- Email: [email protected]
PHAGE THERAPY
1287
The initial study population consisted of 5000 people randomly chosen from the voters’ roll; the numbers were chopped to about half by selection of those registered with specific general practitioners, also randomly chosen. In one year 258 people aged under seventy died unexpectedly or suddenly. Of these, 9 men had been running regularly for more than three months, but 4 of them could hardly be called serious runners, doing only about 60-100 min a week. The remaining 5 ran 180-800 min a week and included 2 marathon runners. This subgroup all had considerable coronary artery disease (more than 70% cross-sectional narrowing) at necropsy. In life, all had had risk factors such as a high serum cholesterol or hypertension or previous myocardial infarction or angina or diabetes mellitus. The incidence of exercise-related death in the Auckland study actually seems rather low, representing less than 3’ 5% of all cardiac deaths in the age-group studied. The few individuals who died were at very high risk with symptomatic disease. Thus, even without running, their lifespan would have been limited. We cannot say whether running lengthened or shortened their life. All we can be sure about is that even severe training such as marathon running cannot fully protect against fatal heart attacks, as initially shown by Noakes et al8 and now confirmed by Jackson et al7 and others.9,10 The earlier proposal of Bassler" that marathon running could confer "immunity" to atherosclerosis now firmly belongs to the realm of
cardiomythology. 12 form of screening required before regular exercise is undertaken? The only possible high-level that be undertaken en masse would be could procedure electrocardiography limited to standard leads in the resting position. Yet this procedure is virtually negated by the high incidence of "abnormalities" in welltrained athletes with seemingly normal hearts. Abnormalities of the ST-segment are found in nearly 10% of apparently normal athletes13and even exercise testing would not eliminate this cause of confusion. Echocardiography is still more impractical, though it
Is
some
should readily pick up hypertrophic cardiomyopathy which is probably the major cause of sudden death in young athletes. 14 Here too there could be a difficulty because some of the very highly trained athletes have "sports hearts" with physiological hypertrophy, which
8. Noakes TD, Opie LH, Rose AG, Kleynhans PHT. Autopsy-proved coronary atherosclerosis in marathon runners. N Engl J Med 1979, 301: 86-89. 9. Waller BF, Roberts WC, Sudden death while running in conditioned runners aged 40 years or over. Am J Cardiol 1980; 45: 1292-1300. 10. Handler JB, Asay RW, Warren SE, Shea PM Symptomatic coronary artery disease in a marathon runner. JAMA 1982; 248: 717-19. 11. Bassler TJ. Marathon running and immunity to atherosclerosis. Ann NY Acad Sci 1977; 301: 579-92. 12. Rennie D, Hollenberg NK. Cardiomythology and marathons. N Engl J Med 1979; 301: 103-04. 13 Spirito P, Maron BJ, Bonow RO, Epstein SE Prevalence and significance of an
abnormal
ST-segment response to exercise in a young athletic population. Am J Cardiol 1983; 51: 1663-66. 14. Maron BJ, Roberts WC, McAllister HA, Rosing DR. Epstein SE Sudden death in young athletes. Circulation 1980; 62: 218-29.
may
not
be
readily distinguished
from
pathological
hypertrophy. Those at risk of sudden death, especially when there is pre-existing cardiovascular disease, will die sooner rather than later. At present we have no sure means of knowing whether regular vigorous exercise prolongs or shortens the lifespan of such individuals. Intensive supervised exercise in those recovering from previous myocardial infarction seems no better than low-level exercise.15 Those in a high-risk group might be well advised to take their exercise gently, rather than engage in bursts of totally exhausting effort.
PHAGE THERAPY not the least of of bacteria of strains emergence often encoded possessing multiple drug resistance, by plasmids,and some attention is now being given to control of infectious diseases by other methods. One that may be worthy of reconsideration is the use of naturally occurring bacteriophages capable of destroying the bacterial cell both in vitro and in vivo. The therapeutic potential of bacteriophages was recognised as early as 1921,2 and some success was recorded with cholera and, to a lesser extent, with shigella dysentery and typhoid fever. In general, however, hopes were not fulfilled and various explanations have been offered including the inhibitory effects of blood, serum, and white cells on the lytic action of phages, and the selection and subsequent proliferation of phage-resistant mutants of bacterial cells. Wilson and Miles concluded that, unless the factors that prevented the antibacterial action of phages in living tissues could be identified, phage therapy would be of limited value.3 Fresh attempts to assess the potential of phages for control of bacterial infections may be stimulated by findings in animals reported by Williams Smith and Huggins,4,5 and some observations of Slopek and co-workers6 on phage therapy in patients with septicaemia. In one series of experiments, Williams Smith and Huggins showed that a single intramuscular dose of one naturally occurring Kl phage cured mice of potentially lethal infections induced by intravenous and intracerebral injection ofa pathogenic strain of Escherichia coli. 4 Phage therapy was compared for efficacy with five intramuscular antibiotics and it was superior to four of them. In addition, -some protection was afforded by administration of phage before challenge with the bacterial
ANTIBIOTIC chemotherapy has limitations,
which is due
to
the
mass
PA, Cunningham DA, Andrew GM, Buck CW, Jones NL, Kavanagh T, Oldridge NB, Parker JO. Shephard RJ, Sutton JR, Donner AP. Relation of exercise to the recurrence rate of myocardial infarction in men. Ontario Exercise Heart Collaborative Study. Am J Cardiol 1983, 51: 65-69. 1. Levy SB. Microbial resistance to antibiotics Lancet 1982; ii: 83-88. 2 Bruynoghe R, Maisin J. Essais de thérapeutique au moyen du bacteriophage. Compt
15. Rechnitzer
Rend Soc Biol 1921; 85: 1120-21. 3. Wilson GS, Miles AA. In: Topley and Wilson’s principles of bacteriology and immunity, 6th ed. London- Edward Arnold, 1975: 1634-36. 4. Williams Smith H, Huggins MB Successful treatment ofexperimental Eschenchia coli
infections
in mice using phage: Microbiol 1982; 128: 307-18.
its
general superiority
over
antibiotics. J Gen
1288 When phage therapy was extended to the control of E coli-induced diarrhoea in calves, piglets, and lambs, results were encouraging,5 although there may be some reservations about the proliferation of phage-resistant mutants in the calf intestine. Slopek et al6 reported favourable results with phage therapy in the treatment of patients with septicaemic infections caused by drug-resistant bacteria and concluded that phage therapy may be helpful in the treatment of long-term suppurative infections that do not respond to antibiotics. Phage therapy has some theoretical advantages over antibiotic chemotherapy. The ability of phages to multiply in living bacterial cells means that only one dose may be necessary to combat infection. By contrast, with an antibiotic repeated doses may be required before tissue concentrations are bactericidal, and this slow process can encourage stepwise mutational change to resistance in the bacterial cells; high concentrations of antibiotic in tissues can cause adverse reactions; and antibiotic combinations given by mouth can totally eliminate the non-pathogenic bacterial flora of the host, allowing superinfection by resistant strains. Ideally, phage therapy would eliminate only the target pathogen. Finally, there is evidence that phage-resistant mutants of bacterial pathogens are less virulent than phage-sensitive variants, whereas the virulence of pathogens with resistance plasmids acquired as a consequence of antibiotic use is not impaired (there have been reports of the occurrence and transfer of plasmids coding for both drug resistance and
pathogen.
enteropathogenicity 7 ,8). A possible obstacle to the large-scale use of phages for therapeutic purposes is their narrow range of activity. Williams Smith and Huggins suggest that this might be overcome if the phage attack points were extended to include different fimbrial antigens,and with techniques now available this is feasible. An important point is that naturally occurring phages may themselves contribute to the pathogenicity of bacterial strains. Takeda and Murphy9 have shown that, in one toxigenic strain of E coli, the genes controlling production of heat-labile toxin (LT) have been phage mediated;9 and Scotland et al10 have reported that, in an enteropathogenic E coli strain of serotype 026.H11, the genes coding for production of a cytotoxin active on Vero cells and designated VT were phage-mediated. Thus therapy with naturally occurring phages may have the undesirable effect of increasing the virulence of non-pathogenic indigenous bacteria by the introduction of genetic material that codes for toxin production. Naturally occurring phages will therefore have to be subjected to thorough genetic characterisation before they are applied on a wide scale to the control of infections in
5. Williams Smith
6.
7.
8.
9. 10.
man.
H, Huggins MB. Effectiveness of phage in treating experimental Escherichia coli diarrhoea in calves, piglets and lambs J Gen Microbiol 1983; 129: 2659-75. Slopek S, Durlakowa I, Weber-Dabrowska B, Kucharewicz-Krukowska A, Dabrowski M, Bisikiewicz R. Results of bacteriophage treatment of suppurative bacterial infection 1. General evaluation of the results. Arch Immunol Ther Exp 1983; 31: 267-91. Scotland SM, Gross RJ, Cheasty T, Rowe B. The occurrence of plasmids carrying genes for both enterotoxin production and drug resistance in Escherichia coli of human origin J Hyg 1979; 83: 531-38. Wachsmuth K, Deboy J, Birkness K, Sack D, Wells J. Genetic transfer of antimicrobial resistance and enterotoxigenicity among Escherichia coli strains. Antimicrob Ag Chemother 1983; 23: 278-83. Takeda Y, Murphy JR Bacteriophage conversions of heat-labile enterotoxins in Escherichia coli J Bacteriol 1978; 133: 172-77. Scotland S, Smith HR, Willshaw GA, Rowe B Vero cytotoxin production in strains of Escherichia coli is determined by genes carried on bacteriophage. Lancet 1983; n: 216.
TREATMENT OF LACTICACIDOSIS WITH DICHLOROACETATE IN the search tor substances that
might
have usetul blood-
glucose lowering effects in diabetes, Randle and his associates 1,2 studied several compounds with disinhibiting action at the rate-limiting steps in the glycolytic pathway-ie, at hexokinase, phosphofructokinase, and pyruvate dehydrogenase. Dichloroacetate was known to lower blood sugar in the diabetic rat3 and in subsequent experiments was found to reverse the inhibition of pyruvate dehydrogenase by fat oxidation in the rat heart in vitro1,2and the dog heart in vivo.2 In the dog studies, arterial lactate and pyruvate fell substantially and extraction of both these compounds by the heart was increased. These findings raised the possibility that dichloroacetate might be used to help lower the lactate in patients with severe lacticacidosis by reducing the amount of lactate released into the circulation from peripheral tissues. This effect was confirmed in animals4.6 and in man.7 Although dichloroacetate has no direct effect on the hepatic portion of the Cori cycle, in which lactate is recycled to glucose via the gluconeogenic pathway, it may have a secondary effect on the liver by increasing bicarbonate production and reversing the decreased hepatic extraction of lactate that is associated with a low intracellular pH. The usually fatal lacticacidosis induced by phenformin in diabetics was due to inhibition of hepatic gluconeogenesis. When dichloroacetate was infused, plasma lactate fell and there was possible clinical benefit.8,9 Since phenformin is no longer on the market the condition is unlikely to arise again. Stackpoole and colleagues10 have lately described the use of dichloroacetate in a heterogeneous group of thirteen nondiabetic, critically ill patients with lacticacidosis. Using up to three 30 min infusions of 35 or 50 mg sodium dichloroacetate per kilogram bodyweight, at intervals of 2 h, they caused arterial lactate to fall in situations where bicarbonate had made no impression. In seven patients arterial lactate was reduced by at least 20% with a mean reduction in this subgroup of 80%. An unexpected and unexplained observation in most of the patients was a 20% rise in cardiac output and systolic blood-pressure. Despite biochemical and
physiological improvement, however, only
one
patient
survived to leave hospital-perhaps reflecting the severity of the underlying illness. Stackpoole and co-workers also reviewed reports of fourteen other patients treated for lacticacidosis-six children with congenital forms of 1 Whitehouse S, Randle PJ. Activation of pyruvate dehydrogenase in perfused rat heart by dichloroacetate. Biochem J 1973; 134: 651-53. 2. McAllister A, Allison SP, Randle PJ Effects of dichloroacetate on the metabolism of glucose, pyruvate, acetate, 3 hydroxybutyrate and palmitate in rat diaphragm and heart muscle and on the extraction of glucose, lactate pyruvate and free fatty acids by dog heart in vivo. Biochem J 1973; 134: 1067-81. 3. Lorini M, Ciman M. Hypoglycaemic action of diisopropyl ammonium salts in experimental diabetes Biochem Pharmacol 1962; 11: 823-27. 4 Holloway PAH, Alberti KGMM. Reversal of phenformin induced hyperlactataemia by dichloroacetate in normal and diabetic rats. Diaberologia 1975; 11: 350-51
(abstr). A, Valette G, Ribes G, Loubatieres-Marianm MM, Rodot AM. Dichloroacetate de sodium; son application a la therapeutique des hyperlactatemies experimentales. Diabète Metab 1978; 4: 5-11. Park R, Arieff AI Treatment of lactic acidosis with dichloroacetate in dogs. J Clin Invest 1982; 70: 853-62. Wells PG, Moore GW, Rabin O, Wilkinson GR, Oates JA, Stackpoole PW Metabolic effects and pharmacokinetics of intravenously administered dichloroacetate in humans Diabetologia 1980; 19: 109-13. Irsigler K, Brandle J, Kaspar L, Kritz H, Lageder H, Regal H Treatment of biguanide induced lactic acidosis with dichloroacetate 3 case histories Arzneimittel Forsch 1979; 29: 555-59. Blackshear PJ, Fang LST, Axelrod L. Treatment of severe lactic acidosis with dichloroacetate. Diabetes Care 1982; 5: 391-94. Stackpoole PW, Harman EM, Curry SH, Baumgartner TG, Misbin RI Treatment of lactic acidosis with dichloroacetate. N Engl J Med 1983; 309: 390-96.
5 Loubatieres
6 7
8.
9. 10.
The initial study population consisted of 5000 people randomly chosen from the voters’ roll; the numbers were chopped to about half by selection of those registered with specific general practitioners, also randomly chosen. In one year 258 people aged under seventy died unexpectedly or suddenly. Of these, 9 men had been running regularly for more than three months, but 4 of them could hardly be called serious runners, doing only about 60-100 min a week. The remaining 5 ran 180-800 min a week and included 2 marathon runners. This subgroup all had considerable coronary artery disease (more than 70% cross-sectional narrowing) at necropsy. In life, all had had risk factors such as a high serum cholesterol or hypertension or previous myocardial infarction or angina or diabetes mellitus. The incidence of exercise-related death in the Auckland study actually seems rather low, representing less than 3’ 5% of all cardiac deaths in the age-group studied. The few individuals who died were at very high risk with symptomatic disease. Thus, even without running, their lifespan would have been limited. We cannot say whether running lengthened or shortened their life. All we can be sure about is that even severe training such as marathon running cannot fully protect against fatal heart attacks, as initially shown by Noakes et al8 and now confirmed by Jackson et al7 and others.9,10 The earlier proposal of Bassler" that marathon running could confer "immunity" to atherosclerosis now firmly belongs to the realm of
cardiomythology. 12 form of screening required before regular exercise is undertaken? The only possible high-level that be undertaken en masse would be could procedure electrocardiography limited to standard leads in the resting position. Yet this procedure is virtually negated by the high incidence of "abnormalities" in welltrained athletes with seemingly normal hearts. Abnormalities of the ST-segment are found in nearly 10% of apparently normal athletes13and even exercise testing would not eliminate this cause of confusion. Echocardiography is still more impractical, though it
Is
some
should readily pick up hypertrophic cardiomyopathy which is probably the major cause of sudden death in young athletes. 14 Here too there could be a difficulty because some of the very highly trained athletes have "sports hearts" with physiological hypertrophy, which
8. Noakes TD, Opie LH, Rose AG, Kleynhans PHT. Autopsy-proved coronary atherosclerosis in marathon runners. N Engl J Med 1979, 301: 86-89. 9. Waller BF, Roberts WC, Sudden death while running in conditioned runners aged 40 years or over. Am J Cardiol 1980; 45: 1292-1300. 10. Handler JB, Asay RW, Warren SE, Shea PM Symptomatic coronary artery disease in a marathon runner. JAMA 1982; 248: 717-19. 11. Bassler TJ. Marathon running and immunity to atherosclerosis. Ann NY Acad Sci 1977; 301: 579-92. 12. Rennie D, Hollenberg NK. Cardiomythology and marathons. N Engl J Med 1979; 301: 103-04. 13 Spirito P, Maron BJ, Bonow RO, Epstein SE Prevalence and significance of an
abnormal
ST-segment response to exercise in a young athletic population. Am J Cardiol 1983; 51: 1663-66. 14. Maron BJ, Roberts WC, McAllister HA, Rosing DR. Epstein SE Sudden death in young athletes. Circulation 1980; 62: 218-29.
may
not
be
readily distinguished
from
pathological
hypertrophy. Those at risk of sudden death, especially when there is pre-existing cardiovascular disease, will die sooner rather than later. At present we have no sure means of knowing whether regular vigorous exercise prolongs or shortens the lifespan of such individuals. Intensive supervised exercise in those recovering from previous myocardial infarction seems no better than low-level exercise.15 Those in a high-risk group might be well advised to take their exercise gently, rather than engage in bursts of totally exhausting effort.
PHAGE THERAPY not the least of of bacteria of strains emergence often encoded possessing multiple drug resistance, by plasmids,and some attention is now being given to control of infectious diseases by other methods. One that may be worthy of reconsideration is the use of naturally occurring bacteriophages capable of destroying the bacterial cell both in vitro and in vivo. The therapeutic potential of bacteriophages was recognised as early as 1921,2 and some success was recorded with cholera and, to a lesser extent, with shigella dysentery and typhoid fever. In general, however, hopes were not fulfilled and various explanations have been offered including the inhibitory effects of blood, serum, and white cells on the lytic action of phages, and the selection and subsequent proliferation of phage-resistant mutants of bacterial cells. Wilson and Miles concluded that, unless the factors that prevented the antibacterial action of phages in living tissues could be identified, phage therapy would be of limited value.3 Fresh attempts to assess the potential of phages for control of bacterial infections may be stimulated by findings in animals reported by Williams Smith and Huggins,4,5 and some observations of Slopek and co-workers6 on phage therapy in patients with septicaemia. In one series of experiments, Williams Smith and Huggins showed that a single intramuscular dose of one naturally occurring Kl phage cured mice of potentially lethal infections induced by intravenous and intracerebral injection ofa pathogenic strain of Escherichia coli. 4 Phage therapy was compared for efficacy with five intramuscular antibiotics and it was superior to four of them. In addition, -some protection was afforded by administration of phage before challenge with the bacterial
ANTIBIOTIC chemotherapy has limitations,
which is due
to
the
mass
PA, Cunningham DA, Andrew GM, Buck CW, Jones NL, Kavanagh T, Oldridge NB, Parker JO. Shephard RJ, Sutton JR, Donner AP. Relation of exercise to the recurrence rate of myocardial infarction in men. Ontario Exercise Heart Collaborative Study. Am J Cardiol 1983, 51: 65-69. 1. Levy SB. Microbial resistance to antibiotics Lancet 1982; ii: 83-88. 2 Bruynoghe R, Maisin J. Essais de thérapeutique au moyen du bacteriophage. Compt
15. Rechnitzer
Rend Soc Biol 1921; 85: 1120-21. 3. Wilson GS, Miles AA. In: Topley and Wilson’s principles of bacteriology and immunity, 6th ed. London- Edward Arnold, 1975: 1634-36. 4. Williams Smith H, Huggins MB Successful treatment ofexperimental Eschenchia coli
infections
in mice using phage: Microbiol 1982; 128: 307-18.
its
general superiority
over
antibiotics. J Gen
1288 When phage therapy was extended to the control of E coli-induced diarrhoea in calves, piglets, and lambs, results were encouraging,5 although there may be some reservations about the proliferation of phage-resistant mutants in the calf intestine. Slopek et al6 reported favourable results with phage therapy in the treatment of patients with septicaemic infections caused by drug-resistant bacteria and concluded that phage therapy may be helpful in the treatment of long-term suppurative infections that do not respond to antibiotics. Phage therapy has some theoretical advantages over antibiotic chemotherapy. The ability of phages to multiply in living bacterial cells means that only one dose may be necessary to combat infection. By contrast, with an antibiotic repeated doses may be required before tissue concentrations are bactericidal, and this slow process can encourage stepwise mutational change to resistance in the bacterial cells; high concentrations of antibiotic in tissues can cause adverse reactions; and antibiotic combinations given by mouth can totally eliminate the non-pathogenic bacterial flora of the host, allowing superinfection by resistant strains. Ideally, phage therapy would eliminate only the target pathogen. Finally, there is evidence that phage-resistant mutants of bacterial pathogens are less virulent than phage-sensitive variants, whereas the virulence of pathogens with resistance plasmids acquired as a consequence of antibiotic use is not impaired (there have been reports of the occurrence and transfer of plasmids coding for both drug resistance and
pathogen.
enteropathogenicity 7 ,8). A possible obstacle to the large-scale use of phages for therapeutic purposes is their narrow range of activity. Williams Smith and Huggins suggest that this might be overcome if the phage attack points were extended to include different fimbrial antigens,and with techniques now available this is feasible. An important point is that naturally occurring phages may themselves contribute to the pathogenicity of bacterial strains. Takeda and Murphy9 have shown that, in one toxigenic strain of E coli, the genes controlling production of heat-labile toxin (LT) have been phage mediated;9 and Scotland et al10 have reported that, in an enteropathogenic E coli strain of serotype 026.H11, the genes coding for production of a cytotoxin active on Vero cells and designated VT were phage-mediated. Thus therapy with naturally occurring phages may have the undesirable effect of increasing the virulence of non-pathogenic indigenous bacteria by the introduction of genetic material that codes for toxin production. Naturally occurring phages will therefore have to be subjected to thorough genetic characterisation before they are applied on a wide scale to the control of infections in
5. Williams Smith
6.
7.
8.
9. 10.
man.
H, Huggins MB. Effectiveness of phage in treating experimental Escherichia coli diarrhoea in calves, piglets and lambs J Gen Microbiol 1983; 129: 2659-75. Slopek S, Durlakowa I, Weber-Dabrowska B, Kucharewicz-Krukowska A, Dabrowski M, Bisikiewicz R. Results of bacteriophage treatment of suppurative bacterial infection 1. General evaluation of the results. Arch Immunol Ther Exp 1983; 31: 267-91. Scotland SM, Gross RJ, Cheasty T, Rowe B. The occurrence of plasmids carrying genes for both enterotoxin production and drug resistance in Escherichia coli of human origin J Hyg 1979; 83: 531-38. Wachsmuth K, Deboy J, Birkness K, Sack D, Wells J. Genetic transfer of antimicrobial resistance and enterotoxigenicity among Escherichia coli strains. Antimicrob Ag Chemother 1983; 23: 278-83. Takeda Y, Murphy JR Bacteriophage conversions of heat-labile enterotoxins in Escherichia coli J Bacteriol 1978; 133: 172-77. Scotland S, Smith HR, Willshaw GA, Rowe B Vero cytotoxin production in strains of Escherichia coli is determined by genes carried on bacteriophage. Lancet 1983; n: 216.
TREATMENT OF LACTICACIDOSIS WITH DICHLOROACETATE IN the search tor substances that
might
have usetul blood-
glucose lowering effects in diabetes, Randle and his associates 1,2 studied several compounds with disinhibiting action at the rate-limiting steps in the glycolytic pathway-ie, at hexokinase, phosphofructokinase, and pyruvate dehydrogenase. Dichloroacetate was known to lower blood sugar in the diabetic rat3 and in subsequent experiments was found to reverse the inhibition of pyruvate dehydrogenase by fat oxidation in the rat heart in vitro1,2and the dog heart in vivo.2 In the dog studies, arterial lactate and pyruvate fell substantially and extraction of both these compounds by the heart was increased. These findings raised the possibility that dichloroacetate might be used to help lower the lactate in patients with severe lacticacidosis by reducing the amount of lactate released into the circulation from peripheral tissues. This effect was confirmed in animals4.6 and in man.7 Although dichloroacetate has no direct effect on the hepatic portion of the Cori cycle, in which lactate is recycled to glucose via the gluconeogenic pathway, it may have a secondary effect on the liver by increasing bicarbonate production and reversing the decreased hepatic extraction of lactate that is associated with a low intracellular pH. The usually fatal lacticacidosis induced by phenformin in diabetics was due to inhibition of hepatic gluconeogenesis. When dichloroacetate was infused, plasma lactate fell and there was possible clinical benefit.8,9 Since phenformin is no longer on the market the condition is unlikely to arise again. Stackpoole and colleagues10 have lately described the use of dichloroacetate in a heterogeneous group of thirteen nondiabetic, critically ill patients with lacticacidosis. Using up to three 30 min infusions of 35 or 50 mg sodium dichloroacetate per kilogram bodyweight, at intervals of 2 h, they caused arterial lactate to fall in situations where bicarbonate had made no impression. In seven patients arterial lactate was reduced by at least 20% with a mean reduction in this subgroup of 80%. An unexpected and unexplained observation in most of the patients was a 20% rise in cardiac output and systolic blood-pressure. Despite biochemical and
physiological improvement, however, only
one
patient
survived to leave hospital-perhaps reflecting the severity of the underlying illness. Stackpoole and co-workers also reviewed reports of fourteen other patients treated for lacticacidosis-six children with congenital forms of 1 Whitehouse S, Randle PJ. Activation of pyruvate dehydrogenase in perfused rat heart by dichloroacetate. Biochem J 1973; 134: 651-53. 2. McAllister A, Allison SP, Randle PJ Effects of dichloroacetate on the metabolism of glucose, pyruvate, acetate, 3 hydroxybutyrate and palmitate in rat diaphragm and heart muscle and on the extraction of glucose, lactate pyruvate and free fatty acids by dog heart in vivo. Biochem J 1973; 134: 1067-81. 3. Lorini M, Ciman M. Hypoglycaemic action of diisopropyl ammonium salts in experimental diabetes Biochem Pharmacol 1962; 11: 823-27. 4 Holloway PAH, Alberti KGMM. Reversal of phenformin induced hyperlactataemia by dichloroacetate in normal and diabetic rats. Diaberologia 1975; 11: 350-51
(abstr). A, Valette G, Ribes G, Loubatieres-Marianm MM, Rodot AM. Dichloroacetate de sodium; son application a la therapeutique des hyperlactatemies experimentales. Diabète Metab 1978; 4: 5-11. Park R, Arieff AI Treatment of lactic acidosis with dichloroacetate in dogs. J Clin Invest 1982; 70: 853-62. Wells PG, Moore GW, Rabin O, Wilkinson GR, Oates JA, Stackpoole PW Metabolic effects and pharmacokinetics of intravenously administered dichloroacetate in humans Diabetologia 1980; 19: 109-13. Irsigler K, Brandle J, Kaspar L, Kritz H, Lageder H, Regal H Treatment of biguanide induced lactic acidosis with dichloroacetate 3 case histories Arzneimittel Forsch 1979; 29: 555-59. Blackshear PJ, Fang LST, Axelrod L. Treatment of severe lactic acidosis with dichloroacetate. Diabetes Care 1982; 5: 391-94. Stackpoole PW, Harman EM, Curry SH, Baumgartner TG, Misbin RI Treatment of lactic acidosis with dichloroacetate. N Engl J Med 1983; 309: 390-96.
5 Loubatieres
6 7
8.
9. 10.