- Email: [email protected]
METRONIDAZOLE AND BRAIN ABSCESS
613
OTHER INDICATIONS FOR CHLORAMPHENICOL AND VANCOMYCIN outlines the clinical uses of chloramphenicol, erythromycin, vancomycin, and the tetracyclines. Whilst advocating the use of chloramphenicol in meningitis caused by Haemophilus influenzae type b he omits to comment on its value in another life-threatening condition caused by this organism-namely, acute epiglottitis. Addy et al.concluded that parenteral chloramphenicol was the drug of choice for this condition, and I believe that, of the more recently introduced antimicrobials, none has proved to be more effective. The potential value of vancomycin in the management of staphylococcal peritonitis in patients undergoing continuous ambulatory peritoneal dialysis (CAPD) is not mentioned. Staphylococci, and in particular Staphylococcus epidermidis which may be resistant to a wide range of antibiotics, are sensitive to vancomycin. In a 58-year-old man on CAPD who was admitted to the County Hospital, Hereford, administration of 1 g of vancomycin intravenously as a stat dose followed by the addition of 15 mg/1 vancomycin in the dialysis fluid (given at a rate of 6 x 2per 24 h) for a total of 5 days resulted in the rapid elimination of a multiple-resistant Staph. epidermidis from the peritoneal fluid. The serum concentration of vancomycin measured on completion of the antibiotic treatment was 15-99 mg/l. This dosage schedule is similar Also Eykyn et al. to that suggested by other used intermittent infusions of vancomycin (1g intravenously every 7 days) in patients on haemodialysis whose shunts were infected by
SIR,-Dr Kucers (Aug. 21,
p.
425)
groups.2,3
4 successfully
staphylococci. I would also suggest that vancomycin is worthy of consideration in patients with endocarditis caused by methicillin sensitive strains of Staph. aureus who fail to respond adequately to the more usual regimens of flucloxacillin plus gentamicin or flucloxacillin plus fusidic acid. Public Health Laboratory, County Hospital,
Hereford HR1 2ER
amikacin and tobramycin,and our findings will be published in detail elsewhere. Nephrotoxicity (an increase in serum creatinine of 0 -5or 1 mg/dl if the initial serum creatinine was less or more than 3 mg/dl, respectively) developed in 6 - 7% of patients given tobramycin and in 129% given amikacin (p<0 05). Auditory toxicity (decrease of 20 or more dB at frequencies from 250 to 8000 Hz either unilaterally or developed in 15-7% given tobramycin and in 11 .7% given amikacin (p>0 05). We suggest that aminoglycosides should be selected for reasons other than toxicity unless clear-cut differences have been demonstrated in well designed clinical trials. more
T. J. COLEMAN
bilaterally)
J. MAÑÁ Infectious Diseases Unit. Medical Clinic B, Hospital Clinico y Provincial,
Faculty of Medicine, Barcelona 36, Spain
J. M. GATELL V. ARAUJO L. ZAMORA J. GARCIA SANMIGUEL
SIR,-Gentamicin usually becomes the focus of attack whenever aminoglycoside nephrotoxicity is talked of. The aminoglycosides, and gentamicin especially, are drugs that clinicians very commonly lean
on when treating patients with many problems who have suspected or obvious acute septic illness. As the numbers of patients on treatment with gentamicin or another aminoglycoside rise, the number of cases of nephrotoxicity will inevitably increase. Compared with non-aminoglycoside drugs, the pharmacological behaviour of these compounds is well established and better known to most clinicians, and this is itself one reason for their widespread use, besides the cost factor, the lack of haematological disturbances, and the coverage of usual organisms that cause sepsis (in contrast to modern cephaloridine or penicillin derivatives). Patients given gentamicin treatment will often be critically ill with associated problems such as renal failure and/or systemic acidosis due to metabolic causes such as sepsis; even patients with acute or chronic renal failure are given gentamicin in preference to other drugs because its dose can be conveniently tailored to produce a definite effect without low risk of toxicity. The incidence of gentamicin toxicity is higher in patients with acidosis or alkalosis
than in those who do not have acid-base disturbances. If the prescribed dose and dose intervals are strictly adhered to, gentamicin toxicity will usually be avoided; and in many of the patients showing a rise in serum creatinine it is difficult to exclude other causes for deterioration in renal function.
AMINOGLYCOSIDE TOXICITY
SIR,-Toxicity is the major factor limiting the clinical usefulness of aminoglycosides. Professor Phillips, in his excellent review (Aug. 7, p. 311) in your series on antibiotics, stated that gentamicin and amikacin are more likely to be nephrotoxic than is tobramycin. This may be true in laboratory animals. To our knowledge, however, few studies have been done in man comparing the toxicity of tobramycin and amikacin. Similar rates of nephrotoxicity (about 20%) were found in a prospective randomised trial in patients with cancer which was
primarily designed to compare efficacy.5 in another, unrandomised, trial in which only a small and probably selected group of patients received amikacin, rates of nephrotoxicity of 25%, 23%, and 36% were found for amikacin, tobramycin, and gentamicin, 6
respectively.
We have reported the results of a prospective randomised trial in 113 patients, comparing the nephrotoxicity and ototoxicity of
Urology Service, Hôpital Bellevue, Centre Hospitalier Regional et Universitaire, 42023 Saint Etienne, France
D. CHANDRASEKAR
METRONIDAZOLE AND BRAIN ABSCESS
SIR,-Reviewing the chemotherapy of anaerobic infections Professor Bartlett (Aug. 28, p. 479) implies, referring to work from this centre,that it has been suggested that metronidazole may be active against both anaerobic and aerobic bacteria in brain abscesses. There -is evidence that metronidazole has some activity against certain aerobes in vitroand in vivo,3and it is possible that, by facilitates removal of associated killing anaerobes, metronidazole aerobes by polymorphs.44 However, we have consistently emphasised the importance of including, in regimens for the 7. Gatell JM, Zamora L, Araujo
V, Marin JL, Elena M, Ballesta A, Bonet M, Bohé M, Farré M, Puig J, García SanMiguel J. Prospective controlled comparison of the nephrotoxicity and auditory toxicity of tobramycin and amikacin. Eighth International Congress of Infectious and Parasitic Diseases (Stockholm, Sweden,
1. Addy
M, Ellis P, Turk D. Haemophilus epiglottitis: Nine recent cases in Oxford. Br Med J 1972; i: 40-42. 2 Nielsen H, Sørensen I, Hansen H. Peritoneal transport of vancomycin during peritoneal dialysis. Nephron 1979; 24: 274-77. 3. Rowttenbourg J, Jacqefingels E, N’Guyen M. Medical management of peritonitis. In: Lagrain M, ed. Proceedings of the International Symposium on Continuous Ambulatory Peritoneal Dialysis. Amsterdam: Excerpta Medica, 1979. 4 Eykyn S, Phillips I, Evans J. Vancomycin for staphylococcal shunt site infections in patients on regular haemodialysis. Br Med J 1970; iii: 80-82. 5. Feld R, Valdivieso M, Bodey GP, Rodriguez V. Comparison of amikacin and tobramycin in the treatment of infection in patients with cancer. J Infect Dis 1977; 135: 61-66. 6. Plaut ME, Schentag JJ, Jusko WJ. Aminoglycoside nephrotoxicity: assessment in critically ill patients. J Med 1979; 10: 257-66.
comparative
1982): abstr p 167 Ingham HR, Selkon JB, Roxby CM Bacteriological study of otogenic cerebral abscess: Chemotherapeutic role of metronidazole. Br Med J 1977; ii: 991-94. 2. Ingham HR, Hall CJ, Sisson PR, Tharagonnet D, Selkon JB. The activity of metronidazole against facultatively anaerobic bacteria. J Antimicrob Chemother 1980; 6: 343-47. 3. Onderonk AB, Louie TJ, Tally FP, Bartlett JG. Activity of metronidazole against Escherichia coli in experimental intraabdominal sepsis. J Antimicrob Chemother 1979; 5: 201-10. 4. Ingham HR, Sisson PR, Tharagonnet D, Selkon JB, Codd AA. Inhibition of phagocytosis in vitro by obligate anaerobes Lancet 1977; ii: 1252-54. 1.
614 of brain abscess, agents specifically active against aerobes besides those active against anaerobes. Currently we use ampicillin, gentamicin, and metronidazole, a combination which appears to be appropriate as judged by our latest published results which show a case fatality rate of 9 - 7% for the quinquennium
chemotherapy
1974-78.5
Public Health
Laboratory,
Institute of Pathology, General Hospital, Newcastle upon Tyne NE4 6BE
11 pressure and plasma renin concentration. Salt intake was the same during the two periods. We found a significant prolongation in bleeding time on n-3 PUFA, with no alteration in platelet numbers and a significant, though small, reduction in systolic blood pressure not associated with any alteration in plasma renin concentration. These results confirm the findings by Sanders and colleagues who, in an open study, found a reduction in blood pressure in volunteers given cod liver oil12 and fit in with data on blood pressure on Arctic
H. R. INGHAM
dwellers. 13,14
J. B. SELKON
n-3 PUFA, and EPA especially, depresses platelet production of the proaggregatory vasoconstrictive thromboxanes. We found no depressive (or even a stimulatory) influence on the production in vessels of antiaggregatory vasodilatatory prostacyclins.15,16 Our latest results strengthen our earlier warning that great care should be taken when transferring results obtained in this area of research from rats to man.
n-3 POLYUNSATURATED FATTY ACIDS AND ISCHAEMIC HEART DISEASE
SIR,-Our studies in Greenland Eskimos have focused attention the possible mechanisms by which dietary n-3 polyunsaturated
on
fatty acids (PUFA) may diminish the incidence of thromboembolic episodes, as indicated by the Greenlanders’ low risk of ischaemic heart disease. 6-8 Dr Hay and colleagues (June 5, p. 1269) found that’ feeding fish oil to patients with ischaemic heart disease resulted in a significant fall in plasma &bgr;-thromboglobulin and platelet factor 4 and a significant lengthening of platelet survival time. They interpret this as further evidence that n-3 PUFA, by reducing the platelet/vessel-wall interaction, may reduce the risk of ischaemic heart disease. Platelet counts, however, fell during the fish oil feeding period, which accords with other studies offish oil diets. 7-9 Dr Jones and Dr Davies (July 24, p. 221) draw attention to the possibility that the effect of n-3 PUFA on haemostasis might be due simply to the fall in platelet numbers, and they warn that in rats on eicosapentaenoic acid (EPA) supplements blood pressure rises, the increase possibly being related to suppression of vascular prostacyclin We have been studying these problems in man and give a preliminary report on our results in this letter. Twenty healthy men aged 25-40 were, in a double-blind crossover study, given daily either 3 g of n-3 PUFA (’MaxEPA’, Seven Seas Health Care Ltd) with a relative content of 20:5, n-3 and 22:6, n-6 of 60 and 40%, respectively, or 3 g of n-6 PUFA, consisting of linoleic acid (18:2, n-6), both in a 10 ml encapsulated oilform. The feeding periods were of 4 weeks’ duration separated by a 4 week washout period. The table gives the results of bleeding times (’Simplate’), platelet count, and recumbent (30 min) and standing (20 min) systolic blood
synthesis. 10
5. Alderson D, Strong AJ, Ingham HR, Selkon JB. Fifteen-year review of the mortality of brain abscess. Neurosurgery 1981; 8: 1-6. 6. Dyerberg J, Bang HO, Stoffersen E, Moncada S, Vane JR. Eicosapentaenoic acid and the prevention of thrombosis and atherosclerosis. Lancet 1978; ii: 117-19. 7. Dyerberg J, Bang HO. Haemostatic function and platelet polyunsaturated fatty acids in Eskimos. Lancet 1979; ii: 433-35. 8. Bang HO, Dyerberg J, Sinclair HM. The composition of the Eskimo food in north western Greenland. Am J Clin Nutr 1980, 33: 2657-61. 9. Goodnight SH, Harris WS, Connor WE The effects of dietary &psgr;3 fatty acids on platelet composition and function in man: A prospective, controlled study Blood
1981; 58: 880-85. 10.
Kramer HJ, Düsing R. Dietary administration of eicosapentaenoic and linolenic acid increases arterial blood pressure and suppresses vascular prostacyclin synthesis in the rat. Prostaglandins 1982; 23: 369-82.
Department of Clinical Chemistry. Aalborg Hospital (North), 9000 Aalborg, Denmark
J. DYERBERG J. Z. MORTENSEN A. H. NIELSEN E. B. SCHMIDT
SIR,-Dr Sinclair’s letter (Aug. 14, p. 393) on eicosa (or icosa)pentaenoic acid (EPA) and ischaemic heart disease, raises some important points about the different fish oils being used in trials. ’MaxEPA’ is a natural triglyceride concentrate from marine oils which is being used in large-scale trials in the U.K. and elsewhere and on which toxicity studies have been done. At one large hospital alone, over 150 patients have been on MaxEPA for the past 2112 years. It is established as a safe, pharmaceutically controlled natural source of EPA and docosahexaenoic acid, low in cetoleic acid, vitamin A, and vitamin D. The results from this work should not be extrapolated to less controlled products or other fish oils with different fatty acid combinations. In particular, concentrates based on catalytic splitting of triglycerides, ester production, solvent urea fractionation, and certain chromatographic techniques-which can give rise to products high in oxidised and polymeric byproducts combined with isomerisation of the EPA and docosahexaenoic acid-can result in misleading and possibly serious side-effects.
Kingsbury
et
al.and Dyerberg and Bang2 both reported products and confirm our own
anomalous results with such
findings. In our view the natural occurrence of these polyunsaturated fatty acids selectively in the beta position of the triglyceride molecule in natural marine oils is significant. The protection and specificity of this beta position is destroyed by the above concentration methods. The efficacy of synthetic concentrates must be properly assessed in long-term clinical trials (as has been done for MaxEPA), before any comparison can be made and before the literature becomes filled with contradictory data. Apart from Sinclair’s indication that there are fish oils and fish oils, there are also fish oils and synthetically derived products therefrom.
Scherhag R,
MEAN VALUES OF PLATELET
NUMBERS, BLEEDING TIME, SYSTOLIC 4 WEEKS OF EITHER 3 g n-3 OR
Refining Ltd, Marfleet, Hull HU9 5NJ
S. A. REED
BP
AND PLASMA RENIN AFTER
3 g n-6
Marfleet
PUFA PER DAY
11. Poulsen
K, Jørgensen J. An easy radioimmunological microassay of renin activity,
and substrate in human and animal plasma and tissues based on angiotensin I trapping by antibody. J Clin Endocrinol Metab 1974; 39: 816-25 12. Sanders TAB, Vickers M, Haines AP. Effect on blood lipids and haemostasis of a supplement of cod-liver oil, rich in eicosapentaenioc and docosahexaenoic acids, in healthy young men Clin Sci 1981; 61: 317-24. 13. Simper LB. Blood pressures in polar Eskimos. Ugeskr Laeg 1976; 138: 1757-58. 14. Bang HO, Dyerberg J Arktisk blodtryk. Ugeskr Laeg 1976; 138: 2503. 15. Dyerberg J, Jørgensen KA. The effect of arachidonic- and eicosapentaenoic acid on the synthesis of prostacyclin-like material in human umbilical vasculature. Artery 1980, 8: 12-17. 16. Dyerberg J, Jørgensen KA, Arnfred T. Human umbilical blood vessel converts all concentration
cis-5,8,11,14,17 eicosapentaenoic acid to prostaglandin I3 Prostaglandins 1981; 22: 857-62 Statistical analysis baseline values).
by
Wilcoxon
test
for
paired differences
(significance
of difference from
1. 2.
Kingsbury KJ, et al. Biochem J 1962; 84: 124. Dyerberg J, Bang HO. Nutritional factors modulating effects on metabolic processes. New York: Raven
Press, 1981.
OTHER INDICATIONS FOR CHLORAMPHENICOL AND VANCOMYCIN outlines the clinical uses of chloramphenicol, erythromycin, vancomycin, and the tetracyclines. Whilst advocating the use of chloramphenicol in meningitis caused by Haemophilus influenzae type b he omits to comment on its value in another life-threatening condition caused by this organism-namely, acute epiglottitis. Addy et al.concluded that parenteral chloramphenicol was the drug of choice for this condition, and I believe that, of the more recently introduced antimicrobials, none has proved to be more effective. The potential value of vancomycin in the management of staphylococcal peritonitis in patients undergoing continuous ambulatory peritoneal dialysis (CAPD) is not mentioned. Staphylococci, and in particular Staphylococcus epidermidis which may be resistant to a wide range of antibiotics, are sensitive to vancomycin. In a 58-year-old man on CAPD who was admitted to the County Hospital, Hereford, administration of 1 g of vancomycin intravenously as a stat dose followed by the addition of 15 mg/1 vancomycin in the dialysis fluid (given at a rate of 6 x 2per 24 h) for a total of 5 days resulted in the rapid elimination of a multiple-resistant Staph. epidermidis from the peritoneal fluid. The serum concentration of vancomycin measured on completion of the antibiotic treatment was 15-99 mg/l. This dosage schedule is similar Also Eykyn et al. to that suggested by other used intermittent infusions of vancomycin (1g intravenously every 7 days) in patients on haemodialysis whose shunts were infected by
SIR,-Dr Kucers (Aug. 21,
p.
425)
groups.2,3
4 successfully
staphylococci. I would also suggest that vancomycin is worthy of consideration in patients with endocarditis caused by methicillin sensitive strains of Staph. aureus who fail to respond adequately to the more usual regimens of flucloxacillin plus gentamicin or flucloxacillin plus fusidic acid. Public Health Laboratory, County Hospital,
Hereford HR1 2ER
amikacin and tobramycin,and our findings will be published in detail elsewhere. Nephrotoxicity (an increase in serum creatinine of 0 -5or 1 mg/dl if the initial serum creatinine was less or more than 3 mg/dl, respectively) developed in 6 - 7% of patients given tobramycin and in 129% given amikacin (p<0 05). Auditory toxicity (decrease of 20 or more dB at frequencies from 250 to 8000 Hz either unilaterally or developed in 15-7% given tobramycin and in 11 .7% given amikacin (p>0 05). We suggest that aminoglycosides should be selected for reasons other than toxicity unless clear-cut differences have been demonstrated in well designed clinical trials. more
T. J. COLEMAN
bilaterally)
J. MAÑÁ Infectious Diseases Unit. Medical Clinic B, Hospital Clinico y Provincial,
Faculty of Medicine, Barcelona 36, Spain
J. M. GATELL V. ARAUJO L. ZAMORA J. GARCIA SANMIGUEL
SIR,-Gentamicin usually becomes the focus of attack whenever aminoglycoside nephrotoxicity is talked of. The aminoglycosides, and gentamicin especially, are drugs that clinicians very commonly lean
on when treating patients with many problems who have suspected or obvious acute septic illness. As the numbers of patients on treatment with gentamicin or another aminoglycoside rise, the number of cases of nephrotoxicity will inevitably increase. Compared with non-aminoglycoside drugs, the pharmacological behaviour of these compounds is well established and better known to most clinicians, and this is itself one reason for their widespread use, besides the cost factor, the lack of haematological disturbances, and the coverage of usual organisms that cause sepsis (in contrast to modern cephaloridine or penicillin derivatives). Patients given gentamicin treatment will often be critically ill with associated problems such as renal failure and/or systemic acidosis due to metabolic causes such as sepsis; even patients with acute or chronic renal failure are given gentamicin in preference to other drugs because its dose can be conveniently tailored to produce a definite effect without low risk of toxicity. The incidence of gentamicin toxicity is higher in patients with acidosis or alkalosis
than in those who do not have acid-base disturbances. If the prescribed dose and dose intervals are strictly adhered to, gentamicin toxicity will usually be avoided; and in many of the patients showing a rise in serum creatinine it is difficult to exclude other causes for deterioration in renal function.
AMINOGLYCOSIDE TOXICITY
SIR,-Toxicity is the major factor limiting the clinical usefulness of aminoglycosides. Professor Phillips, in his excellent review (Aug. 7, p. 311) in your series on antibiotics, stated that gentamicin and amikacin are more likely to be nephrotoxic than is tobramycin. This may be true in laboratory animals. To our knowledge, however, few studies have been done in man comparing the toxicity of tobramycin and amikacin. Similar rates of nephrotoxicity (about 20%) were found in a prospective randomised trial in patients with cancer which was
primarily designed to compare efficacy.5 in another, unrandomised, trial in which only a small and probably selected group of patients received amikacin, rates of nephrotoxicity of 25%, 23%, and 36% were found for amikacin, tobramycin, and gentamicin, 6
respectively.
We have reported the results of a prospective randomised trial in 113 patients, comparing the nephrotoxicity and ototoxicity of
Urology Service, Hôpital Bellevue, Centre Hospitalier Regional et Universitaire, 42023 Saint Etienne, France
D. CHANDRASEKAR
METRONIDAZOLE AND BRAIN ABSCESS
SIR,-Reviewing the chemotherapy of anaerobic infections Professor Bartlett (Aug. 28, p. 479) implies, referring to work from this centre,that it has been suggested that metronidazole may be active against both anaerobic and aerobic bacteria in brain abscesses. There -is evidence that metronidazole has some activity against certain aerobes in vitroand in vivo,3and it is possible that, by facilitates removal of associated killing anaerobes, metronidazole aerobes by polymorphs.44 However, we have consistently emphasised the importance of including, in regimens for the 7. Gatell JM, Zamora L, Araujo
V, Marin JL, Elena M, Ballesta A, Bonet M, Bohé M, Farré M, Puig J, García SanMiguel J. Prospective controlled comparison of the nephrotoxicity and auditory toxicity of tobramycin and amikacin. Eighth International Congress of Infectious and Parasitic Diseases (Stockholm, Sweden,
1. Addy
M, Ellis P, Turk D. Haemophilus epiglottitis: Nine recent cases in Oxford. Br Med J 1972; i: 40-42. 2 Nielsen H, Sørensen I, Hansen H. Peritoneal transport of vancomycin during peritoneal dialysis. Nephron 1979; 24: 274-77. 3. Rowttenbourg J, Jacqefingels E, N’Guyen M. Medical management of peritonitis. In: Lagrain M, ed. Proceedings of the International Symposium on Continuous Ambulatory Peritoneal Dialysis. Amsterdam: Excerpta Medica, 1979. 4 Eykyn S, Phillips I, Evans J. Vancomycin for staphylococcal shunt site infections in patients on regular haemodialysis. Br Med J 1970; iii: 80-82. 5. Feld R, Valdivieso M, Bodey GP, Rodriguez V. Comparison of amikacin and tobramycin in the treatment of infection in patients with cancer. J Infect Dis 1977; 135: 61-66. 6. Plaut ME, Schentag JJ, Jusko WJ. Aminoglycoside nephrotoxicity: assessment in critically ill patients. J Med 1979; 10: 257-66.
comparative
1982): abstr p 167 Ingham HR, Selkon JB, Roxby CM Bacteriological study of otogenic cerebral abscess: Chemotherapeutic role of metronidazole. Br Med J 1977; ii: 991-94. 2. Ingham HR, Hall CJ, Sisson PR, Tharagonnet D, Selkon JB. The activity of metronidazole against facultatively anaerobic bacteria. J Antimicrob Chemother 1980; 6: 343-47. 3. Onderonk AB, Louie TJ, Tally FP, Bartlett JG. Activity of metronidazole against Escherichia coli in experimental intraabdominal sepsis. J Antimicrob Chemother 1979; 5: 201-10. 4. Ingham HR, Sisson PR, Tharagonnet D, Selkon JB, Codd AA. Inhibition of phagocytosis in vitro by obligate anaerobes Lancet 1977; ii: 1252-54. 1.
614 of brain abscess, agents specifically active against aerobes besides those active against anaerobes. Currently we use ampicillin, gentamicin, and metronidazole, a combination which appears to be appropriate as judged by our latest published results which show a case fatality rate of 9 - 7% for the quinquennium
chemotherapy
1974-78.5
Public Health
Laboratory,
Institute of Pathology, General Hospital, Newcastle upon Tyne NE4 6BE
11 pressure and plasma renin concentration. Salt intake was the same during the two periods. We found a significant prolongation in bleeding time on n-3 PUFA, with no alteration in platelet numbers and a significant, though small, reduction in systolic blood pressure not associated with any alteration in plasma renin concentration. These results confirm the findings by Sanders and colleagues who, in an open study, found a reduction in blood pressure in volunteers given cod liver oil12 and fit in with data on blood pressure on Arctic
H. R. INGHAM
dwellers. 13,14
J. B. SELKON
n-3 PUFA, and EPA especially, depresses platelet production of the proaggregatory vasoconstrictive thromboxanes. We found no depressive (or even a stimulatory) influence on the production in vessels of antiaggregatory vasodilatatory prostacyclins.15,16 Our latest results strengthen our earlier warning that great care should be taken when transferring results obtained in this area of research from rats to man.
n-3 POLYUNSATURATED FATTY ACIDS AND ISCHAEMIC HEART DISEASE
SIR,-Our studies in Greenland Eskimos have focused attention the possible mechanisms by which dietary n-3 polyunsaturated
on
fatty acids (PUFA) may diminish the incidence of thromboembolic episodes, as indicated by the Greenlanders’ low risk of ischaemic heart disease. 6-8 Dr Hay and colleagues (June 5, p. 1269) found that’ feeding fish oil to patients with ischaemic heart disease resulted in a significant fall in plasma &bgr;-thromboglobulin and platelet factor 4 and a significant lengthening of platelet survival time. They interpret this as further evidence that n-3 PUFA, by reducing the platelet/vessel-wall interaction, may reduce the risk of ischaemic heart disease. Platelet counts, however, fell during the fish oil feeding period, which accords with other studies offish oil diets. 7-9 Dr Jones and Dr Davies (July 24, p. 221) draw attention to the possibility that the effect of n-3 PUFA on haemostasis might be due simply to the fall in platelet numbers, and they warn that in rats on eicosapentaenoic acid (EPA) supplements blood pressure rises, the increase possibly being related to suppression of vascular prostacyclin We have been studying these problems in man and give a preliminary report on our results in this letter. Twenty healthy men aged 25-40 were, in a double-blind crossover study, given daily either 3 g of n-3 PUFA (’MaxEPA’, Seven Seas Health Care Ltd) with a relative content of 20:5, n-3 and 22:6, n-6 of 60 and 40%, respectively, or 3 g of n-6 PUFA, consisting of linoleic acid (18:2, n-6), both in a 10 ml encapsulated oilform. The feeding periods were of 4 weeks’ duration separated by a 4 week washout period. The table gives the results of bleeding times (’Simplate’), platelet count, and recumbent (30 min) and standing (20 min) systolic blood
synthesis. 10
5. Alderson D, Strong AJ, Ingham HR, Selkon JB. Fifteen-year review of the mortality of brain abscess. Neurosurgery 1981; 8: 1-6. 6. Dyerberg J, Bang HO, Stoffersen E, Moncada S, Vane JR. Eicosapentaenoic acid and the prevention of thrombosis and atherosclerosis. Lancet 1978; ii: 117-19. 7. Dyerberg J, Bang HO. Haemostatic function and platelet polyunsaturated fatty acids in Eskimos. Lancet 1979; ii: 433-35. 8. Bang HO, Dyerberg J, Sinclair HM. The composition of the Eskimo food in north western Greenland. Am J Clin Nutr 1980, 33: 2657-61. 9. Goodnight SH, Harris WS, Connor WE The effects of dietary &psgr;3 fatty acids on platelet composition and function in man: A prospective, controlled study Blood
1981; 58: 880-85. 10.
Kramer HJ, Düsing R. Dietary administration of eicosapentaenoic and linolenic acid increases arterial blood pressure and suppresses vascular prostacyclin synthesis in the rat. Prostaglandins 1982; 23: 369-82.
Department of Clinical Chemistry. Aalborg Hospital (North), 9000 Aalborg, Denmark
J. DYERBERG J. Z. MORTENSEN A. H. NIELSEN E. B. SCHMIDT
SIR,-Dr Sinclair’s letter (Aug. 14, p. 393) on eicosa (or icosa)pentaenoic acid (EPA) and ischaemic heart disease, raises some important points about the different fish oils being used in trials. ’MaxEPA’ is a natural triglyceride concentrate from marine oils which is being used in large-scale trials in the U.K. and elsewhere and on which toxicity studies have been done. At one large hospital alone, over 150 patients have been on MaxEPA for the past 2112 years. It is established as a safe, pharmaceutically controlled natural source of EPA and docosahexaenoic acid, low in cetoleic acid, vitamin A, and vitamin D. The results from this work should not be extrapolated to less controlled products or other fish oils with different fatty acid combinations. In particular, concentrates based on catalytic splitting of triglycerides, ester production, solvent urea fractionation, and certain chromatographic techniques-which can give rise to products high in oxidised and polymeric byproducts combined with isomerisation of the EPA and docosahexaenoic acid-can result in misleading and possibly serious side-effects.
Kingsbury
et
al.and Dyerberg and Bang2 both reported products and confirm our own
anomalous results with such
findings. In our view the natural occurrence of these polyunsaturated fatty acids selectively in the beta position of the triglyceride molecule in natural marine oils is significant. The protection and specificity of this beta position is destroyed by the above concentration methods. The efficacy of synthetic concentrates must be properly assessed in long-term clinical trials (as has been done for MaxEPA), before any comparison can be made and before the literature becomes filled with contradictory data. Apart from Sinclair’s indication that there are fish oils and fish oils, there are also fish oils and synthetically derived products therefrom.
Scherhag R,
MEAN VALUES OF PLATELET
NUMBERS, BLEEDING TIME, SYSTOLIC 4 WEEKS OF EITHER 3 g n-3 OR
Refining Ltd, Marfleet, Hull HU9 5NJ
S. A. REED
BP
AND PLASMA RENIN AFTER
3 g n-6
Marfleet
PUFA PER DAY
11. Poulsen
K, Jørgensen J. An easy radioimmunological microassay of renin activity,
and substrate in human and animal plasma and tissues based on angiotensin I trapping by antibody. J Clin Endocrinol Metab 1974; 39: 816-25 12. Sanders TAB, Vickers M, Haines AP. Effect on blood lipids and haemostasis of a supplement of cod-liver oil, rich in eicosapentaenioc and docosahexaenoic acids, in healthy young men Clin Sci 1981; 61: 317-24. 13. Simper LB. Blood pressures in polar Eskimos. Ugeskr Laeg 1976; 138: 1757-58. 14. Bang HO, Dyerberg J Arktisk blodtryk. Ugeskr Laeg 1976; 138: 2503. 15. Dyerberg J, Jørgensen KA. The effect of arachidonic- and eicosapentaenoic acid on the synthesis of prostacyclin-like material in human umbilical vasculature. Artery 1980, 8: 12-17. 16. Dyerberg J, Jørgensen KA, Arnfred T. Human umbilical blood vessel converts all concentration
cis-5,8,11,14,17 eicosapentaenoic acid to prostaglandin I3 Prostaglandins 1981; 22: 857-62 Statistical analysis baseline values).
by
Wilcoxon
test
for
paired differences
(significance
of difference from
1. 2.
Kingsbury KJ, et al. Biochem J 1962; 84: 124. Dyerberg J, Bang HO. Nutritional factors modulating effects on metabolic processes. New York: Raven
Press, 1981.