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CLOFIBRATE AND HYPERLIPIDAEMIA
1241
Letters
to
group when mortality during the first year after leaving the trial was included in the analysis. There is not yet any evidence in this trial for a drug-related increase in mortality from other causes.
the Editor
Guy’s Hospital, CLOFIBRATE AND HYPERLIPIDAEMIA
(2.) Severe endogenous hypertriglyceridaemia (type IV- V hyperlipoproteinaemia). In this condition there is a concentrationrelated risk of acute relapsing pancreatitis when plasma triglyceride levels exceed 6-7 mmol/1. Although many patients respond well to correction of obesity, dietary modification, and treatment of underlying causes (e.g., alcohol abuse, diabetes mellitus), a significant proportion remain severely hypertriglyceridaemic. In these subjects a good lipid-lowering effect is often achieved with either nicotinic acid or clofibrate, but nicotinic acid has the disadvantage that it may worsen diabetes mellitus and hyperuricaemia (common in endogenous hypertriglyceridaemia). (3.) Familial combined hyperlipidaemia is the commonest genetic hyperlipidaemia in ischaemic heart disease patients.4 For the few patients who do not respond adequately to diet, either cholestyramine, clofibrate, nicotinic acid, or probucol may empirically be found to be optimal. (4.) A fourth indication for clofibrate, in selected cases, is diabetic retinopathy when the clinical picture is dominated by massive accumulation of retinal exudate, especially if it encroaches on the macular region. Dietary measures and improved metabolic control are of great importance, and, although clearance of exudate with clofibrate fails to restore visual loss, the drug may slow the new deposition of exudate.5 In advancing maculopathy, early consideration of photocoagulation is of course very important. In all of these conditions the effect of clofibrate on plasma lipids must be monitored regularly, and treatment with the drug must be stopped if the response is inadequate. A recent interim report from the Stockholm trial of secondary prevention of ischaemic heart disease (IHD) should be taken into account.6 Patients given nicotinic acid plus clofibrate (achieving a substantial mean plasma cholesterol reduction of approximately 15070) had significantly lower 5-year incidences of non-fatal myocardial infarction and of major IHD events than patients treated by diet alone. Although the group difference in IHD mortality during the trial just failed to reach statistical significance (p = 0 - 06) there were significantly fewer (p=0-007) IHD deaths in the drug-treated 1.
Coronary Drug Project Group.
Clofibrate and niacin
in
coronary disease.
St Thomas’ Hospital, London SE1
H. KEEN B. LEWIS N. E. MILLER
St Mary’s Hospital, London W2
V. WYNN
London SE1
SIR,-Clinical indications for the use of clofibrate have come under scrutiny as a result of the findings of two extensive clinical trials of this drug. 1,2 Risk-benefit considerations require that its use be confined to those disorders in which there is good reason to anticipate clinical benefit. The notice on clofibrate distributed to medical practitioners by the Committee on Safety of Medicines refers to specific hyperlipidaemias. As physicians with responsibility for the care of such patients, we should like to suggest the following in extension of this recommendation: (1.) Type III hyperlipoproteinaemia (broad-beta disease)-a condition in which early-onset peripheral vascular disease and cardiac ischaemia are common. Although this disorder may respond adequately to dietary measures, medication is needed to achieve normal plasma lipid concentrations in most patients. Clofibrate is a most effective lipid-lowering drug in such patients,3producing normal or near normal plasma cholesterol concentrations and rapid disappearance of xanthomas.
JAMA
PONTIAC FEVER AND AMOEBAE
SIR,-The intriguing aspects of Pontiac fever are that it resembles although of longer duration, as Dr Rowbotham points out (Nov. 1, p. 969), and is associated with a rise in antibody
humidifier fever,
specific for Legionella pneumophila,l -yet it results in pneumonia nor deaths. We support the hypothesis that fever is
a
neither
Pontiac form of humidifier fever in association with L.
pneumophila antigen. Like Rowbotham we have fed L. pneumophila to the soil amoeba Acanthamoeba polyphaga. Our intention was to see if the legionella endotoxin2or exotoxin3might be strong enough to disable the amoeba and cause premature encystment such that viable legionellae might be enabled to survive drying within the cysts and so explain survival in environmental conditions of alternate wet and
dry. We found that A. polyphaga fed as readily on living L. pneumophila serogroup 1 strain Pontiac and the recently isolated Cambridge 14 strain at room temperature (21-23°C) as it did on Klebsiella and other coliform organisms. In fact the L. pneumophila was so readily consumed that viable organisms were difficult to recover, on solid media, after 4 days, and by 7 days the amoebae encysted from lack of food, as did amoebae fed on Klebsiella spp. Cultures ofL. pneumophila in the absence of amoebae survived air drying at room temperature for at least 15 days and were still readily recoverable. At that time the agar was still tacky and might resemble the state of dryness of a colloidal clay or dried muddy sediment. Once the agar was completely dry and crisply friable the organisms were no longer recoverable (46 days). Thus L. pneumophila can survive more drying than one might expect. It is probably less well able to survive when acting as fodder for amoebae and these predators may well act as cleaners in humidifier systems. Amoebae could reduce the number of viable legionellae below that required to cause clinical infection by inhalation. They could present a package of ingested legionellae and possibly also provide legionella antigenic debris. Inhalation of these materials could provide an immunising stimulus and protect Pontiac fever candidates from legionnaires’ disease yet give rise to the antibody response of it. Public Health Laboratory, Addenbrooke’s Hospital,
NAGINGTON D. J. SMITH
J.
Cambridge CB2 2QW
HEPATITIS A IN NON-HUMAN PRIMATES IN NATURE
SIR,-Since Hillis’ report5 of an outbreak of viral hepatitis in veterinarians exposed to newly imported chimpanzees at an airforce base in New Mexico, more than 200 human cases of viral hepatitis subsequent to contact with newly imported non-human primates have been reported. It is now generally accepted that non-human
1975; 231: 360-81. 2. Committee of Principal Investigators. WHO cooperative trial on primary prevention of ischaemic heart disease using clofibrate to lower serum cholesterol: Mortality follow-up. Lancet 1980; ii: 379-85. 3. Levy RI, Fredrickson DS, Schulman R et al Dietary and drug treatment of primary hyperlipoproteinemia. Ann Intern Med 1972, 77: 267-94 4. Goldstein JL, Schrott HG, Hazzard WR, Bierman EL, Motulsky AG. Hyperlipidemia in coronary artery disease II. Genetic analysis of lipid levels in 176 families and delineation ofa new inherited disorder, combined hyerlipidemia. J Clin Invest 1973; 52: 1544-68. 5. Cullen JF, Town SM, Campbell CJ. A double-blind trial of Atromid-S in exudative diabetic retinopathy Trans Ophthalmol Soc UK 1974; 94: 554-62. 6. Rosenhamer G, Carlson LA. Effect of combined clofibrate-nicotinic acid treatment in ischemic heart disease. Atherosclerosis 1980; 37: 129-38.
TH, Gregg MB, Berman B, Mallison G, Rhodes WW, Kassanol I. Pontiac fever: epidemic of unknown etiology in a health department I Clinical and epidemiologic aspects Am J Epidermol 1978; 107: 149-60. Fumarola D. Legionnaires’ disease agent and Limulus endotoxin assay. Microbiologica 1979; 2: 89-92. Baine WB, Rasheed JK, Mackel DC, Bopp CA, Wells JG, Kaufmann AF. Exotoxin activity associated with the Legionnaires disease bacterium. J Clin Microbiol 1979; 9:
1. Glick
an
2. 3.
453-56.
Smith DJ, Wreghitt TG. Isolation of Legionnaires disease organism Cambridge Lancet 1978; ii 1144
4.
Nagington J,
5.
Hillis WD. An outbreak of infectious hepatitis among chimpanzee handlers at a United States Air Force base
Am JHyg 1961;
73: 316-28
in
Letters
to
group when mortality during the first year after leaving the trial was included in the analysis. There is not yet any evidence in this trial for a drug-related increase in mortality from other causes.
the Editor
Guy’s Hospital, CLOFIBRATE AND HYPERLIPIDAEMIA
(2.) Severe endogenous hypertriglyceridaemia (type IV- V hyperlipoproteinaemia). In this condition there is a concentrationrelated risk of acute relapsing pancreatitis when plasma triglyceride levels exceed 6-7 mmol/1. Although many patients respond well to correction of obesity, dietary modification, and treatment of underlying causes (e.g., alcohol abuse, diabetes mellitus), a significant proportion remain severely hypertriglyceridaemic. In these subjects a good lipid-lowering effect is often achieved with either nicotinic acid or clofibrate, but nicotinic acid has the disadvantage that it may worsen diabetes mellitus and hyperuricaemia (common in endogenous hypertriglyceridaemia). (3.) Familial combined hyperlipidaemia is the commonest genetic hyperlipidaemia in ischaemic heart disease patients.4 For the few patients who do not respond adequately to diet, either cholestyramine, clofibrate, nicotinic acid, or probucol may empirically be found to be optimal. (4.) A fourth indication for clofibrate, in selected cases, is diabetic retinopathy when the clinical picture is dominated by massive accumulation of retinal exudate, especially if it encroaches on the macular region. Dietary measures and improved metabolic control are of great importance, and, although clearance of exudate with clofibrate fails to restore visual loss, the drug may slow the new deposition of exudate.5 In advancing maculopathy, early consideration of photocoagulation is of course very important. In all of these conditions the effect of clofibrate on plasma lipids must be monitored regularly, and treatment with the drug must be stopped if the response is inadequate. A recent interim report from the Stockholm trial of secondary prevention of ischaemic heart disease (IHD) should be taken into account.6 Patients given nicotinic acid plus clofibrate (achieving a substantial mean plasma cholesterol reduction of approximately 15070) had significantly lower 5-year incidences of non-fatal myocardial infarction and of major IHD events than patients treated by diet alone. Although the group difference in IHD mortality during the trial just failed to reach statistical significance (p = 0 - 06) there were significantly fewer (p=0-007) IHD deaths in the drug-treated 1.
Coronary Drug Project Group.
Clofibrate and niacin
in
coronary disease.
St Thomas’ Hospital, London SE1
H. KEEN B. LEWIS N. E. MILLER
St Mary’s Hospital, London W2
V. WYNN
London SE1
SIR,-Clinical indications for the use of clofibrate have come under scrutiny as a result of the findings of two extensive clinical trials of this drug. 1,2 Risk-benefit considerations require that its use be confined to those disorders in which there is good reason to anticipate clinical benefit. The notice on clofibrate distributed to medical practitioners by the Committee on Safety of Medicines refers to specific hyperlipidaemias. As physicians with responsibility for the care of such patients, we should like to suggest the following in extension of this recommendation: (1.) Type III hyperlipoproteinaemia (broad-beta disease)-a condition in which early-onset peripheral vascular disease and cardiac ischaemia are common. Although this disorder may respond adequately to dietary measures, medication is needed to achieve normal plasma lipid concentrations in most patients. Clofibrate is a most effective lipid-lowering drug in such patients,3producing normal or near normal plasma cholesterol concentrations and rapid disappearance of xanthomas.
JAMA
PONTIAC FEVER AND AMOEBAE
SIR,-The intriguing aspects of Pontiac fever are that it resembles although of longer duration, as Dr Rowbotham points out (Nov. 1, p. 969), and is associated with a rise in antibody
humidifier fever,
specific for Legionella pneumophila,l -yet it results in pneumonia nor deaths. We support the hypothesis that fever is
a
neither
Pontiac form of humidifier fever in association with L.
pneumophila antigen. Like Rowbotham we have fed L. pneumophila to the soil amoeba Acanthamoeba polyphaga. Our intention was to see if the legionella endotoxin2or exotoxin3might be strong enough to disable the amoeba and cause premature encystment such that viable legionellae might be enabled to survive drying within the cysts and so explain survival in environmental conditions of alternate wet and
dry. We found that A. polyphaga fed as readily on living L. pneumophila serogroup 1 strain Pontiac and the recently isolated Cambridge 14 strain at room temperature (21-23°C) as it did on Klebsiella and other coliform organisms. In fact the L. pneumophila was so readily consumed that viable organisms were difficult to recover, on solid media, after 4 days, and by 7 days the amoebae encysted from lack of food, as did amoebae fed on Klebsiella spp. Cultures ofL. pneumophila in the absence of amoebae survived air drying at room temperature for at least 15 days and were still readily recoverable. At that time the agar was still tacky and might resemble the state of dryness of a colloidal clay or dried muddy sediment. Once the agar was completely dry and crisply friable the organisms were no longer recoverable (46 days). Thus L. pneumophila can survive more drying than one might expect. It is probably less well able to survive when acting as fodder for amoebae and these predators may well act as cleaners in humidifier systems. Amoebae could reduce the number of viable legionellae below that required to cause clinical infection by inhalation. They could present a package of ingested legionellae and possibly also provide legionella antigenic debris. Inhalation of these materials could provide an immunising stimulus and protect Pontiac fever candidates from legionnaires’ disease yet give rise to the antibody response of it. Public Health Laboratory, Addenbrooke’s Hospital,
NAGINGTON D. J. SMITH
J.
Cambridge CB2 2QW
HEPATITIS A IN NON-HUMAN PRIMATES IN NATURE
SIR,-Since Hillis’ report5 of an outbreak of viral hepatitis in veterinarians exposed to newly imported chimpanzees at an airforce base in New Mexico, more than 200 human cases of viral hepatitis subsequent to contact with newly imported non-human primates have been reported. It is now generally accepted that non-human
1975; 231: 360-81. 2. Committee of Principal Investigators. WHO cooperative trial on primary prevention of ischaemic heart disease using clofibrate to lower serum cholesterol: Mortality follow-up. Lancet 1980; ii: 379-85. 3. Levy RI, Fredrickson DS, Schulman R et al Dietary and drug treatment of primary hyperlipoproteinemia. Ann Intern Med 1972, 77: 267-94 4. Goldstein JL, Schrott HG, Hazzard WR, Bierman EL, Motulsky AG. Hyperlipidemia in coronary artery disease II. Genetic analysis of lipid levels in 176 families and delineation ofa new inherited disorder, combined hyerlipidemia. J Clin Invest 1973; 52: 1544-68. 5. Cullen JF, Town SM, Campbell CJ. A double-blind trial of Atromid-S in exudative diabetic retinopathy Trans Ophthalmol Soc UK 1974; 94: 554-62. 6. Rosenhamer G, Carlson LA. Effect of combined clofibrate-nicotinic acid treatment in ischemic heart disease. Atherosclerosis 1980; 37: 129-38.
TH, Gregg MB, Berman B, Mallison G, Rhodes WW, Kassanol I. Pontiac fever: epidemic of unknown etiology in a health department I Clinical and epidemiologic aspects Am J Epidermol 1978; 107: 149-60. Fumarola D. Legionnaires’ disease agent and Limulus endotoxin assay. Microbiologica 1979; 2: 89-92. Baine WB, Rasheed JK, Mackel DC, Bopp CA, Wells JG, Kaufmann AF. Exotoxin activity associated with the Legionnaires disease bacterium. J Clin Microbiol 1979; 9:
1. Glick
an
2. 3.
453-56.
Smith DJ, Wreghitt TG. Isolation of Legionnaires disease organism Cambridge Lancet 1978; ii 1144
4.
Nagington J,
5.
Hillis WD. An outbreak of infectious hepatitis among chimpanzee handlers at a United States Air Force base
Am JHyg 1961;
73: 316-28
in