Valdes-Rodriguez, A., Drew, A. L. 7.
Ibid, p. 752. Smith, R. T., Kron, K. M., Peak,
8.
Illingworth,
W. P., Herman, I. F.
p. 745.
R. S. Arch. Dis. Childh. 1955, 30, 529.
Ibid,
ment were retained to a surprising degree. The initial fits were of various types, but later most of the children had salaam attacks. Neurological examination revealed no physical signs; but electro-encephalography showed the pattern which Gibbs et al.9 call hypsarrhythmia. This pattern consists in bursts of very-high-voltage slow waves, together with spike activity which shifts rapidly from site to site : the abnormalities are diffuse, and normal patches of record are not found. The hypsarrhythmic pattern is common in young epileptic children with massive damage involving the subcortical masses. The disorder described by Illingworth may be less unusual than is supposed because the characteristic epilepsy does not last long, nor does the E.E.G. pattern endure. One of the most striking features of the epilepsies of childhood is their sensitivity to maturation. Ounsted 10 has shown that the phenotypic expression of the convulsive genotype is rapidly overcome by maturation, and he has pointed out that this is true also of those epilepsies which go with hypsarrhythmia, and which stem from gross anatomical lesions: "The anatomical lesions remain ; the mental defect remains ; the characteristic E.E.G. pattern lingers on, but the fits themselves are inhibited by quite a slight advance in maturity." Research into the epileptic diseases of childhood has been much neglected in this country. Children of the type that Professor Illingworth has described formerly died young. They now live on, a burden of hopeless pity to those who care for them.
TUBERCULOSIS AFTER PARTIAL GASTRECTOMY DURING the past decade all too many defects have been attributed to partial gastrectomy ; and it seemed that an increased incidence of pulmonary tuberculosis might prove to be one. Forsgren 11 was one of the first to show that after partial gastrectomy patients were more liable to pulmonary tuberculosis and that the risk to them might be ten times greater than to the general population. In this country Pulvertaft,"- reviewing Visick’s cases, found that of 23 intercurrent deaths from a total of 632 patients 7 had been due to pulmonary tuberculosis and 1 to tuberculous meningitis. Bruce Pearson 13 reported 11 cases, 4 of which were found in a follow-up of 93 patients ; the other 7 were seen as cases of tuberculosis and could not therefore be measured as a proportion of a definite gastrectomy series. Tanner 14 was unable to demonstrate a prevalence of more than 5 per 1000 in the 403 patients submitted to mass radiography two to seven years after partial gastrectomy-the rate to be expected in the general public. But there were also 2 deaths from tuberculosis and 8 patients under treatment in the 611 consecutive cases of gastrectomy from whom the 403 were selected for mass radiography. These last figures are rather against Tanner’s view that there is no increased proneness to tuberculosis. Allison 15 described 21 cases but gave no indication as to incidence ; he suggested that " the faulty assimilation of nourishment together with metabolic imbalance brought about by chemical factors in the body, so lower a person’s resistance that tuberculosis is a likely sequel in a certain proportion of patients." Thorn et al.16 have now been more specific. They followed 955 patients in whom an X-ray examination of the chest was performed as a routine before partial gastrectomy, and they found that 6.3% had evidence of pulmonary tuberculosis before operation. In an admirable 9. 10. 11. 12.
13. 14. 15. 16.
Gibbs, E. L., Fleming, M. M., Gibbs, F. A. Pediatrics, 1954, 13, 66. Ounsted, C. Eugen. Rev. 1955, 47, 33. Forsgren, E. Svenska Läkartidn. 1947, 44, 1587 ; Ibid, 1948, 45, 700. Pulvertaft, C. N. Lancet, 1952, i, 225. Bruce Pearson, R. S. Postgrad. med. J. 1954, 30, 159 ; Gastroenterologia, Basel, 1954, 81, 91. Tanner, N. C. Postgrad. med. J. 1954, 30, 523. Allison, S. T. New Engl. J. Med. 1955, 252, 862. Thorn, P. A., Brookes, V. S., Waterhouse, J. A. H. Brit. med. J. March 17, 1956, p. 603.
Annotations MUSCLE RELAXANT MuscLE relaxants have so far been used mainly in anaesthesia, where a short duration of action and the need for parenteral injection are not disadvantages. A new preparation, zoxazolamine (2-amino-5-chlorobenzoxazole), is active by mouth and has a relatively long action.l-3 It’seems to act centrally and to depress the subcortical and spinal polysynaptic pathways. It has essentially no action on the monosynaptic arcs, motor nerves, myoneural junctions, or striated muscle. Zoxazolamine thus resembles mephenesin rather than the peripheral neuromuscular blocking agents such as tubocurarine or suxamethonium. Given to animals, zoxazolamine can produce a flaccid paralysis lasting several hours without a significant change in consciousness, blood-pressure, or respiration. Repeated daily, oral doses in rats and dogs produced no cumulative or toxic effects. This new drug has been used in the treatment of spasticity caused by neurological disorders, and some preliminary reports have appealed. 4-6 Many conditions have been studied and the results have been variable. Clinical observation and electromyographic studies have confirmed that zoxazolamine is a mild muscle relaxant in some spastic states ; but its action varies from case to case and even in the same patient at different times. Unfortunately reduction of spasticity. does not necessarily mean improved voluntary control of limb movements, and it is often achieved at the expense of reduced muscle strength. A diminution in muscle tone has been noted, chiefly in patients with spinal-cord lesions ; and this has been associated with abolition of uncontrolled mass flexion movements and considerable subjectiveimprovement. The benefit in patients with spasticity of cortical origin and in paralysis agitans has been inconsistent and indefinite. The drug has also been used in patients with muscular stiffness and aching due to rheumatic diseases.7 Side-effects have not been unduly troublesome with doses up to 0-5 g. four times a day. The commonest have been nausea, vomiting, epigastric discomfort, and dizziness. Fever and transient skin rashes have occasionally been noted. No blood abnormalities have been A NEW
recorded. doubt that zoxazolamine has pharmacothat make it Chief amongst these are its effectiveness by mouth, duration of action, and low toxicity. But the benefit to be achieved by its use in spastic and rheumatic states cannot yet be assessed. Zoxazolamine can do nothing to the underlying disease, but by reducing spasticity it may aid physiotherapy and reablement. Conditions such as disseminated sclerosis and rheumatoid arthritis are notoriously variable in their course and this makes assessment of the drug difficult and it seems itself to be rather irregular in its behaviour after oral doses. No further conclusions can be drawn on the evidence we have seen so far. There is
no
logical properties as a muscle relaxant suitable for long-continued administration.
MENTAL DEFECT AND HYPSARRHYTHMIA Prof. R. S. Illingworth 8 has described twelve children in whom severe dementia and convulsive disorders developed rapidly between the ages of four and eight months. The striking feature was an abrupt change in social responsiveness ; motor and manipulative develop1. Marsh, D. F. Fed. Proc. 1955, 14, 366. 2. Kamijo, K., Koelle, G. B. Proc. Soc. exp.
Biol., N.Y. 1955, 88,
565. 3. Funderburk, W. H., Woodcock, R. T. Fed. Proc. 1955, 14, 341. 4. Amols, W. J. Amer. med. Ass. 1956, 160, 742. 5. Abrahamsen, E. H., Baird, H. W. Ibid, p. 749. 6. Rodriguez-Gomez, M., Valdes-Rodriguez, A., Drew, A. L. 7.
Ibid, p. 752. Smith, R. T., Kron, K. M., Peak,
8.
Illingworth,
W. P., Herman, I. F.
p. 745.
R. S. Arch. Dis. Childh. 1955, 30, 529.
Ibid,
ment were retained to a surprising degree. The initial fits were of various types, but later most of the children had salaam attacks. Neurological examination revealed no physical signs; but electro-encephalography showed the pattern which Gibbs et al.9 call hypsarrhythmia. This pattern consists in bursts of very-high-voltage slow waves, together with spike activity which shifts rapidly from site to site : the abnormalities are diffuse, and normal patches of record are not found. The hypsarrhythmic pattern is common in young epileptic children with massive damage involving the subcortical masses. The disorder described by Illingworth may be less unusual than is supposed because the characteristic epilepsy does not last long, nor does the E.E.G. pattern endure. One of the most striking features of the epilepsies of childhood is their sensitivity to maturation. Ounsted 10 has shown that the phenotypic expression of the convulsive genotype is rapidly overcome by maturation, and he has pointed out that this is true also of those epilepsies which go with hypsarrhythmia, and which stem from gross anatomical lesions: "The anatomical lesions remain ; the mental defect remains ; the characteristic E.E.G. pattern lingers on, but the fits themselves are inhibited by quite a slight advance in maturity." Research into the epileptic diseases of childhood has been much neglected in this country. Children of the type that Professor Illingworth has described formerly died young. They now live on, a burden of hopeless pity to those who care for them.
TUBERCULOSIS AFTER PARTIAL GASTRECTOMY DURING the past decade all too many defects have been attributed to partial gastrectomy ; and it seemed that an increased incidence of pulmonary tuberculosis might prove to be one. Forsgren 11 was one of the first to show that after partial gastrectomy patients were more liable to pulmonary tuberculosis and that the risk to them might be ten times greater than to the general population. In this country Pulvertaft,"- reviewing Visick’s cases, found that of 23 intercurrent deaths from a total of 632 patients 7 had been due to pulmonary tuberculosis and 1 to tuberculous meningitis. Bruce Pearson 13 reported 11 cases, 4 of which were found in a follow-up of 93 patients ; the other 7 were seen as cases of tuberculosis and could not therefore be measured as a proportion of a definite gastrectomy series. Tanner 14 was unable to demonstrate a prevalence of more than 5 per 1000 in the 403 patients submitted to mass radiography two to seven years after partial gastrectomy-the rate to be expected in the general public. But there were also 2 deaths from tuberculosis and 8 patients under treatment in the 611 consecutive cases of gastrectomy from whom the 403 were selected for mass radiography. These last figures are rather against Tanner’s view that there is no increased proneness to tuberculosis. Allison 15 described 21 cases but gave no indication as to incidence ; he suggested that " the faulty assimilation of nourishment together with metabolic imbalance brought about by chemical factors in the body, so lower a person’s resistance that tuberculosis is a likely sequel in a certain proportion of patients." Thorn et al.16 have now been more specific. They followed 955 patients in whom an X-ray examination of the chest was performed as a routine before partial gastrectomy, and they found that 6.3% had evidence of pulmonary tuberculosis before operation. In an admirable 9. 10. 11. 12.
13. 14. 15. 16.
Gibbs, E. L., Fleming, M. M., Gibbs, F. A. Pediatrics, 1954, 13, 66. Ounsted, C. Eugen. Rev. 1955, 47, 33. Forsgren, E. Svenska Läkartidn. 1947, 44, 1587 ; Ibid, 1948, 45, 700. Pulvertaft, C. N. Lancet, 1952, i, 225. Bruce Pearson, R. S. Postgrad. med. J. 1954, 30, 159 ; Gastroenterologia, Basel, 1954, 81, 91. Tanner, N. C. Postgrad. med. J. 1954, 30, 523. Allison, S. T. New Engl. J. Med. 1955, 252, 862. Thorn, P. A., Brookes, V. S., Waterhouse, J. A. H. Brit. med. J. March 17, 1956, p. 603.