- Email: [email protected]
OCCUPANCY APPROACH TO COLCHICINE DOSAGE
1250
Secondly, Mrs. Tomlinson suggests that serious and permanent damage could result. This suggestion is based on the erroneous assumption that the toes take up the claw position in exercise-sandals. This has no doubt raised in people’s minds the picture of claw-toes or claw-foot, as seen in idiopathic pes cavus and rheumatoid arthritis. No-one who has worn exercise-sandals would credit this. Postural deformity can only cause fixed deformity if an abnormal posture is rigidly maintained. Exercise-sandals cannot be worn with the metatarsophalangeal joint hyperextended and the interphalangeal joints hyperflexed as seen in these pathological conditions. In fact, the sandals demand the normal synergic action of the flexor digitorum longus, flexor hallucis longus, flexor digitorum brevis, the lumbricals, and the interossei. Exercise-sandals are widely used by hospital workers. I myself have worn the kind made by’Dr. Scholl’. Patients and doctors alike have noted that many foot aches and pains disappear when correctly fitted exercise-sandals Robert Jones and Agnes Hunt
Orthopædic Hospital, Oswestry, Shropshire.
M. P. ROBINSON.
OCCUPANCY APPROACH TO COLCHICINE DOSAGE
SIR,-Orr et aLl have suggested a new pharmacokinetic method for the estimation of individual drug-dosage regimens, involving the concept of occupancy. The occupancy of a drug for a part of the body is the time during which a of the drug, administered in a particular way, quantity " occupies " a specified volume of that body compartment or tissue before the drug is metabolised or excreted. The calculation of occupancy, according to Orr et al., involves measuring the concentration of drug per unit volume of serum in regularly collected samples, adding these quantities together, dividing the resulting sum by the amount of drug administered in the test dose (expressed in the same units), and multiplying the result by the duration of the regular interval between samples. Once the occupancy in serum is determined, total daily dosage is determined by the formula: average serum-level Desired optimal Occupancy (hr.)
Total ota daily a1 y osage--
>
24
Orr and his co-workers estimated daily dosages of three antibacterial agents in illustration of the method. Implicit in their hypothesis is that the serum concentration of a drug is directly related to its therapeutic and toxic effects, and that sustained optimal serum concentrations are necessary Neither of these to accomplish a therapeutic result. assumptions is necessarily warranted. Darrell and Waterworth2 and Mitchison and Foxhave already contested the need for maintenance serum concentrations of drugs during therapy, Mitchison and Fox pointing out that for certain antituberculosis agents intermittent therapy is as effective as sustained. All three sets of workers, however, limited their considerations of this new pharmacokinetic approach to antibacterial drugs. We have devised a new method for measuring colchicine in body fluids and cells, and have completed studies of plasma4 and leucocyte5 colchicine concentrations after intravenous administration of single doses of therapeutic size. Colchicine disappears from plasma very rapidly Orr, J. S., Shimmins, J., Speirs, C. F. Lancet, 1969, ii, 771. Darrell, J. H., Waterworth, P. M. ibid. p. 1069. Mitchison, D. A., Fox, W. ibid. Wallace, S. L., Omokoku, B., Ertel, N. H. Am. J. Med. 1970, 43, 443. Ertel, N. H., Omokoku, B., Wallace, S. L. Arthritis Rheum. 1969, 12, 293.
less than 20 minutes).4 Leucocyte-colchicine concentrations, as late as 72 hours after administration, are significantly greater than the highest plasma concentrations, and at that time they are more than five times the plasma concentration at 15 minutes.5 Malawista 6 has summarised evidence suggesting strongly that colchicine exerts its beneficial effect in the treatment of acute gout by acting on the polymorphonuclear leucocyte. It seemed of interest, therefore, to calculate and contrast the occupancies of colchicine in plasma and in leucocytes. Fig. 1 summarises mean plasma-colchicine concentrations in five patients selected for the absence of significant renal or hepatic disease or hyperuricaemia, after intravenous administration of 2 mg. colchicine. Using the formula of Orr et al., colchicine occupancy of 100 ml. of plasma in these patients averaged 0-078 minutes. Fig. 2 presents
(half-time
are worn.
1. 2. 3. 4. 5.
Fig. I-Plasma-colchicine concentrations.
_
_.
._
__
HOURS
Fig. 2-Leucocyte-colchicine concentrations.
colchicine concentrations per 100 ml. of leucocyte’ in three patients, selected similarly for the absence oj kidney or liver disease or hyperuricoemia, after intravenous administration of 3 mg. of colchicine. Colchicine occupancy of 100 ml. of leucocytes in these patients was 53.1 minutes. Since a therapeutically effective single intravenous dose of colchicine produces such a short plasma half-time, there " can be no point in making calculations based on desired optimal average serum (or plasma) level", at least foi colchicine. Substituting leucocyte occupancy and " desired optimal average " leucocyte concentration in the formula would seem more logical. However, since considerable leucocyte concentrations of colchicine persist for more than three days after one intravenous administration, even here mean
6.
Malawista, S. E. ibid. 1968, 11, 191.
1251 the occupancy approach to calculating dosages does not work without further modification. At least for colchicine, the Orr method seems an oversimnlification. Jewish Hospital
and
Medical Center of Brooklyn, N.Y. 11238.
STANLEY L. WALLACE NORMAN H. ERTEL.
TEMPERATURE REGULATION DURING FEVER
SiR,-The hypothesis advanced by Dr. Roberts (Nov. 14, 1015) is not supported by the evidence available. In essence, his hypothesis is that fever is initiated by sweating, which cools the skin and increases the activity of coldsensitive thermoreceptors. The shivering which this induces raises deep body temperature until a break-point " is reached, when defervescence occurs. This proposition is at variance with the following evidence: p.
"
1. Changes in deep body temperature of less than 0’2°C will induce appropriate peripheral vasomotor responses in normal individuals, and during feverwhether caused by disease or injection of pyrogen. 2. According to Dr. Roberts’s hypothesis, cooling the skin of normal individuals should induce fever. In fact, sudden cooling causes reflex vasoconstriction with a small transient rise in deep body temperature of less than 0.1 oC.3 3. Pyrogen injections given to normal subjects with a high sweat-rate caused a reduction in sweating.4 4. Between us, we have received at least a dozen infusions or injections of autologous endogenous pyrogen. We cannot recall sweating at any time except during defervescence.
only observation of Dr. Roberts that is in serious disagreement with currently accepted views on temperature regulation is the simultaneous occurrence of peripheral vasoconstriction and a clammy skin. There are at least two possible explanations for this: firstly, a clammy skin does not necessarily imply active sweating (some moisture may have remained on the skin following earlier defervescence); secondly, not all sweating is thermoregulatory (fear and hypoglycoemia, for example, will increase sweat secretion). The
Department of Medicine, St. Thomas’s Hospital Medical School, London S.E.1.
W. I. CRANSTON M. D. RAWLINS.
L.S.D. IN PSYCHIATRY SIR,-Over the past year I have seen 9 male students who admitted ingestion of L.S.D. (and usually also cannabis) out of some 570 total consulters, two-thirds of whom were male. No women admitted taking it. All the L.s.D.-takers had psychological problems with oedipal features before ingestion, and had new experiences with the drug such as release, acting out, mania, psychodelia, paranoid features, or acute anxiety, hostility, and destructiveness. In 3 other cases L.s.D.-taking was suspected. These had more prolonged schizophrenic illnesses. People who take L.S.D. often have profound interpersonal oral stage-leading them to problems of early origin-e.g., seek self-realisation in a " trip " involving regressive perceptions. The therapist often feels he too is going for a ride back through the classical psychoanalytical stages to the womb. This happens particularly with patients with knowledge of developmental psychology. The patient’s relationship with the doctor may be like " good and bad" feeds, and he may avoid psychotherapy and prefer his own medicine to relieve feelings of impotence. Naturally he finds that L.S.D. is also a mixture of good and bad. The 1. Gerbrandy, J., Snell, E. S., Cranston, W. I. Clin. Sci. 1954, 13, 615. 2. Cooper, K. E., Cranston, W. I., Snell, E. S. ibid. 1964, 27, 345. 3. Cranston, W. I., Gerbrandy, J., Snell, E. S. J. Physiol., Lond. 1954, 126, 347. 4. Bannister, R. G. Lancet, 1960, ii, 118.
patient
not
under medical treatment, having a trip on his so insightful as to know why he is doing it.
own, may not be
Indeed, insight and L.S.D. are painful experiences. In clinical psychiatry, L.S.D. is used in the hope that the mind-expanding properties of the drug will help in giving insight. It is up to those who advocate this use of L.S.D. to show its safety. Central Hospital, Near Warwick.
T. L. AVERY.
REVERSIBLE LEFT-VENTRICULAR FAILURE IN ANGINA PECTORIS SiR,—The interesting paper by Dr. Sharma and Dr. Taylor (Oct. 31, p. 902) shows that the left ventricle is distended in angina pectoris. They find that, of the four primary determinants of left-ventricular oxygen consumption, only the end-diastolic pressure, which is usually taken as a measure of left-ventricular end-diastolic size, is significantly increased during angina. This confirms that there is acute left-ventricular distension during an attack of angina. The other parameters of left-ventricular failure remain unaltered. This suggests that distension of the left ventricle may be the sole finding in their cases, which is not necessarily synonymous with left-ventricular failure. the atrial gallop sound and the raised pulmonary However, " wedge " pressure found during attacks of anginal pain has always suggested that the pain is accompanied by left-ventricular failure. Sharma and Taylor do not attempt to relate their findings to the mechanism of how anginal pain is produced. It is doubtful whether hypoxia is the sole cause of anginal pain. An alternative to the ischsemic theory for the production of angina was first proposed by Merklen in 1908.1 He suggested, on the basis of clinical observations, that acute left-ventricular distension was responsible for angina. We have reported 2 the case of a patient with angina, sinus bradycardia, and inability to increase the heart-rate by more than ten beats per minute on severe exertion. The coronary arteries were normal, as judged by the cardiogram and selective coronary angiography. Acceleration of the heart by atrial pacing produced a virtually normal exercise capacity. Angina during exercise could be produced and relieved within two beats by stopping and starting the pacemaker. The normal coronary arteriogram and extremely rapid onset and cessation of pain made it unlikely that ischxmic metabolites were responsible. This investigation, together with clinical observations on angina produced by sudden slowing of the heart due to transient heart-block,3 led us to define an anginal syndrome due to relative or absolute bradycardia-bradycardia angina.44 These clinical observations in bradycardia angina can only be explained on Merklen’s hypothesis of acute chamber distension as the afferent stimulus in the production of angina. Sharma and Taylor’s work suggests that it is the same acute distension which accounts for the pain in all cases of angina pectoris. Perhaps the final evidence in support of Merklen’s hypothesis is the drastic experiment of producing and relieving angina by loading and unloading the circulation with blood.5 Charing Cross Hospital, London W.C.2.
P. B. S. FOWLER HAMID IKRAM.
Merklen, M. J. F. P. Leçons sur les troubles fonctionnels du coeur Paris, 1908. 2. Fowler, P. B. S., Ikram, H., Maini, R. N., Makey, A. R., Kirkham J. S. Br. med. J. 1969, i, 92. 3. Fowler, P. B. S. ibid. 1962, ii, 1638. 4. Fowler, P. B. S., Ikram, H., Maini, R. N. Am. Heart J. 1970, 80, 288 5. Parker, J. O., Case, R. B., Khaja, F., Ledwich, J. R., Armstrong P. W. Circulation, 1970, 41, 593. 1.
Secondly, Mrs. Tomlinson suggests that serious and permanent damage could result. This suggestion is based on the erroneous assumption that the toes take up the claw position in exercise-sandals. This has no doubt raised in people’s minds the picture of claw-toes or claw-foot, as seen in idiopathic pes cavus and rheumatoid arthritis. No-one who has worn exercise-sandals would credit this. Postural deformity can only cause fixed deformity if an abnormal posture is rigidly maintained. Exercise-sandals cannot be worn with the metatarsophalangeal joint hyperextended and the interphalangeal joints hyperflexed as seen in these pathological conditions. In fact, the sandals demand the normal synergic action of the flexor digitorum longus, flexor hallucis longus, flexor digitorum brevis, the lumbricals, and the interossei. Exercise-sandals are widely used by hospital workers. I myself have worn the kind made by’Dr. Scholl’. Patients and doctors alike have noted that many foot aches and pains disappear when correctly fitted exercise-sandals Robert Jones and Agnes Hunt
Orthopædic Hospital, Oswestry, Shropshire.
M. P. ROBINSON.
OCCUPANCY APPROACH TO COLCHICINE DOSAGE
SIR,-Orr et aLl have suggested a new pharmacokinetic method for the estimation of individual drug-dosage regimens, involving the concept of occupancy. The occupancy of a drug for a part of the body is the time during which a of the drug, administered in a particular way, quantity " occupies " a specified volume of that body compartment or tissue before the drug is metabolised or excreted. The calculation of occupancy, according to Orr et al., involves measuring the concentration of drug per unit volume of serum in regularly collected samples, adding these quantities together, dividing the resulting sum by the amount of drug administered in the test dose (expressed in the same units), and multiplying the result by the duration of the regular interval between samples. Once the occupancy in serum is determined, total daily dosage is determined by the formula: average serum-level Desired optimal Occupancy (hr.)
Total ota daily a1 y osage--
>
24
Orr and his co-workers estimated daily dosages of three antibacterial agents in illustration of the method. Implicit in their hypothesis is that the serum concentration of a drug is directly related to its therapeutic and toxic effects, and that sustained optimal serum concentrations are necessary Neither of these to accomplish a therapeutic result. assumptions is necessarily warranted. Darrell and Waterworth2 and Mitchison and Foxhave already contested the need for maintenance serum concentrations of drugs during therapy, Mitchison and Fox pointing out that for certain antituberculosis agents intermittent therapy is as effective as sustained. All three sets of workers, however, limited their considerations of this new pharmacokinetic approach to antibacterial drugs. We have devised a new method for measuring colchicine in body fluids and cells, and have completed studies of plasma4 and leucocyte5 colchicine concentrations after intravenous administration of single doses of therapeutic size. Colchicine disappears from plasma very rapidly Orr, J. S., Shimmins, J., Speirs, C. F. Lancet, 1969, ii, 771. Darrell, J. H., Waterworth, P. M. ibid. p. 1069. Mitchison, D. A., Fox, W. ibid. Wallace, S. L., Omokoku, B., Ertel, N. H. Am. J. Med. 1970, 43, 443. Ertel, N. H., Omokoku, B., Wallace, S. L. Arthritis Rheum. 1969, 12, 293.
less than 20 minutes).4 Leucocyte-colchicine concentrations, as late as 72 hours after administration, are significantly greater than the highest plasma concentrations, and at that time they are more than five times the plasma concentration at 15 minutes.5 Malawista 6 has summarised evidence suggesting strongly that colchicine exerts its beneficial effect in the treatment of acute gout by acting on the polymorphonuclear leucocyte. It seemed of interest, therefore, to calculate and contrast the occupancies of colchicine in plasma and in leucocytes. Fig. 1 summarises mean plasma-colchicine concentrations in five patients selected for the absence of significant renal or hepatic disease or hyperuricaemia, after intravenous administration of 2 mg. colchicine. Using the formula of Orr et al., colchicine occupancy of 100 ml. of plasma in these patients averaged 0-078 minutes. Fig. 2 presents
(half-time
are worn.
1. 2. 3. 4. 5.
Fig. I-Plasma-colchicine concentrations.
_
_.
._
__
HOURS
Fig. 2-Leucocyte-colchicine concentrations.
colchicine concentrations per 100 ml. of leucocyte’ in three patients, selected similarly for the absence oj kidney or liver disease or hyperuricoemia, after intravenous administration of 3 mg. of colchicine. Colchicine occupancy of 100 ml. of leucocytes in these patients was 53.1 minutes. Since a therapeutically effective single intravenous dose of colchicine produces such a short plasma half-time, there " can be no point in making calculations based on desired optimal average serum (or plasma) level", at least foi colchicine. Substituting leucocyte occupancy and " desired optimal average " leucocyte concentration in the formula would seem more logical. However, since considerable leucocyte concentrations of colchicine persist for more than three days after one intravenous administration, even here mean
6.
Malawista, S. E. ibid. 1968, 11, 191.
1251 the occupancy approach to calculating dosages does not work without further modification. At least for colchicine, the Orr method seems an oversimnlification. Jewish Hospital
and
Medical Center of Brooklyn, N.Y. 11238.
STANLEY L. WALLACE NORMAN H. ERTEL.
TEMPERATURE REGULATION DURING FEVER
SiR,-The hypothesis advanced by Dr. Roberts (Nov. 14, 1015) is not supported by the evidence available. In essence, his hypothesis is that fever is initiated by sweating, which cools the skin and increases the activity of coldsensitive thermoreceptors. The shivering which this induces raises deep body temperature until a break-point " is reached, when defervescence occurs. This proposition is at variance with the following evidence: p.
"
1. Changes in deep body temperature of less than 0’2°C will induce appropriate peripheral vasomotor responses in normal individuals, and during feverwhether caused by disease or injection of pyrogen. 2. According to Dr. Roberts’s hypothesis, cooling the skin of normal individuals should induce fever. In fact, sudden cooling causes reflex vasoconstriction with a small transient rise in deep body temperature of less than 0.1 oC.3 3. Pyrogen injections given to normal subjects with a high sweat-rate caused a reduction in sweating.4 4. Between us, we have received at least a dozen infusions or injections of autologous endogenous pyrogen. We cannot recall sweating at any time except during defervescence.
only observation of Dr. Roberts that is in serious disagreement with currently accepted views on temperature regulation is the simultaneous occurrence of peripheral vasoconstriction and a clammy skin. There are at least two possible explanations for this: firstly, a clammy skin does not necessarily imply active sweating (some moisture may have remained on the skin following earlier defervescence); secondly, not all sweating is thermoregulatory (fear and hypoglycoemia, for example, will increase sweat secretion). The
Department of Medicine, St. Thomas’s Hospital Medical School, London S.E.1.
W. I. CRANSTON M. D. RAWLINS.
L.S.D. IN PSYCHIATRY SIR,-Over the past year I have seen 9 male students who admitted ingestion of L.S.D. (and usually also cannabis) out of some 570 total consulters, two-thirds of whom were male. No women admitted taking it. All the L.s.D.-takers had psychological problems with oedipal features before ingestion, and had new experiences with the drug such as release, acting out, mania, psychodelia, paranoid features, or acute anxiety, hostility, and destructiveness. In 3 other cases L.s.D.-taking was suspected. These had more prolonged schizophrenic illnesses. People who take L.S.D. often have profound interpersonal oral stage-leading them to problems of early origin-e.g., seek self-realisation in a " trip " involving regressive perceptions. The therapist often feels he too is going for a ride back through the classical psychoanalytical stages to the womb. This happens particularly with patients with knowledge of developmental psychology. The patient’s relationship with the doctor may be like " good and bad" feeds, and he may avoid psychotherapy and prefer his own medicine to relieve feelings of impotence. Naturally he finds that L.S.D. is also a mixture of good and bad. The 1. Gerbrandy, J., Snell, E. S., Cranston, W. I. Clin. Sci. 1954, 13, 615. 2. Cooper, K. E., Cranston, W. I., Snell, E. S. ibid. 1964, 27, 345. 3. Cranston, W. I., Gerbrandy, J., Snell, E. S. J. Physiol., Lond. 1954, 126, 347. 4. Bannister, R. G. Lancet, 1960, ii, 118.
patient
not
under medical treatment, having a trip on his so insightful as to know why he is doing it.
own, may not be
Indeed, insight and L.S.D. are painful experiences. In clinical psychiatry, L.S.D. is used in the hope that the mind-expanding properties of the drug will help in giving insight. It is up to those who advocate this use of L.S.D. to show its safety. Central Hospital, Near Warwick.
T. L. AVERY.
REVERSIBLE LEFT-VENTRICULAR FAILURE IN ANGINA PECTORIS SiR,—The interesting paper by Dr. Sharma and Dr. Taylor (Oct. 31, p. 902) shows that the left ventricle is distended in angina pectoris. They find that, of the four primary determinants of left-ventricular oxygen consumption, only the end-diastolic pressure, which is usually taken as a measure of left-ventricular end-diastolic size, is significantly increased during angina. This confirms that there is acute left-ventricular distension during an attack of angina. The other parameters of left-ventricular failure remain unaltered. This suggests that distension of the left ventricle may be the sole finding in their cases, which is not necessarily synonymous with left-ventricular failure. the atrial gallop sound and the raised pulmonary However, " wedge " pressure found during attacks of anginal pain has always suggested that the pain is accompanied by left-ventricular failure. Sharma and Taylor do not attempt to relate their findings to the mechanism of how anginal pain is produced. It is doubtful whether hypoxia is the sole cause of anginal pain. An alternative to the ischsemic theory for the production of angina was first proposed by Merklen in 1908.1 He suggested, on the basis of clinical observations, that acute left-ventricular distension was responsible for angina. We have reported 2 the case of a patient with angina, sinus bradycardia, and inability to increase the heart-rate by more than ten beats per minute on severe exertion. The coronary arteries were normal, as judged by the cardiogram and selective coronary angiography. Acceleration of the heart by atrial pacing produced a virtually normal exercise capacity. Angina during exercise could be produced and relieved within two beats by stopping and starting the pacemaker. The normal coronary arteriogram and extremely rapid onset and cessation of pain made it unlikely that ischxmic metabolites were responsible. This investigation, together with clinical observations on angina produced by sudden slowing of the heart due to transient heart-block,3 led us to define an anginal syndrome due to relative or absolute bradycardia-bradycardia angina.44 These clinical observations in bradycardia angina can only be explained on Merklen’s hypothesis of acute chamber distension as the afferent stimulus in the production of angina. Sharma and Taylor’s work suggests that it is the same acute distension which accounts for the pain in all cases of angina pectoris. Perhaps the final evidence in support of Merklen’s hypothesis is the drastic experiment of producing and relieving angina by loading and unloading the circulation with blood.5 Charing Cross Hospital, London W.C.2.
P. B. S. FOWLER HAMID IKRAM.
Merklen, M. J. F. P. Leçons sur les troubles fonctionnels du coeur Paris, 1908. 2. Fowler, P. B. S., Ikram, H., Maini, R. N., Makey, A. R., Kirkham J. S. Br. med. J. 1969, i, 92. 3. Fowler, P. B. S. ibid. 1962, ii, 1638. 4. Fowler, P. B. S., Ikram, H., Maini, R. N. Am. Heart J. 1970, 80, 288 5. Parker, J. O., Case, R. B., Khaja, F., Ledwich, J. R., Armstrong P. W. Circulation, 1970, 41, 593. 1.