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DISCREPANCY BETWEEN SOLUTION AND BIOAVAILABILITY OF DIGOXIN TABLETS
629 circumstances of
SCLEROSING PERITONITIS AND PRACTOLOL
practice. Fortunately, screening is now being carried out, and If properly more is being planned, in many countries. there is little doubt that will result. benefit great applied, At present, mass community screening, as described by
SIR,—We should like to add two more possible cases of practolol-induced sclerosing peritonitis to the three reported by Brown et al.1 A 64-year-old woman with atrial fibrillation and attacks of chest pain associated with supraventricular tachycardia was
best ways of
doing
so
under
varying
Hawthorne, is essential for research. Like Tudor Hart and
Coope, we favour routine screening by health examinations in general practice, and in Edinburgh pilot studies by various methods are being carried out. The view of a small group of epidemiologists should not influence Governments and health authorities to delay such projects. If they did so, it could be disastrous at a time when encouragement with financial support is needed. How long do they intend to wait for the results of more research into behavioural problems before taking any action ? Ten years ? Meanwhile a veritable mountain of human misery would have grown. How much more satisfactory it would have been if your final article, reflecting the clinical experience, had concluded, as do Kannel and Dawber, that hypertension is the most common, potent, easily detected, and readily controlled of the major contributors to cardiovascular morbidity and mortality. 12
George Square, EH8 9JZ. Central Middlesex Hospital,
Edinburgh
London NW10 7NS.
R. W. D. TURNER. KEITH BALL.
treated with practolol (100 mg. three times daily) from 1971 to May, 1973. In August, 1972, she developed thickening of the skin of the palms and soles with psoriasis-like plaques over the knees and elbows and an erythematous rash over the trunk. Shortly after, she complained of weight loss, bouts of fever, and soreness of the eyes and mouth, with a feeling of diminished tear secretion and salivation. In January, 1974, she was admitted with signs of intestinal obstruction and a palpable mass in the central abdomen. Laparotomy revealed a thickened parietal peritoneum with multiple adhesions to virtually the entire small bowel, which was shortened and encased in a thick, fibrous membrane. The membrane was dissected off the gut and she made an uneventful recovery. Biopsy of the peritoneum showed fibrous tissue with unspecific chronic-inflammatory-cell infiltrate. The erythrocyte-sedimentation rate (E.S.R.) was 45 mm. in one hour, the test for antinuclear factor (A.N.F.) was positive, but no lupuserythematosus cells (L.E. cells) were found in the blood. Practolol was stopped and she was treated with prednisone with some improvement in symptoms and laboratory tests, but the A.N.F. test remained positive. Practolol, lanatoside (’Cedilanid’), and hydrochloroquine were the only drugs taken regularly. Thus, no other 5-adrenergic blocking agent was prescribed. A 72-year-old woman with atrial fibrillation and paroxysmal tachycardia was treated with digoxin and propranolol since 1969.
November, 1971, propranolol was replaced by practolol (100 mg. twice daily). In December, 1972, she complained of weight loss, severe dryness in the eyes, mouth, and vagina, hyperkeratosis of palms, and lichenoid eruptions over the foreIn May, 1973, she presented arms and distal parts of the legs. with a carcinoma of the left breast, which was radically removed. In February, 1974, she was admitted with a palpable abdominal fullness and progressive signs of intestinal obstruction. Findings at laparotomy were essentially the same as in the first case, with a striking shortening of almost the entire small bowel to less than The postoperative period was a quarter its normal length. uneventful. Practolol was stopped and prednisone was prescribed. The E.S.R. was normal, but IgG was slightly raised. The A.N.F. test was positive, with no detectable L.E. cells in the blood. She had not been taking other drugs known to induce a syndrome
In
DISCREPANCY BETWEEN SOLUTION AND BIOAVAILABILITY OF DIGOXIN TABLETS Sm,—Dr Ylitalo and others (Feb. 8, p. 343) conclude that " the solution test given in the United States Pharmacopeia is not a satisfactory method of evaluating the bioavailability of commercial digoxin tablets ". The dissolution standard and test for digoxin tablets in U.S.P. XVIII are not intended as a method for ascertaining the bioavailability of the active ingredient in a particular specimen of digoxin tablets. The dissolution standard is one of a set of requirements intended to ensure that all digoxin tablets meeting the specified criteria will perform similarly in vivo. This subtle difference in intention is crucial for comprehending the purpose of drug standardisation. As Ylitalo et al. point out, many investigators have demonstrated that digoxin tablets with a rapid dissolutionrate consistently yield high and reproducible blood-levels of digoxin, while many digoxin tablets with a slow dissolutionrate have been shown to yield low and erratic blood-levels of digoxin. Therefore, to achieve standardisation of commercial digoxin tablets, it is desirable to establish a criterion for the dissolution-rate of digoxin from the tablet matrix. A borderline specimen that barely fails to comply with a dissolution requirement and yet yields satisfactory bloodlevels of digoxin (such as that cited by Ylitalo et al.) does not vitiate the validity or the utility of the standard. Neither would a batch of tablets with a zero dissolution-rate and 100% bioavailability. In view of the clinical and experimental findings to date, tablets with relatively slow
release characteristics are open to suspicion unless they are absolved by an in-vivo bioavailability study, whereas tablets that release their digoxin rapidly are acceptable if they also comply with all of the other pharmacopoeial requirements, without in-vivo testing. We agree with Ylitalo et al. that some digoxin tablets may fail the U.S.P. dissolution requirements and may nevertheless yield satisfactory blood levels of digoxin; but we object to the implication that the standard is therefore unsatisfactory as a pharmacopoeial criterion.
U.S.A.
DANIEL BANES.
to s.L.E.
We think these cases offer additional evidence that may give rise to serious abdominal symptoms besides the well-documented development of S.L.E. and pronounced ocular and cutaneous manifestations.2,3
practolol
Medical Department TA, Rigshospitalet University Hospital, Copenhagen, Denmark.
SiR,—The article by following case.
Brown
K. BENDTZEN M. SØBORG.
et
al. prompts
us to
report
the
A 60-year-old man was treated with propranolol 10 mg. three times a day for angina of effort in 1970. In May, 1971, the drug was changed to practolol 100 mg. three times a day.
In June, 1973, conjunctivitis and generalised eczema together with a psoriasiform eruption developed, and in November, 1973, left corneal ulceration and increasing bilateral deafness developed. He was investigated in May, 1974, for central abdominal pain which was unrelated to food. He also had intermittent diarrhoea with loss of appetite and weight (3 stone in 1 year). Examination revealed a distended abdomen and an ill-defined mass. Barium 1. 2. 3. 4.
United States Pharmacopeia, 12601 Twinbrook Parkway,
Rockville, Maryland 20852,
similar
Brown, P., Baddeley, H., Read, A. E., Davies, J. D., McGarry, J. Lancet, 1974, ii, 1477. Raftery, E. B., Denman, A. M. Br. med. J. 1973, ii, 452. Felix, R. H., Ive, F. A., Dahl, M. G. C. ibid. 1974, iv, 321. Brown, P., Baddeley, H., Read, A. E., Davies, J. D., McGarry, J. Lancet, 1974, ii, 1477.
SCLEROSING PERITONITIS AND PRACTOLOL
practice. Fortunately, screening is now being carried out, and If properly more is being planned, in many countries. there is little doubt that will result. benefit great applied, At present, mass community screening, as described by
SIR,—We should like to add two more possible cases of practolol-induced sclerosing peritonitis to the three reported by Brown et al.1 A 64-year-old woman with atrial fibrillation and attacks of chest pain associated with supraventricular tachycardia was
best ways of
doing
so
under
varying
Hawthorne, is essential for research. Like Tudor Hart and
Coope, we favour routine screening by health examinations in general practice, and in Edinburgh pilot studies by various methods are being carried out. The view of a small group of epidemiologists should not influence Governments and health authorities to delay such projects. If they did so, it could be disastrous at a time when encouragement with financial support is needed. How long do they intend to wait for the results of more research into behavioural problems before taking any action ? Ten years ? Meanwhile a veritable mountain of human misery would have grown. How much more satisfactory it would have been if your final article, reflecting the clinical experience, had concluded, as do Kannel and Dawber, that hypertension is the most common, potent, easily detected, and readily controlled of the major contributors to cardiovascular morbidity and mortality. 12
George Square, EH8 9JZ. Central Middlesex Hospital,
Edinburgh
London NW10 7NS.
R. W. D. TURNER. KEITH BALL.
treated with practolol (100 mg. three times daily) from 1971 to May, 1973. In August, 1972, she developed thickening of the skin of the palms and soles with psoriasis-like plaques over the knees and elbows and an erythematous rash over the trunk. Shortly after, she complained of weight loss, bouts of fever, and soreness of the eyes and mouth, with a feeling of diminished tear secretion and salivation. In January, 1974, she was admitted with signs of intestinal obstruction and a palpable mass in the central abdomen. Laparotomy revealed a thickened parietal peritoneum with multiple adhesions to virtually the entire small bowel, which was shortened and encased in a thick, fibrous membrane. The membrane was dissected off the gut and she made an uneventful recovery. Biopsy of the peritoneum showed fibrous tissue with unspecific chronic-inflammatory-cell infiltrate. The erythrocyte-sedimentation rate (E.S.R.) was 45 mm. in one hour, the test for antinuclear factor (A.N.F.) was positive, but no lupuserythematosus cells (L.E. cells) were found in the blood. Practolol was stopped and she was treated with prednisone with some improvement in symptoms and laboratory tests, but the A.N.F. test remained positive. Practolol, lanatoside (’Cedilanid’), and hydrochloroquine were the only drugs taken regularly. Thus, no other 5-adrenergic blocking agent was prescribed. A 72-year-old woman with atrial fibrillation and paroxysmal tachycardia was treated with digoxin and propranolol since 1969.
November, 1971, propranolol was replaced by practolol (100 mg. twice daily). In December, 1972, she complained of weight loss, severe dryness in the eyes, mouth, and vagina, hyperkeratosis of palms, and lichenoid eruptions over the foreIn May, 1973, she presented arms and distal parts of the legs. with a carcinoma of the left breast, which was radically removed. In February, 1974, she was admitted with a palpable abdominal fullness and progressive signs of intestinal obstruction. Findings at laparotomy were essentially the same as in the first case, with a striking shortening of almost the entire small bowel to less than The postoperative period was a quarter its normal length. uneventful. Practolol was stopped and prednisone was prescribed. The E.S.R. was normal, but IgG was slightly raised. The A.N.F. test was positive, with no detectable L.E. cells in the blood. She had not been taking other drugs known to induce a syndrome
In
DISCREPANCY BETWEEN SOLUTION AND BIOAVAILABILITY OF DIGOXIN TABLETS Sm,—Dr Ylitalo and others (Feb. 8, p. 343) conclude that " the solution test given in the United States Pharmacopeia is not a satisfactory method of evaluating the bioavailability of commercial digoxin tablets ". The dissolution standard and test for digoxin tablets in U.S.P. XVIII are not intended as a method for ascertaining the bioavailability of the active ingredient in a particular specimen of digoxin tablets. The dissolution standard is one of a set of requirements intended to ensure that all digoxin tablets meeting the specified criteria will perform similarly in vivo. This subtle difference in intention is crucial for comprehending the purpose of drug standardisation. As Ylitalo et al. point out, many investigators have demonstrated that digoxin tablets with a rapid dissolutionrate consistently yield high and reproducible blood-levels of digoxin, while many digoxin tablets with a slow dissolutionrate have been shown to yield low and erratic blood-levels of digoxin. Therefore, to achieve standardisation of commercial digoxin tablets, it is desirable to establish a criterion for the dissolution-rate of digoxin from the tablet matrix. A borderline specimen that barely fails to comply with a dissolution requirement and yet yields satisfactory bloodlevels of digoxin (such as that cited by Ylitalo et al.) does not vitiate the validity or the utility of the standard. Neither would a batch of tablets with a zero dissolution-rate and 100% bioavailability. In view of the clinical and experimental findings to date, tablets with relatively slow
release characteristics are open to suspicion unless they are absolved by an in-vivo bioavailability study, whereas tablets that release their digoxin rapidly are acceptable if they also comply with all of the other pharmacopoeial requirements, without in-vivo testing. We agree with Ylitalo et al. that some digoxin tablets may fail the U.S.P. dissolution requirements and may nevertheless yield satisfactory blood levels of digoxin; but we object to the implication that the standard is therefore unsatisfactory as a pharmacopoeial criterion.
U.S.A.
DANIEL BANES.
to s.L.E.
We think these cases offer additional evidence that may give rise to serious abdominal symptoms besides the well-documented development of S.L.E. and pronounced ocular and cutaneous manifestations.2,3
practolol
Medical Department TA, Rigshospitalet University Hospital, Copenhagen, Denmark.
SiR,—The article by following case.
Brown
K. BENDTZEN M. SØBORG.
et
al. prompts
us to
report
the
A 60-year-old man was treated with propranolol 10 mg. three times a day for angina of effort in 1970. In May, 1971, the drug was changed to practolol 100 mg. three times a day.
In June, 1973, conjunctivitis and generalised eczema together with a psoriasiform eruption developed, and in November, 1973, left corneal ulceration and increasing bilateral deafness developed. He was investigated in May, 1974, for central abdominal pain which was unrelated to food. He also had intermittent diarrhoea with loss of appetite and weight (3 stone in 1 year). Examination revealed a distended abdomen and an ill-defined mass. Barium 1. 2. 3. 4.
United States Pharmacopeia, 12601 Twinbrook Parkway,
Rockville, Maryland 20852,
similar
Brown, P., Baddeley, H., Read, A. E., Davies, J. D., McGarry, J. Lancet, 1974, ii, 1477. Raftery, E. B., Denman, A. M. Br. med. J. 1973, ii, 452. Felix, R. H., Ive, F. A., Dahl, M. G. C. ibid. 1974, iv, 321. Brown, P., Baddeley, H., Read, A. E., Davies, J. D., McGarry, J. Lancet, 1974, ii, 1477.