972
techniques used were enzyme-linked immunosorbent assay (ELISA), particle agglutination, indirect fluorescent assay (IFA), western blot, and mono-epitope ELISA. 11 samples with dual reactivity were interpreted as double infection with HIV-1 and HIV-2, or a single infection with antigenetical cross-reactivity with the other. 16 indeterminate specimens showed some reactivity with HIV-1and HIV-2 by IFA. Nonetheless, they did not show specific bands on western blotting with HIV-1and HIV-2 infected cells as antigens, whereas the positive samples clearly revealed typical gag, pol, and env bands of each virus. The result by mono-epitope ELISA for differentiating the viral type was also negative. Virus isolation from peripheral blood cells was attempted, with negative results. We therefore assume that there might be unknown agents (viruses) which are antigenetically different from any known type of HIV, since in west African countries there is a unique circulating collection of various HIV strains. In fact, we have previously isolated from a Ghanaian patient with ARC a highly divergent strain of HIV-2 that is genomically equidistant from a simian immunodeficiency virus of sooty mangabeys (SIV sm) and that of rhesus macaques (SIV mac).5 Gao et al6 have lately reported human infection in Liberia by genetically diverse HIV-2 strains that are more closely related to SIVSIV. Thus, there is a possibility that some AIDS cases in this region might be caused by viruses that cannot be detected by the current HIV laboratory assay system. Our attention is now focused on the considerably large number of the seronegative group (135/227, 59%) who were clinically diagnosed as having AIDS. All the patients had three major signs: weight loss, prolonged diarrhoea, and chronic fever. Many of them also had other AIDS-associated signs, such as lymphadenopathy, tuberculosis, dermatological diseases, and neurological disorders,
The
though CD4 cells were not counted because of insufficient facilities. We believe that many patients of this group were perhaps improperly diagnosed and had other unidentified diseases. Even if that is true, the number is still more than negligible. In relation to the AIDS
cases
Egros et al have raised an old and much discussed difficulty about the best schedule of administration of high-dose metoclopramide in the prevention of cisplatin-induced emesis. Five of seven comparative trials,3-7 including the most recent,6.7 indicate that intermittent infusion is as efficacious as continuous infusion. In fact, intermittent infusion became the method of choice of the most important groups in antiemetic research. Also noteworthy is the evidence that a single high dose of metoclopramide (4 mg/kg) infused in 15 minutes before chemotherapy can protect from cisplatin-induced nausea and vomiting similar to a repeated bolus regimen (3 mg/kg x 2).8 Furthermore, Egros and colleagues misinterpret the results of Warrington’s studyl cited in support of their claims. This work did not show complete protection from vomiting (zero emetic episodes) in 82% of patients treated by continuous infusion, but did show a major response (2emetic episodes). A similar response rate has been achieved in other studies by intermittent bolus injection of metoclopramide.8,9 We believe that we used one of the best antiemetic combination therapies that included metoclopramide in an appropriate schedule and dose by comparison with ondansetron plus dexamethasone, and our results clearly showed the superiority of the ondansetron treatment. Furthermore, we think that future research should not be directed to the evaluation of the methods of metoclopramide administration but rather to other important, still unsolved difficulties-ie, identification of the best 5-HT3 antagonists, evaluation of efficacy during subsequent cycles of chemotherapy, and study of more efficacious strategies to prevent delayed emesis from cisplatin. F. ROILA M. TONATO E. BALLATORI Medical Oncology Division, A. DEL FAVERO, Policlinico Monteluce, 06100 Perugia, Italy
for the Italian Group for Antiemetic Research
in the USA without evidence of known retroviral
infection, our African cases are especially intriguing. The existence of other agents causing AIDS-like syndromes might be possible among these so-called HIV-negative cases. Further searching for such novel aetiological agents of the disease should be continued.
Kyoto University, Sakyo-ku, Kyoto 606, Japan
OSAMU HISHIDA EIJI IDO TATSUHIKO IGARASHI MASANORI HAYAMI
Faculty of Agriculture, Kyoto University
AKIRA MIYAZAKI
Noguchi Memorial Institute for Medical Research, University of Ghana, Accra, Ghana
NANA K. AYISI MUBARAK OSEI-KWASI
Research Centre for Immunodeficiency Viruses, Institute for Virus Research,
1. Beral V, Peterman TA, Berkelman RL, Jaffe HW. Kaposi’s sarcoma among persons with AIDS: a sexually transmitted infection? Lancet 1990; 335: 123-28. 2. Safai B, Peralata H, Menzies K, et al. Kaposi’s sarcoma among HIV seronegative high-risk populations. VII International Conference on AIDS, Florence, Italy, June 16-21, 1991: abstr TuB83. 3. Castro A, Pedreira J, Sopirano V, et al. Kaposi’s sarcoma and disseminated tuberculosis in HIV-negative individual. Lancet 1992; 339: 868. 4. Kawamura M, Ishikawa K, Mingle JAA, et al. Immunological reactivities of Ghanaian sera with HIV-1, HIV-2, and simian immunodeficiency virus AIDS
1989; 3: 609-11. T, Sakuragi J, Kawamura M,
SIVagm.
al. Establishment of a phylogenetic survey system for AIDS-related lentiviruses and demonstration of a new HIV-2 subgroup. AIDS 1990; 4: 1257-61. 6. Gao F, Yue L, White AT, et al. Human infection by genetically diverse SIVsm-related HIV-2 in West Africa. Nature 1992; 358: 495-99. 5. Miura
Prevention of
et
cisplatin-induced emesis
SIR,-Dr Egros and colleagues (Sept 5, p 619) challenge the conclusions of our study (July 11, p 96) that ondansetron plus dexamethasone is more effective than metoclopramide plus dexamethasone plus diphenhydramine in the prevention of cisplatin-induced emesis, mainly because we did not use the best therapeutic scheme for metoclopramide. They claim that a continuous infusion preceded by a loading dose has proved a more efficacious regimen1.2 than the intermittent infusion schedule of metoclopramide chosen by us.
Warrington PS, Allan SG, Cornbleet MA, et al. Optimising antiemesis in cancer chemotherapy: efficacy of continuous versus intermittent infusion of high dose metoclopramide in emesis induced by cisplatin. BMJ 1986; 293: 1334-37. 2. Navari RM. Comparison of intermittent versus continuous infusion metoclopramide in control of acute nausea induced by cisplatin chemotherapy. J Clin Oncol 1989; 7: 1.
943-46. 3. Dana BW, McDermott M, Evens E, et al. A randomized trial of high dose bolus metoclopramide versus low-dose continuous infusion metoclopramide in the prevention of cisplatin-induced emesis. Am J Clin Oncol 1987; 10: 253-56. 4. Weiss J, Leming P, Leder W, et al. A comparison of metoclopramide (MET) given asa continuous infusion (CI) versus intermittent administraton (IA) for the treatment of cisplatin-induced nausea and vomiting Proc ASCO 1987; 6: 262. 5. Agostinucci WA, Cannon RH, Schauer PK, et al. Continuous infusion of metoclopramide for prevention of chemotherapy-induced emesis. Clin Pharm
1986; 5: 150-53. Kajita M, Niimi T, et al. Randomized crossover trial of continuous infusion
6. Saito H,
metoclopramide (MCP) or intermittent infusion metoclopramide given with dexamethasone (DEX) and diphenhydramine (DPH) for acute emesis induced by cisplatin (CDDP). Proc ASCO 1992; 11: 390. 7. Ribelles N, Moreno I, Rosel R, et al. Randomized study of high doses of metoclopramide (MCP) administered by bolus (B) vs continuous infusion (CI) in cisplatin (DDP) treated patients. Eur J Cancer 1991; (suppl 2): S298. 8. Roila F, Basurto C, Bracarda S, et al Double-blind cross-over trial of single vs divided dose of metoclopramide in a combined regimen for treatment of cisplatin-induced emesis. Eur J Cancer 1991; 27: 119-21. 9. Roila F, Tonato M, Basurto C, et al. Protection from nausea and vomiting in cisplatin-treated patients: high-dose metoclopramide combined with methylprednisolone versus metoclopramide combined with dexamethasone and diphenhydramine: a study of the Italian Oncology Group for Clinical Research. J Clin Oncol 1989; 7: 1693-700.
Urticaria and
angioedema induced by low-molecular-weight heparin
SIR,-Unfractionated heparin (UFH) and low-molecularweight heparins (LMWH) are glycosaminoglycan chains of alternating residues of D-glucosamine and a uronic acid, either gluconic acid or iduronic acid.1 LMWHs are potent thromboprophylactic agents, and have the advantage over UFH of daily administration and reduced risk of bleeding.2 Allergic reactions due to LMWHs are rare, and skin eruptions and angioedema have not been associated with these agents. We report widespread urticaria and angioedema in association with LMWH (enoxaparin).
973
A 67-year-old woman with a history of angina, aneurysm of the ascending aorta, and bilateral carotid artery stenosis, was admitted for acute stroke complicated by mild left hemiparesis and right homonymous hemianopsia. She had been on isosorbide-5mononitrate and diltiazem for the past three years. Brain computed tomographic findings were compatible with temporo-occipital infarction. The patient continued on her previous medications, and was treated with enoxaparin 20 mg subcutaneously daily. Three days later, a widespread progressive pruritic urticaria developed, followed by swelling of lips and tongue. The patient had no history of drug or food allergy, and had not had such a reaction before. Treatment with antihistamines and prednisone for three days was not helpful and the allergic reaction became more severe. Enoxaparin was stopped and the urticaria and angioedema rapidly resolved. Rechallenge with enoxaparin was not done. Later the patient received coumarin as a prophylactic treatment with no
side-effects.
Hypersensitivity
reactions
to
UFH, although
uncommon,
are
well recognised, and generally manifest as skin necrosis and vasculitis overlying the injection sites when the drug is given subcutaneously.3 Sometimes distant cutaneous necrosis may develop.’ Skin reactions to systemic UFH associated with local vasculitis have been described.5 Involvement of other organs by vasculitis has been reported ;6 the heparin-induced skin necrosis was complicated by glomerulonephritis. LMWH-induced painful, red indurations at injection sites have also been described in a patient with a previous UFH-induced skin reaction.7 However, widespread urticaria and angioedema, as in our patient, have not been reported with UFH or LMWHs. Department of Internal Medicine "B", Bnai Zion Medical Centre, and Technion Faculty of Medicine, Israel Institute of Technology, Haifa 31063, Israel
M. ODEH A. OLIVEN
1. Choay J, Petitou M. The chemistry of heparin:
a
of expedience rather than choice. Jarrett implies that assay and measurement difficulties may lead to error in favour of the link between hyperinsulinaemia and hypertension, but it is equally likely that error might occur in the other direction. Fortunately, specific assays for insulin and proinsulin are now becoming available.4 Jarrett’s concentration on insulin rather than insulin resistance is weakened by his statement that "hyperinsulinaemia is not part of the syndrome", yet the reference that he cites includes hyperinsulinaemia in its definition of syndrome X.1 Jarrett makes much of the diminished importance of the association between hyperinsulinaemia and hypertension in several epidemiological studies after stratification for body mass index. Obesity is associated with insulin resistance,s and weight gain is associated with increasing insulin resistance.6 The effect of insulin resistance on blood pressure is unlikely to be independent of weight. Although obesity is not part of syndrome X, Reaven states elsewhere that the relation between obesity and hypertension may best be understood by the hypothesis that blood pressure can be regulated by changes in insulin metabolism.7 The real question for investigation should be "is insulin resistance, which is present in some cases of essential hypertension, causative or incidental?". Further work is also needed to supplement our knowledge of the insulin receptor and insulin-mediated changes in blood flow. There is probably considerable genetic heterogeneity in essential hypertension. The recent description of a molecular genetic basis for the long-recognised syndrome of glucocorticoid-remediable hyperaldosteronism8 demonstrates that careful description of the phenotype may pay considerable dividends. Perhaps insulinresistant hypertensives should be considered as a distinct group of essential hypertensives for epidemiological purposes. There is not enough evidence to regard insulin therapy as contraindicated in non-insulin dependent diabetes mellitus, but while the data are conflicting, careful consideration should be given to insulin dose reduction in obese, hypertensive, non-insulin dependent diabetics.9 matter
way to understand its mode of action.
Med J Aust 1986; 144: 7-16. 2. Hirsh J, Levine MN. Low molecular weight heparin. Blood 1992; 79: 1-17. 3. Platell CFE, Tan EGC. Hypersensitivity reactions to heparin: delayed onset thrombocytopenia and necrotizing skin lesions. Aust N ZJ Surg 1986; 56: 621-24. 4. Verstraete M, Vermylen J. Drugs affecting blood coagulation and hemostasis. In: Dukes MNG, Beele L, eds. Side effects of drugs annual 12. Amsterdam: Elsevier, 1988. 309-15. 5. Stavorosky M, Lichtenstein D, Nissim F. Skin petechiae and ecchymosis (vasculitis) due to anticoagulant therapy. Dermatologia 1979; 158: 451-61. 6. Jones BF, Epstein MT. Cutaneous heparin necrosis associated with glomerolunephritis. Aust J Dermatol 1987; 28: 117-20. 7. Manoharan A. Heparin-induced skin reaction with low molecular-weight heparin. Eur J Haematol 1992; 48: 234.
Department of Medicine and Therapeutics, Gardiner Institute, Western Infirmary, Glasgow G11 6NT, UK 1. Reaven GM. Role of insulin
and
syndrome X
SIR,-Professor Jarrett (Aug 22, p 469) in his critique of Reaven’s syndrome X reviews the evidence against the belief that hyperinsulinaemia is directly linked to hypertension. He implies that the hypothesis against which he is arguing is that hyperinsulinaemia, rather than insulin resistance, is a causal factor in essential hypertension. In fact, the hypothesis is that insulin resistance is associated with glucose intolerance, compensatory hyperinsulinaemia, hypertension, and abnormalities of lipid metabolism.1 The biological mechanism of insulin resistance is not established. In investigating its association with hypertension, one cannot use the terms hyperinsulinaemia and insulin resistance interchangeably merely because plasma insulin is generally assumed to be the link. Resistance to insulin-stimulated glucose uptake can be measured with the hyperinsulinaemic euglycaemic clamp2 or the insulin suppression test.3 These techniques take about 3-5 hours per subject to do and thus have generally been used on small groups of subjects, rather than in epidemiological studies. Plasma insulin concentrations (fasting or post-load) as measured by one-site radioimmunoassay have been used in epidemiological studies as surrogate measures of insulin resistance, but proinsulin and split forms produce up to 100% crossreaction.4 Their correlation with insulin resistance as measured by clamping studies is poor, despite the use of elaborate computer models, and their use has been a
m human disease. Diabetes 1988; 37: 1595-607. RA, Tobin JD, Andres R. Glucose clamp technique: a method for quantifying insulin secretion and resistance. Am J Physiol 1979; 237: E214-23. Shen SW, Reaven GM, Farquhar JW. Comparison of insulin-mediated glucose uptake in normal subjects and m subjects with latent diabetes. J Clin Invest 1970;
2. De Fronzo
3.
49: 2151-60. Beer
SF, Carrington CA. Sensitive and specific two-site immunoradiometric assays for human insulin, proinsulin, 65-66 split and 32-33 split proinsulins. Biochem J 1989; 260: 535-41. Caro JF. Insulin resistance in obese and non-obese man. J Clin Endocrinol Metab 1991; 73: 691-95. Ravussin E, Swinburn BA. Pathophysiology of obesity. Lancet 1992; 340: 404-08. Reaven GM. Relationship between insulin resistance and hypertension. Diabetes Care 1991; 14 (suppl 4): 33-38. Lifton RP, Dluhy RG, Powers M, et al. A chimaeric 11 &bgr;-hydroxylase/aldosterone synthase gene causes glucocorticoid remediable hyperaldosteronism and human hypertension. Nature 1992; 355: 262-65. Tedde R, Sechi LA, Marigliano A, et al. Antihypertensive effect of insulin reduction in
4. Sobey WJ, 5.
Hyperinsulinaemia
JOHN PETRIE
6. 7. 8.
9.
diabetic-hypertensive patients. Am J Hypertens 1989; 2:
163-70.
SiR,—The interrelations between insulin, hypertension, obesity, glucose have assumed increasing importance in the epidemiological study of diabetes mellitus. Researchers have concentrated on established insulin-dependent or non-insulindependent diabetic patients, in whom the ambient insulin concentrations will have been altered by therapeutic interventions. Investigation of a large group of diabetic patients at first diagnosis would be preferable. Professor Jarrett vigorously defends insulin, pointing out that endogenous hyperinsulinaemia due to an islet-cell tumour, or hyperinsulinaemia induced by insulin therapy, does not and blood
lead to raised blood pressure. In the Belfast diet study, measurements of weight, systolic and diastolic blood pressure, fasting plasma glucose, and fasting serum insulin were undertaken at the time of diagnosis in 432 patients, between 1972 and 1982. All patients were aged 40-69 years at diagnosis and all had symptoms related to hyperglycaemia. A long period of intensive dietary management was undertaken before
techniques used were enzyme-linked immunosorbent assay (ELISA), particle agglutination, indirect fluorescent assay (IFA), western blot, and mono-epitope ELISA. 11 samples with dual reactivity were interpreted as double infection with HIV-1 and HIV-2, or a single infection with antigenetical cross-reactivity with the other. 16 indeterminate specimens showed some reactivity with HIV-1and HIV-2 by IFA. Nonetheless, they did not show specific bands on western blotting with HIV-1and HIV-2 infected cells as antigens, whereas the positive samples clearly revealed typical gag, pol, and env bands of each virus. The result by mono-epitope ELISA for differentiating the viral type was also negative. Virus isolation from peripheral blood cells was attempted, with negative results. We therefore assume that there might be unknown agents (viruses) which are antigenetically different from any known type of HIV, since in west African countries there is a unique circulating collection of various HIV strains. In fact, we have previously isolated from a Ghanaian patient with ARC a highly divergent strain of HIV-2 that is genomically equidistant from a simian immunodeficiency virus of sooty mangabeys (SIV sm) and that of rhesus macaques (SIV mac).5 Gao et al6 have lately reported human infection in Liberia by genetically diverse HIV-2 strains that are more closely related to SIVSIV. Thus, there is a possibility that some AIDS cases in this region might be caused by viruses that cannot be detected by the current HIV laboratory assay system. Our attention is now focused on the considerably large number of the seronegative group (135/227, 59%) who were clinically diagnosed as having AIDS. All the patients had three major signs: weight loss, prolonged diarrhoea, and chronic fever. Many of them also had other AIDS-associated signs, such as lymphadenopathy, tuberculosis, dermatological diseases, and neurological disorders,
The
though CD4 cells were not counted because of insufficient facilities. We believe that many patients of this group were perhaps improperly diagnosed and had other unidentified diseases. Even if that is true, the number is still more than negligible. In relation to the AIDS
cases
Egros et al have raised an old and much discussed difficulty about the best schedule of administration of high-dose metoclopramide in the prevention of cisplatin-induced emesis. Five of seven comparative trials,3-7 including the most recent,6.7 indicate that intermittent infusion is as efficacious as continuous infusion. In fact, intermittent infusion became the method of choice of the most important groups in antiemetic research. Also noteworthy is the evidence that a single high dose of metoclopramide (4 mg/kg) infused in 15 minutes before chemotherapy can protect from cisplatin-induced nausea and vomiting similar to a repeated bolus regimen (3 mg/kg x 2).8 Furthermore, Egros and colleagues misinterpret the results of Warrington’s studyl cited in support of their claims. This work did not show complete protection from vomiting (zero emetic episodes) in 82% of patients treated by continuous infusion, but did show a major response (2emetic episodes). A similar response rate has been achieved in other studies by intermittent bolus injection of metoclopramide.8,9 We believe that we used one of the best antiemetic combination therapies that included metoclopramide in an appropriate schedule and dose by comparison with ondansetron plus dexamethasone, and our results clearly showed the superiority of the ondansetron treatment. Furthermore, we think that future research should not be directed to the evaluation of the methods of metoclopramide administration but rather to other important, still unsolved difficulties-ie, identification of the best 5-HT3 antagonists, evaluation of efficacy during subsequent cycles of chemotherapy, and study of more efficacious strategies to prevent delayed emesis from cisplatin. F. ROILA M. TONATO E. BALLATORI Medical Oncology Division, A. DEL FAVERO, Policlinico Monteluce, 06100 Perugia, Italy
for the Italian Group for Antiemetic Research
in the USA without evidence of known retroviral
infection, our African cases are especially intriguing. The existence of other agents causing AIDS-like syndromes might be possible among these so-called HIV-negative cases. Further searching for such novel aetiological agents of the disease should be continued.
Kyoto University, Sakyo-ku, Kyoto 606, Japan
OSAMU HISHIDA EIJI IDO TATSUHIKO IGARASHI MASANORI HAYAMI
Faculty of Agriculture, Kyoto University
AKIRA MIYAZAKI
Noguchi Memorial Institute for Medical Research, University of Ghana, Accra, Ghana
NANA K. AYISI MUBARAK OSEI-KWASI
Research Centre for Immunodeficiency Viruses, Institute for Virus Research,
1. Beral V, Peterman TA, Berkelman RL, Jaffe HW. Kaposi’s sarcoma among persons with AIDS: a sexually transmitted infection? Lancet 1990; 335: 123-28. 2. Safai B, Peralata H, Menzies K, et al. Kaposi’s sarcoma among HIV seronegative high-risk populations. VII International Conference on AIDS, Florence, Italy, June 16-21, 1991: abstr TuB83. 3. Castro A, Pedreira J, Sopirano V, et al. Kaposi’s sarcoma and disseminated tuberculosis in HIV-negative individual. Lancet 1992; 339: 868. 4. Kawamura M, Ishikawa K, Mingle JAA, et al. Immunological reactivities of Ghanaian sera with HIV-1, HIV-2, and simian immunodeficiency virus AIDS
1989; 3: 609-11. T, Sakuragi J, Kawamura M,
SIVagm.
al. Establishment of a phylogenetic survey system for AIDS-related lentiviruses and demonstration of a new HIV-2 subgroup. AIDS 1990; 4: 1257-61. 6. Gao F, Yue L, White AT, et al. Human infection by genetically diverse SIVsm-related HIV-2 in West Africa. Nature 1992; 358: 495-99. 5. Miura
Prevention of
et
cisplatin-induced emesis
SIR,-Dr Egros and colleagues (Sept 5, p 619) challenge the conclusions of our study (July 11, p 96) that ondansetron plus dexamethasone is more effective than metoclopramide plus dexamethasone plus diphenhydramine in the prevention of cisplatin-induced emesis, mainly because we did not use the best therapeutic scheme for metoclopramide. They claim that a continuous infusion preceded by a loading dose has proved a more efficacious regimen1.2 than the intermittent infusion schedule of metoclopramide chosen by us.
Warrington PS, Allan SG, Cornbleet MA, et al. Optimising antiemesis in cancer chemotherapy: efficacy of continuous versus intermittent infusion of high dose metoclopramide in emesis induced by cisplatin. BMJ 1986; 293: 1334-37. 2. Navari RM. Comparison of intermittent versus continuous infusion metoclopramide in control of acute nausea induced by cisplatin chemotherapy. J Clin Oncol 1989; 7: 1.
943-46. 3. Dana BW, McDermott M, Evens E, et al. A randomized trial of high dose bolus metoclopramide versus low-dose continuous infusion metoclopramide in the prevention of cisplatin-induced emesis. Am J Clin Oncol 1987; 10: 253-56. 4. Weiss J, Leming P, Leder W, et al. A comparison of metoclopramide (MET) given asa continuous infusion (CI) versus intermittent administraton (IA) for the treatment of cisplatin-induced nausea and vomiting Proc ASCO 1987; 6: 262. 5. Agostinucci WA, Cannon RH, Schauer PK, et al. Continuous infusion of metoclopramide for prevention of chemotherapy-induced emesis. Clin Pharm
1986; 5: 150-53. Kajita M, Niimi T, et al. Randomized crossover trial of continuous infusion
6. Saito H,
metoclopramide (MCP) or intermittent infusion metoclopramide given with dexamethasone (DEX) and diphenhydramine (DPH) for acute emesis induced by cisplatin (CDDP). Proc ASCO 1992; 11: 390. 7. Ribelles N, Moreno I, Rosel R, et al. Randomized study of high doses of metoclopramide (MCP) administered by bolus (B) vs continuous infusion (CI) in cisplatin (DDP) treated patients. Eur J Cancer 1991; (suppl 2): S298. 8. Roila F, Basurto C, Bracarda S, et al Double-blind cross-over trial of single vs divided dose of metoclopramide in a combined regimen for treatment of cisplatin-induced emesis. Eur J Cancer 1991; 27: 119-21. 9. Roila F, Tonato M, Basurto C, et al. Protection from nausea and vomiting in cisplatin-treated patients: high-dose metoclopramide combined with methylprednisolone versus metoclopramide combined with dexamethasone and diphenhydramine: a study of the Italian Oncology Group for Clinical Research. J Clin Oncol 1989; 7: 1693-700.
Urticaria and
angioedema induced by low-molecular-weight heparin
SIR,-Unfractionated heparin (UFH) and low-molecularweight heparins (LMWH) are glycosaminoglycan chains of alternating residues of D-glucosamine and a uronic acid, either gluconic acid or iduronic acid.1 LMWHs are potent thromboprophylactic agents, and have the advantage over UFH of daily administration and reduced risk of bleeding.2 Allergic reactions due to LMWHs are rare, and skin eruptions and angioedema have not been associated with these agents. We report widespread urticaria and angioedema in association with LMWH (enoxaparin).
973
A 67-year-old woman with a history of angina, aneurysm of the ascending aorta, and bilateral carotid artery stenosis, was admitted for acute stroke complicated by mild left hemiparesis and right homonymous hemianopsia. She had been on isosorbide-5mononitrate and diltiazem for the past three years. Brain computed tomographic findings were compatible with temporo-occipital infarction. The patient continued on her previous medications, and was treated with enoxaparin 20 mg subcutaneously daily. Three days later, a widespread progressive pruritic urticaria developed, followed by swelling of lips and tongue. The patient had no history of drug or food allergy, and had not had such a reaction before. Treatment with antihistamines and prednisone for three days was not helpful and the allergic reaction became more severe. Enoxaparin was stopped and the urticaria and angioedema rapidly resolved. Rechallenge with enoxaparin was not done. Later the patient received coumarin as a prophylactic treatment with no
side-effects.
Hypersensitivity
reactions
to
UFH, although
uncommon,
are
well recognised, and generally manifest as skin necrosis and vasculitis overlying the injection sites when the drug is given subcutaneously.3 Sometimes distant cutaneous necrosis may develop.’ Skin reactions to systemic UFH associated with local vasculitis have been described.5 Involvement of other organs by vasculitis has been reported ;6 the heparin-induced skin necrosis was complicated by glomerulonephritis. LMWH-induced painful, red indurations at injection sites have also been described in a patient with a previous UFH-induced skin reaction.7 However, widespread urticaria and angioedema, as in our patient, have not been reported with UFH or LMWHs. Department of Internal Medicine "B", Bnai Zion Medical Centre, and Technion Faculty of Medicine, Israel Institute of Technology, Haifa 31063, Israel
M. ODEH A. OLIVEN
1. Choay J, Petitou M. The chemistry of heparin:
a
of expedience rather than choice. Jarrett implies that assay and measurement difficulties may lead to error in favour of the link between hyperinsulinaemia and hypertension, but it is equally likely that error might occur in the other direction. Fortunately, specific assays for insulin and proinsulin are now becoming available.4 Jarrett’s concentration on insulin rather than insulin resistance is weakened by his statement that "hyperinsulinaemia is not part of the syndrome", yet the reference that he cites includes hyperinsulinaemia in its definition of syndrome X.1 Jarrett makes much of the diminished importance of the association between hyperinsulinaemia and hypertension in several epidemiological studies after stratification for body mass index. Obesity is associated with insulin resistance,s and weight gain is associated with increasing insulin resistance.6 The effect of insulin resistance on blood pressure is unlikely to be independent of weight. Although obesity is not part of syndrome X, Reaven states elsewhere that the relation between obesity and hypertension may best be understood by the hypothesis that blood pressure can be regulated by changes in insulin metabolism.7 The real question for investigation should be "is insulin resistance, which is present in some cases of essential hypertension, causative or incidental?". Further work is also needed to supplement our knowledge of the insulin receptor and insulin-mediated changes in blood flow. There is probably considerable genetic heterogeneity in essential hypertension. The recent description of a molecular genetic basis for the long-recognised syndrome of glucocorticoid-remediable hyperaldosteronism8 demonstrates that careful description of the phenotype may pay considerable dividends. Perhaps insulinresistant hypertensives should be considered as a distinct group of essential hypertensives for epidemiological purposes. There is not enough evidence to regard insulin therapy as contraindicated in non-insulin dependent diabetes mellitus, but while the data are conflicting, careful consideration should be given to insulin dose reduction in obese, hypertensive, non-insulin dependent diabetics.9 matter
way to understand its mode of action.
Med J Aust 1986; 144: 7-16. 2. Hirsh J, Levine MN. Low molecular weight heparin. Blood 1992; 79: 1-17. 3. Platell CFE, Tan EGC. Hypersensitivity reactions to heparin: delayed onset thrombocytopenia and necrotizing skin lesions. Aust N ZJ Surg 1986; 56: 621-24. 4. Verstraete M, Vermylen J. Drugs affecting blood coagulation and hemostasis. In: Dukes MNG, Beele L, eds. Side effects of drugs annual 12. Amsterdam: Elsevier, 1988. 309-15. 5. Stavorosky M, Lichtenstein D, Nissim F. Skin petechiae and ecchymosis (vasculitis) due to anticoagulant therapy. Dermatologia 1979; 158: 451-61. 6. Jones BF, Epstein MT. Cutaneous heparin necrosis associated with glomerolunephritis. Aust J Dermatol 1987; 28: 117-20. 7. Manoharan A. Heparin-induced skin reaction with low molecular-weight heparin. Eur J Haematol 1992; 48: 234.
Department of Medicine and Therapeutics, Gardiner Institute, Western Infirmary, Glasgow G11 6NT, UK 1. Reaven GM. Role of insulin
and
syndrome X
SIR,-Professor Jarrett (Aug 22, p 469) in his critique of Reaven’s syndrome X reviews the evidence against the belief that hyperinsulinaemia is directly linked to hypertension. He implies that the hypothesis against which he is arguing is that hyperinsulinaemia, rather than insulin resistance, is a causal factor in essential hypertension. In fact, the hypothesis is that insulin resistance is associated with glucose intolerance, compensatory hyperinsulinaemia, hypertension, and abnormalities of lipid metabolism.1 The biological mechanism of insulin resistance is not established. In investigating its association with hypertension, one cannot use the terms hyperinsulinaemia and insulin resistance interchangeably merely because plasma insulin is generally assumed to be the link. Resistance to insulin-stimulated glucose uptake can be measured with the hyperinsulinaemic euglycaemic clamp2 or the insulin suppression test.3 These techniques take about 3-5 hours per subject to do and thus have generally been used on small groups of subjects, rather than in epidemiological studies. Plasma insulin concentrations (fasting or post-load) as measured by one-site radioimmunoassay have been used in epidemiological studies as surrogate measures of insulin resistance, but proinsulin and split forms produce up to 100% crossreaction.4 Their correlation with insulin resistance as measured by clamping studies is poor, despite the use of elaborate computer models, and their use has been a
m human disease. Diabetes 1988; 37: 1595-607. RA, Tobin JD, Andres R. Glucose clamp technique: a method for quantifying insulin secretion and resistance. Am J Physiol 1979; 237: E214-23. Shen SW, Reaven GM, Farquhar JW. Comparison of insulin-mediated glucose uptake in normal subjects and m subjects with latent diabetes. J Clin Invest 1970;
2. De Fronzo
3.
49: 2151-60. Beer
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SiR,—The interrelations between insulin, hypertension, obesity, glucose have assumed increasing importance in the epidemiological study of diabetes mellitus. Researchers have concentrated on established insulin-dependent or non-insulindependent diabetic patients, in whom the ambient insulin concentrations will have been altered by therapeutic interventions. Investigation of a large group of diabetic patients at first diagnosis would be preferable. Professor Jarrett vigorously defends insulin, pointing out that endogenous hyperinsulinaemia due to an islet-cell tumour, or hyperinsulinaemia induced by insulin therapy, does not and blood
lead to raised blood pressure. In the Belfast diet study, measurements of weight, systolic and diastolic blood pressure, fasting plasma glucose, and fasting serum insulin were undertaken at the time of diagnosis in 432 patients, between 1972 and 1982. All patients were aged 40-69 years at diagnosis and all had symptoms related to hyperglycaemia. A long period of intensive dietary management was undertaken before
