CORRESPONDENCE
this asymptomatic patient suggests that particular attention must be given to the prescribing of zidovudine in patients with microcytosis without iron deficiency. We suggest that hemoglobin electrophoresis, family study, and eventually other studies of hemoglobin should be systematically performed before treatment in patients presenting with microcytosis, no matter what the daily dosage of zidovudine prescribed or what the clinical status regarding HIV infection.
correct. Two new drug applications, 19-280 for tablets and 19281 for injection, were submitted by Kabi to the Food and Drug Administration (FDA) on May 7, 1984, and approval was requested for three indications: (1) dental extraction in persons with hemophilia, (2) HAE, and (3) prostate&my. Approval was received (Orphan Drug Designation) for dental extraction in hemophiliacs (December 30, 1986), while the applications for the other two indications were denied. The reaD. VITTECOQ son in the case of HAE was that E. DELABESSE the clinical documentation, acM. BARY cording to the FDA’s view, was R. GIROT M. MAIER REDELSPERGER not sufficient since, of the five J.F. BACH studies submitted, only one small Hapita Necker study [2] was of double-blind deParis, France sign whereas the others were 1. Richman DD, Fischl MA, Grieco MH, eta/, and the open studies. It is easy to underAZT Collaborative Study Group. The toxicity of azidothymidine (AZT) in the treatment of patients with stand that the rareness of this AIDS and AIDS related complex. A double-blind, pladisorder makes the collection of a cebo-controlled trial. N Engl J Med 1987; 317: large amount of clinical material 192-7. difficult and that most publica2. Volberding PA, Lagakos SW, Koch MA, et al, and the AIDS Clinical Trials Group of the National Institions instead are in the form of tute of Allergy and Infectious Diseases. Zidovudine case reports. in asymptomatic human immunodeficiency virus inThus, Sim and Grant are corfection: a controlled trial in persons with fewer than rect when stating that Cykloka500 CDCpositive cells per cubic millimeter. N Engl J Med 1990; 322: 941-9. pron is not available in the Unit3. Boudes P, Balloul E, Sobel A. Tolerance de la zidoed States for the treatment of vudine chez les malades atteints de &thalassemie. HAE, in contrast to the majority Presse Med 1989; 18: 777. of countries in Europe, Asia, and Submitted December 14,1990, and accepted JanuLatin America. In all other counary 12. 1991 tries where Cyklokapron is registered, the HAE indication is approved and the drug constitutes a well-established therapy for this TRANEXAMICACID IN THE serious disorder. However, since TREATMENT OF HEREDITARY Sim and Grant were misinformed ANGIOEDEMA about the reason for this situaTo the Editor: tion, we hereby want to correct Although Sim and Grant’s [l] ar- their statement in order to avoid ticle was a well-rounded review of unnecessary confusion. LARS BIRGERSON,M.D., Ph.D. current treatment for hereditary Kabi Pharma angioedema (HAE), certain Solna, Sweden points related to HAE and the 1. Sim TC, Grant JA. Hereditary angioedema: its diuse of tranexamic acid were agnostic and management perspectives. Am J Med somewhat misleading. 1990; 88: 656-64. The article states that tranexa2. Blohme G. Treatment of hereditary angioneuromic acid is no longer available be- tic oedema with tranexamic acid. A random doubleblind cross-over study. Acta Med Stand 1972; 192: cause of its oncogenic potential 293-8. and findings of retinal changes in animals, especially after longSubmitted December 4. 1990, and accepted January 12. 1991 term administration. This is not 102
July 1991 The American Journal of Medicine
Volume 91
PORPHYRIAAND LIVER CANCER To the Editor: I found the article by Gubler et al [l] rather thought-provoking and it warrants further comments. The authors state that the concomitant occurrence of primary liver carcinoma and acute intermittent porphyria was reported from Scandinavia [2,3]. However, Hurst and Paget [4] were the pioneers who provided the original findings of erythropoietic protoporphyria and disorders of liver structure and symptoms of photosensitivity, which are shared by the two conditions. Hurst and Page [4] were the first researchers to describe the association of porphyria and liver cancer after administration of griseofulvin to mice. Increased porphyrin biosynthesis and porphyrin under-utilization were the mechanisms for porphyrin accumulation in porphyria. Induction of ALA-synthase and of ferrochelatase inhibition came to be appreciated and the role of N-methyl protoporphyrin in inhibiting ferrochelatase was discovered. Griseofulvin and similarly acting drugs convert the heme of cytochrome P450 into N-methyl protoporphyrin, a powerful inhibitor of ferrochelatase; the inhibition of this enzyme is responsible for a block in the metabolism of protoporphyrin, while the stimulation of ALA-synthase leads to marked accumulation of protoporphyrin PI. The authors stated that their patients had been imbibing alcohol regularly. It is pertinent and important that such patients should not only refrain from alcohol, but that other commonly used drugs like barbiturates, chlordiazepoxide, chlorpropamide, chloroquine, phenytoin, estrogens, and sulfonamides should also be contraindicated. This letter is intended to keep the medical history in perspec-
this asymptomatic patient suggests that particular attention must be given to the prescribing of zidovudine in patients with microcytosis without iron deficiency. We suggest that hemoglobin electrophoresis, family study, and eventually other studies of hemoglobin should be systematically performed before treatment in patients presenting with microcytosis, no matter what the daily dosage of zidovudine prescribed or what the clinical status regarding HIV infection.
correct. Two new drug applications, 19-280 for tablets and 19281 for injection, were submitted by Kabi to the Food and Drug Administration (FDA) on May 7, 1984, and approval was requested for three indications: (1) dental extraction in persons with hemophilia, (2) HAE, and (3) prostate&my. Approval was received (Orphan Drug Designation) for dental extraction in hemophiliacs (December 30, 1986), while the applications for the other two indications were denied. The reaD. VITTECOQ son in the case of HAE was that E. DELABESSE the clinical documentation, acM. BARY cording to the FDA’s view, was R. GIROT M. MAIER REDELSPERGER not sufficient since, of the five J.F. BACH studies submitted, only one small Hapita Necker study [2] was of double-blind deParis, France sign whereas the others were 1. Richman DD, Fischl MA, Grieco MH, eta/, and the open studies. It is easy to underAZT Collaborative Study Group. The toxicity of azidothymidine (AZT) in the treatment of patients with stand that the rareness of this AIDS and AIDS related complex. A double-blind, pladisorder makes the collection of a cebo-controlled trial. N Engl J Med 1987; 317: large amount of clinical material 192-7. difficult and that most publica2. Volberding PA, Lagakos SW, Koch MA, et al, and the AIDS Clinical Trials Group of the National Institions instead are in the form of tute of Allergy and Infectious Diseases. Zidovudine case reports. in asymptomatic human immunodeficiency virus inThus, Sim and Grant are corfection: a controlled trial in persons with fewer than rect when stating that Cykloka500 CDCpositive cells per cubic millimeter. N Engl J Med 1990; 322: 941-9. pron is not available in the Unit3. Boudes P, Balloul E, Sobel A. Tolerance de la zidoed States for the treatment of vudine chez les malades atteints de &thalassemie. HAE, in contrast to the majority Presse Med 1989; 18: 777. of countries in Europe, Asia, and Submitted December 14,1990, and accepted JanuLatin America. In all other counary 12. 1991 tries where Cyklokapron is registered, the HAE indication is approved and the drug constitutes a well-established therapy for this TRANEXAMICACID IN THE serious disorder. However, since TREATMENT OF HEREDITARY Sim and Grant were misinformed ANGIOEDEMA about the reason for this situaTo the Editor: tion, we hereby want to correct Although Sim and Grant’s [l] ar- their statement in order to avoid ticle was a well-rounded review of unnecessary confusion. LARS BIRGERSON,M.D., Ph.D. current treatment for hereditary Kabi Pharma angioedema (HAE), certain Solna, Sweden points related to HAE and the 1. Sim TC, Grant JA. Hereditary angioedema: its diuse of tranexamic acid were agnostic and management perspectives. Am J Med somewhat misleading. 1990; 88: 656-64. The article states that tranexa2. Blohme G. Treatment of hereditary angioneuromic acid is no longer available be- tic oedema with tranexamic acid. A random doubleblind cross-over study. Acta Med Stand 1972; 192: cause of its oncogenic potential 293-8. and findings of retinal changes in animals, especially after longSubmitted December 4. 1990, and accepted January 12. 1991 term administration. This is not 102
July 1991 The American Journal of Medicine
Volume 91
PORPHYRIAAND LIVER CANCER To the Editor: I found the article by Gubler et al [l] rather thought-provoking and it warrants further comments. The authors state that the concomitant occurrence of primary liver carcinoma and acute intermittent porphyria was reported from Scandinavia [2,3]. However, Hurst and Paget [4] were the pioneers who provided the original findings of erythropoietic protoporphyria and disorders of liver structure and symptoms of photosensitivity, which are shared by the two conditions. Hurst and Page [4] were the first researchers to describe the association of porphyria and liver cancer after administration of griseofulvin to mice. Increased porphyrin biosynthesis and porphyrin under-utilization were the mechanisms for porphyrin accumulation in porphyria. Induction of ALA-synthase and of ferrochelatase inhibition came to be appreciated and the role of N-methyl protoporphyrin in inhibiting ferrochelatase was discovered. Griseofulvin and similarly acting drugs convert the heme of cytochrome P450 into N-methyl protoporphyrin, a powerful inhibitor of ferrochelatase; the inhibition of this enzyme is responsible for a block in the metabolism of protoporphyrin, while the stimulation of ALA-synthase leads to marked accumulation of protoporphyrin PI. The authors stated that their patients had been imbibing alcohol regularly. It is pertinent and important that such patients should not only refrain from alcohol, but that other commonly used drugs like barbiturates, chlordiazepoxide, chlorpropamide, chloroquine, phenytoin, estrogens, and sulfonamides should also be contraindicated. This letter is intended to keep the medical history in perspec-
