212
Freedberg RS, Gindea AJ, Dieterich DT, Greene JB. Herpes simplex pericarditis in AIDS. NY J Med 1987; 87: 304-06. 18. Malu K, Longo-Mbenza B, Lurhuma Z, Odio W. Pericarditis and acquired immunodeficiency syndrome. Arch Mal Coeur 1988; 81: 17.
207-11.
19. Centers
for Disease Control. Tuberculosis and acquired immunodeficiency syndrome—New York. JAMA 1988; 259: 338-45. 20. Handwerger S, Mildvan D, Senie R, McKinley FW. Tuberculosis and the acquired immunodeficiency syndrome at a New York City hospital: 1978-1985. Chest 1987; 91: 176-80. 21. Sunderam G, McDonald RJ, Maniatis
T,
et
al. Tuberculosis
as a
manifestation of the acquired immunodeficiency syndrome (AIDS). JAMA 1986; 256: 362-66. 22. Blaser MJ, Cohn DL. Opportunistic infections in patients with AIDS: clues to the epidemiology of AIDS and the relative virulence of pathogens. Rev Infect Dis 1986; 8: 21-30. 23. Quinn TC, Mann JM, Curran JW, Piot P. AIDS in Africa: an epidemiologic paradigm. Science 1986; 234: 955-63.
24. Dalli E, Quesada A, Juan G, et al. Tuberculous pericarditis as the first manifestation of acquired immunodeficiency syndrome. Am Heart J 1987; 114: 905-06. 25. Lorell BH, Braunwald E. Pericardial disease. In: Braunwald E, ed. Heart disease, 3rd ed. Philadelphia: WB Saunders, 1988: 1484-534.
26.
Reilly JM, Cunnion RE, Anderson DW, et al. Frequency of myocarditis, left ventricular dysfunction and ventricular tachycardia in the acquired immunodeficiency syndrome. Am J Cardiol 1988; 62: 789-93.
G, van der Groen G, Piot P. Comparison of enzyme immunoassays and an immunofluorescence test for detection of antibody to human immunodeficiency virus in African sera. Eur J Clin
27. Vercautern
Microbiol 1987; 6: 132-35. 28. Urassa W, Bredberg Raden U, Mbena E, et al. Field evaluation of 6 HIV-1 antibody screening assays in Dar es Salaam, Tanzania. Poster 111, presented at IVth International Conference on AIDS and Associated Cancers in Africa; Oct 18-20, 1989; Marseille, France.
Self-management of adrenal insufficiency by rectal hydrocortisone
An alternative to intramuscular hydrocortisone self-injection was evaluated in healthy controls and in patients with adrenal insufficiency. Plasma cortisol concentrations were assayed after administration of 200 mg hydrocortisone by intramuscular injection (10 healthy subjects) or after insertion of an identical dose by rectal suppository (12 healthy subjects, 3 patients with adrenal failure). Plasma cortisol concentrations peaked at 1 hour (about 4000 nmol/l) following intramuscular injection and declined thereafter. After rectal administration, levels peaked at between 1 and 2 hours and persisted for 8 or more hours. Similar levels were achieved at 4 hours (about 1000 nmol/l) by both methods of administration. Self-treatment rectal by suppository may be useful in the prevention of Addisonian crises.
Introduction Addison’s disease, commonly caused by autoimmune adrenalitis, is a benign disorder with an excellent prognosis if diagnosed and treated appropriately. Virtually the only related risk of death is due to acute adrenal crisis. Addisonian crises are often provoked by intercurrent illness and are associated with persistent vomiting, which prevents adequate gastrointestinal absorption of hydrocortisone (HC); intramuscular HC is therefore often advocated. Successful self-management could be achieved by rectal administration if HC is well absorbed by this route, and there would be no need for repeated parenteral injections. We have therefore studied the rectal absorption of HC by
suppository with
those
and compared obtained by
concentrations of HC conventional intramuscular
plasma
treatment.
Subjects and methods healthy subjects (13 men, 9 women; age range 21-44 years; weight range 56-81 kg) were studied according to the following protocol. At midnight all subjects took 2 mg dexamethasone by mouth. Venous blood for baseline plasma cortisol was taken at 0900 h. 12 subjects then inserted one suppository per rectum (200 mg hydrocortisone BP powder per 2 g suppository in ’Witepsol 22
H15’ base [Brome and Schimmer, UK]). 10 subjects received 200 mg HC as a deep intramuscular injection into the right buttock. Venous blood was then sampled via an indwelling catheter at 15, 30, 60, 90, 120, 240, 480, and 720 min. The first 2 ml of blood was discarded. A similar protocol (without the dexamethasone) was followed in 3 patients: a 39-year-old man and a 49-year-old woman with primary autoimmune adrenal failure, and a 40-year-old man with hypopituitarism secondary to craniopharyngioma. They were each given an HC suppository instead of their usual morning dose (20 mg) of HC. Cortisol levels were assayed in a single batch (coefficient of variation 3%) by radioimmunoassay (’Farmos’). Permission for this study was given by the local ethical committee.
Results Intramuscular injection of HC was painful or very painful for all subjects. There was no discomfort associated with the
ADDRESS. Department of Medicine, Bristol Royal Infirmary, Bristol BS2 8HW, UK (P G Newrick, MRCP, G. Braatvedt, MRCP, J Hancock, MB, R. J. M. Corral, FRCP). Correspondence to Dr P G Newrick.
213
could interfere with absorption, although in a study of bioavailability of HC enemas4 this was not believed to be an important factor. In previous studies, injured or moderately stressed individuals had a mean plasma cortisol of 820 nmol/l within 5 hours of injury5 and cortisol levels between 600 and 1100 nmol/1 within 8 hours of injury. We have shown that administration of HC by rectal suppository leads to mean plasma HC concentrations that are as high as are those attained by intramuscular injection; such concentrations should provide adequate replacement for the stressed patient. Furthermore,the local pain and risk of anaphylaxis3 associated with intramuscular HC can be avoided. However, patients must still be advised to seek assistance if their condition deteriorates. We thank Mrs S. Simpson and Mr J. Gooding, department of chemical pathology, Bristol Royal Infirmary for measurement of plasma cortisol levels. G. B. is supported by Fidia SpA.
Median
(interquartile range) plasma
cortisol
curves.
Healthy subjects given HC by suppository (broken lines) or intramuscularly (thick black line), patients given HC by suppository (thin black line).
suppositories. Mean plasma cortisol concentrations peaked in the first hour in the subjects given intramuscular HC (about 4000 nmol/1), decreased to about 1000 nmol/1 at 4 hours, and continued to decline thereafter. By contrast, in the two groups given HC per rectum, plasma cortisol concentrations increased from low baseline levels to about 1000 nmol/1 over the first 1-2 hours and persisted for 8 or more hours (figure).
REFERENCES 1. Martindale. The Extra Pharmacopoeia. Reynolds JEF, ed. 29th ed. London: The Pharmaceutical Press, 1989: 872. 2. de Boer AG, Moolenaar F, de Leede LGJ, Breimer DD. Rectal drug administration: clinical and pharmacokinetic considerations. Clin Pharmacokinet 1982; 7: 285-311. 3. Cann PA, Holdsworth CD. Systemic absorption from hydrocortisone foam enemas in ulcerative colitis. Lancet 1987; i: 922-23. 4. Lima JJ, Jusko WJ. Bioavailability of hydrocortisone retention enemas in relation to absorption kinetics. Clin Pharmacol Ther 1980; 28: 262-69. 5. Barton RN, Passingham BJ. Effect of binding to plasma proteins on the interpretation of plasma cortisol concentrations after accidental injury. Clin Sci 1981; 61: 399-405. 6. Stoner HB, Frayn KN, Barton RN, Threlfall CJ, Little RA. The relationships between plasma substrates and hormones and the severity of injury in 277 recently injured patients. Clin Sci 1979; 56: 563-73.
Discussion
appropriate patient education about the need for supplementary glucocorticoid during illness, Addisonian crises should be preventable or, if not, recognised and treated promptly. Patients prefer oral treatment to the discomfort of injections and may be tempted to persist with HC tablets, despite vomiting, rather than self-inject or seek medical assistance. An additional risk, though rare, is anaphylaxis to injected HC.1 Rectal administration of HC may be a useful and potentially life-saving alternative, especially for the patient who is vomiting. Factors that influence drug absorption from the rectum include the physicochemical properties of the rectal fluid, and the nature of the drug and its vehicle.2 The inferior and middle rectal veins drain eventually into the inferior vena cava, whereas blood from the superior rectal veins drains to the portal vein.2 Thus, drugs inserted into the lower part of the rectum may pass directly to the systemic circulation and without undergoing hepatic first-pass elimination, with consequently higher plasma levels. Cann and Holdsworth33 have studied systemic absorption of HC from retention enemas; they recorded physiological plasma concentrations in all of 6 patients with colitis within an hour with a peak at 4 hours. Despite evidence of adequate absorption by this route, sufficiently high plasma levels may not be attained for several reasons. Diarrhoea might preclude adequate suppository retention; and altered rectal bacterial flora could enhance local HC degradation. Faecal loading of the rectum With
Then
as
Now
A Channel bridge In the engineering and railway world, as also among the general public, considerable conversation has been held as to the construction of a great iron bridge which would unite England with the continent of Europe. The plan has been declared quite feasible, and financial, together with military and political considerations, are the principal questions that are raised. To these, however, we would add another and very important point which we fear has not received sufficient prominence. To build the bridge it will be to work below the surface of the water, and this at very considerable depths, under a pressure perhaps of six atmospheres. How will it be possible for men to live and work under such conditions? Theoretically the air could only be breathed if it contains but a feeble proportion of oxygen. It will be necessary to ascertain exactly what mixture will suit men working under a pressure of five or six atmospheres, and how practically the air could be suitably but artificially modified, and then pumped down below the sea in sufficient quantities. Finally, when all this is done, how long can workmen remain below the surface without injury to their health? Hygienists will have to keep very sharp watch, or all these points may be neglected; and whoever contracted to execute such a difficult work would have to be careful to reckon the cost that such necessary measures would be likely to entail ... the authorities should stipulate that all projects must comprise a very full account of the measures proposed to be taken to protect the life and limbs of workmen who would be engaged in carrying out the scheme.
necessary
(From The Lancet of 18 January 1890)
Freedberg RS, Gindea AJ, Dieterich DT, Greene JB. Herpes simplex pericarditis in AIDS. NY J Med 1987; 87: 304-06. 18. Malu K, Longo-Mbenza B, Lurhuma Z, Odio W. Pericarditis and acquired immunodeficiency syndrome. Arch Mal Coeur 1988; 81: 17.
207-11.
19. Centers
for Disease Control. Tuberculosis and acquired immunodeficiency syndrome—New York. JAMA 1988; 259: 338-45. 20. Handwerger S, Mildvan D, Senie R, McKinley FW. Tuberculosis and the acquired immunodeficiency syndrome at a New York City hospital: 1978-1985. Chest 1987; 91: 176-80. 21. Sunderam G, McDonald RJ, Maniatis
T,
et
al. Tuberculosis
as a
manifestation of the acquired immunodeficiency syndrome (AIDS). JAMA 1986; 256: 362-66. 22. Blaser MJ, Cohn DL. Opportunistic infections in patients with AIDS: clues to the epidemiology of AIDS and the relative virulence of pathogens. Rev Infect Dis 1986; 8: 21-30. 23. Quinn TC, Mann JM, Curran JW, Piot P. AIDS in Africa: an epidemiologic paradigm. Science 1986; 234: 955-63.
24. Dalli E, Quesada A, Juan G, et al. Tuberculous pericarditis as the first manifestation of acquired immunodeficiency syndrome. Am Heart J 1987; 114: 905-06. 25. Lorell BH, Braunwald E. Pericardial disease. In: Braunwald E, ed. Heart disease, 3rd ed. Philadelphia: WB Saunders, 1988: 1484-534.
26.
Reilly JM, Cunnion RE, Anderson DW, et al. Frequency of myocarditis, left ventricular dysfunction and ventricular tachycardia in the acquired immunodeficiency syndrome. Am J Cardiol 1988; 62: 789-93.
G, van der Groen G, Piot P. Comparison of enzyme immunoassays and an immunofluorescence test for detection of antibody to human immunodeficiency virus in African sera. Eur J Clin
27. Vercautern
Microbiol 1987; 6: 132-35. 28. Urassa W, Bredberg Raden U, Mbena E, et al. Field evaluation of 6 HIV-1 antibody screening assays in Dar es Salaam, Tanzania. Poster 111, presented at IVth International Conference on AIDS and Associated Cancers in Africa; Oct 18-20, 1989; Marseille, France.
Self-management of adrenal insufficiency by rectal hydrocortisone
An alternative to intramuscular hydrocortisone self-injection was evaluated in healthy controls and in patients with adrenal insufficiency. Plasma cortisol concentrations were assayed after administration of 200 mg hydrocortisone by intramuscular injection (10 healthy subjects) or after insertion of an identical dose by rectal suppository (12 healthy subjects, 3 patients with adrenal failure). Plasma cortisol concentrations peaked at 1 hour (about 4000 nmol/l) following intramuscular injection and declined thereafter. After rectal administration, levels peaked at between 1 and 2 hours and persisted for 8 or more hours. Similar levels were achieved at 4 hours (about 1000 nmol/l) by both methods of administration. Self-treatment rectal by suppository may be useful in the prevention of Addisonian crises.
Introduction Addison’s disease, commonly caused by autoimmune adrenalitis, is a benign disorder with an excellent prognosis if diagnosed and treated appropriately. Virtually the only related risk of death is due to acute adrenal crisis. Addisonian crises are often provoked by intercurrent illness and are associated with persistent vomiting, which prevents adequate gastrointestinal absorption of hydrocortisone (HC); intramuscular HC is therefore often advocated. Successful self-management could be achieved by rectal administration if HC is well absorbed by this route, and there would be no need for repeated parenteral injections. We have therefore studied the rectal absorption of HC by
suppository with
those
and compared obtained by
concentrations of HC conventional intramuscular
plasma
treatment.
Subjects and methods healthy subjects (13 men, 9 women; age range 21-44 years; weight range 56-81 kg) were studied according to the following protocol. At midnight all subjects took 2 mg dexamethasone by mouth. Venous blood for baseline plasma cortisol was taken at 0900 h. 12 subjects then inserted one suppository per rectum (200 mg hydrocortisone BP powder per 2 g suppository in ’Witepsol 22
H15’ base [Brome and Schimmer, UK]). 10 subjects received 200 mg HC as a deep intramuscular injection into the right buttock. Venous blood was then sampled via an indwelling catheter at 15, 30, 60, 90, 120, 240, 480, and 720 min. The first 2 ml of blood was discarded. A similar protocol (without the dexamethasone) was followed in 3 patients: a 39-year-old man and a 49-year-old woman with primary autoimmune adrenal failure, and a 40-year-old man with hypopituitarism secondary to craniopharyngioma. They were each given an HC suppository instead of their usual morning dose (20 mg) of HC. Cortisol levels were assayed in a single batch (coefficient of variation 3%) by radioimmunoassay (’Farmos’). Permission for this study was given by the local ethical committee.
Results Intramuscular injection of HC was painful or very painful for all subjects. There was no discomfort associated with the
ADDRESS. Department of Medicine, Bristol Royal Infirmary, Bristol BS2 8HW, UK (P G Newrick, MRCP, G. Braatvedt, MRCP, J Hancock, MB, R. J. M. Corral, FRCP). Correspondence to Dr P G Newrick.
213
could interfere with absorption, although in a study of bioavailability of HC enemas4 this was not believed to be an important factor. In previous studies, injured or moderately stressed individuals had a mean plasma cortisol of 820 nmol/l within 5 hours of injury5 and cortisol levels between 600 and 1100 nmol/1 within 8 hours of injury. We have shown that administration of HC by rectal suppository leads to mean plasma HC concentrations that are as high as are those attained by intramuscular injection; such concentrations should provide adequate replacement for the stressed patient. Furthermore,the local pain and risk of anaphylaxis3 associated with intramuscular HC can be avoided. However, patients must still be advised to seek assistance if their condition deteriorates. We thank Mrs S. Simpson and Mr J. Gooding, department of chemical pathology, Bristol Royal Infirmary for measurement of plasma cortisol levels. G. B. is supported by Fidia SpA.
Median
(interquartile range) plasma
cortisol
curves.
Healthy subjects given HC by suppository (broken lines) or intramuscularly (thick black line), patients given HC by suppository (thin black line).
suppositories. Mean plasma cortisol concentrations peaked in the first hour in the subjects given intramuscular HC (about 4000 nmol/1), decreased to about 1000 nmol/1 at 4 hours, and continued to decline thereafter. By contrast, in the two groups given HC per rectum, plasma cortisol concentrations increased from low baseline levels to about 1000 nmol/1 over the first 1-2 hours and persisted for 8 or more hours (figure).
REFERENCES 1. Martindale. The Extra Pharmacopoeia. Reynolds JEF, ed. 29th ed. London: The Pharmaceutical Press, 1989: 872. 2. de Boer AG, Moolenaar F, de Leede LGJ, Breimer DD. Rectal drug administration: clinical and pharmacokinetic considerations. Clin Pharmacokinet 1982; 7: 285-311. 3. Cann PA, Holdsworth CD. Systemic absorption from hydrocortisone foam enemas in ulcerative colitis. Lancet 1987; i: 922-23. 4. Lima JJ, Jusko WJ. Bioavailability of hydrocortisone retention enemas in relation to absorption kinetics. Clin Pharmacol Ther 1980; 28: 262-69. 5. Barton RN, Passingham BJ. Effect of binding to plasma proteins on the interpretation of plasma cortisol concentrations after accidental injury. Clin Sci 1981; 61: 399-405. 6. Stoner HB, Frayn KN, Barton RN, Threlfall CJ, Little RA. The relationships between plasma substrates and hormones and the severity of injury in 277 recently injured patients. Clin Sci 1979; 56: 563-73.
Discussion
appropriate patient education about the need for supplementary glucocorticoid during illness, Addisonian crises should be preventable or, if not, recognised and treated promptly. Patients prefer oral treatment to the discomfort of injections and may be tempted to persist with HC tablets, despite vomiting, rather than self-inject or seek medical assistance. An additional risk, though rare, is anaphylaxis to injected HC.1 Rectal administration of HC may be a useful and potentially life-saving alternative, especially for the patient who is vomiting. Factors that influence drug absorption from the rectum include the physicochemical properties of the rectal fluid, and the nature of the drug and its vehicle.2 The inferior and middle rectal veins drain eventually into the inferior vena cava, whereas blood from the superior rectal veins drains to the portal vein.2 Thus, drugs inserted into the lower part of the rectum may pass directly to the systemic circulation and without undergoing hepatic first-pass elimination, with consequently higher plasma levels. Cann and Holdsworth33 have studied systemic absorption of HC from retention enemas; they recorded physiological plasma concentrations in all of 6 patients with colitis within an hour with a peak at 4 hours. Despite evidence of adequate absorption by this route, sufficiently high plasma levels may not be attained for several reasons. Diarrhoea might preclude adequate suppository retention; and altered rectal bacterial flora could enhance local HC degradation. Faecal loading of the rectum With
Then
as
Now
A Channel bridge In the engineering and railway world, as also among the general public, considerable conversation has been held as to the construction of a great iron bridge which would unite England with the continent of Europe. The plan has been declared quite feasible, and financial, together with military and political considerations, are the principal questions that are raised. To these, however, we would add another and very important point which we fear has not received sufficient prominence. To build the bridge it will be to work below the surface of the water, and this at very considerable depths, under a pressure perhaps of six atmospheres. How will it be possible for men to live and work under such conditions? Theoretically the air could only be breathed if it contains but a feeble proportion of oxygen. It will be necessary to ascertain exactly what mixture will suit men working under a pressure of five or six atmospheres, and how practically the air could be suitably but artificially modified, and then pumped down below the sea in sufficient quantities. Finally, when all this is done, how long can workmen remain below the surface without injury to their health? Hygienists will have to keep very sharp watch, or all these points may be neglected; and whoever contracted to execute such a difficult work would have to be careful to reckon the cost that such necessary measures would be likely to entail ... the authorities should stipulate that all projects must comprise a very full account of the measures proposed to be taken to protect the life and limbs of workmen who would be engaged in carrying out the scheme.
necessary
(From The Lancet of 18 January 1890)
