1015
Mfermentans (incognitus) seems to be susceptible to doxycycline, tetracycline, and ciprofloxacin but resistant to erythromycin.4 In another previously healthy young man with fever, malaise, weight loss, diarrhoea, and extensive tissue necrosis of liver and spleen, M fermentans (incognitus) was concentrated at the advancing margins of the necrotising lesions.5 After treatment with 300 mg recovered and has doxycycline per day orally for 6 weeks, he fully remained disease-free for more than a year.5 Recent interest in mycoplasma has also focused on a possible role as co-factor for disease progression in AIDS6 and M fermentens (incognitus) has been implicated in AID S-associated nephropathy.7 The Chief, Navy Bureau of Medicine and
Surgery, Washington, DC,
Clinical Investigation Program sponsored this report no 84-16-1968-291. Departments of Internal Medicine
(Infectious Disease Division), Laboratory (Pathology Division), and Clinical Investigation, Naval Hospital, San Diego, California 92134, USA; and Department of Infectious and Parasitic Disease-Pathology, Armed Forces Institute of Pathology, Washington, DC
HARRY J. BEECHAM, III SHYH C. Lo DREW E. LEWIS STEWART W. COMER KENNETH J. RILEY EDWARD C. OLDFIELD, III
SC, Lawson MS, Newton PB III, et al. Association of the virus-like infectious agent originally reported in patients with AIDS with acute fatal disease in previously healthy non-AIDS patients. Am J Trop Med Hyg 1989; 41: 364-76. 2. Lo SC, Shih JWK, Newton PB III, et al. Virus-like infectious agent (VLIA) is a novel pathogenic mycoplasma: Mycoplasma incognitus. Am J Trop Med Hyg 1989; 41: 586-600. 3. Lo SC, Dawson MS, Wong DM, et al. Identification of Mycoplasma incognitus infection in patients with AIDS: an immunohistochemical, in-situ hybridization and ultrastructural study. Am J Trop Med Hyg 1989; 41: 601-16. 4. Hayes MM, Wear DJ, Lo S-C. In vitro antimicrobial susceptibility testing for the newly identified AIDS-associated myocplasma—Mycoplasma fermentans (incognitos strain). Arch Pathol Lab Med 1991; 115: 464-66. 5. Lo S-C, Buchholz CL, Wear DJ, Hohm RC, Marty AM. Histopathology and doxycyline treatment in a previously healthy non-AIDS patient systematically infected by Mycoplasma fermentans (incognitus strain) Mod Pathol (in press). 6. Editorial. Mycoplasma and AIDS—what connection? Lancet 1991; 337: 20-22. 7. Bauer FA, Wear DJ, Angritt P, Lo SC. Mycoplasma fermentans (incognitus strain) infection in the kidneys of patients with acquired immunodeficiency syndrome and associated nephropathy: a light microscopic, immunohistochemical, and ultrastructural study. Human Pathol 1991; 22: 63-69. 1. Lo
Inhibitory effects of chloroform extracts of fresh feverfew leaves on rings of rabbit aorta contracted by cumulative doses of serotonin (5-HT). (.) responses under control conditions, (0) 20 min and (A) 40 min after addition of 100 gglml feverfew Mean values from 3-8 tests at each serotonin dose are shown Inset: Cumulative doses (ranging from 10’’to 10-4 mol/I) were applied to an aortic ring preparation before (upper), during (middle) and after (lower) 100 Ilg/ml feverfew extract. Relaxations of the tissue after completing additions of serotonin were obtained by repeatedly washing with fresh Krebs solution. Typical of four similar experiments.
sesquiterpene a-methylene butyrolactone parthenolide,’’ purified from the crude extracts, but
Irreversible inhibition of vascular reactivity by feverfew SIR,-Extracts of feverfew(Tanacetum parthenium) have been taken orally for centuries for various conditions including arthritis and fever, and there is now clinical evidence showing prophylactic benefit in migraine.2,3 In view of the considerable interest in possible roles of changes in vascular reactivity and the contributions of serotonin to the pathogenesis of migraine,4,5 we have studied the actions of crude extracts of feverfew on the responses of isolated rings of rabbit aorta in vitro. Rings of 2 mm thickness were cut from the thoracic aorta of New Zealand White rabbits and suspended under 2 g tension in 3 ml tissue baths containing well oxygenated Krebs solution. Contractions to various agonists including serotonin, phenylephrine, the thromboxane A2 mimetic U46619, and
angiotensin II were recorded isometrically. Treatment of aortic rings with 25-200 ltg/ml feverfew extract (prepared by steeping fresh leaves in chloroform and evaporating solvent to yield a viscous dark brown-green residue, which was then dissolved in methanol) led to a progressive and time-dependent inhibition of responses to all the contractile agonists. The figure shows data for serotonin. Similar results were obtained for phenylephrine, U46619, and angiotensin, all of which act on smooth muscle through independent receptors. Thus the inhibitory effects of feverfew are non-specific, and may result from interference with post-receptor contractile mechanisms. The inhibition was also irreversible (see inset to figure), implying a long-lasting toxic effect on the tissue. We also found that addition of feverfew extract to precontracted rings caused a gradual loss of tone, after which the rings were refractory to further stimulation by any of the contractile agonists (confirming the irreversible nature of the inhibitory feverfew action). Similar results were obtained with the
were not seen
when
extracts were
prepared from dried feverfew leaves (of unknown age) obtained commercially from a health-food shop. Extracts of the dried leaves did not inhibit aortic contractility, and by chemical highperformance liquid chromatography did not contain parthenolide or other a-methylenelactones. Our results show that fresh leaves of feverfew contain compounds that have a non-specific inhibitory and potentially toxic action on vascular smooth muscle. This might arise by a Michael-type addition reaction between the activated a-methylene butyrolactone function of the parthenolide and other sesquiterpenes present in the feverfew and essential sulphydryl groups in the vascular smooth muscle.7 It remains to be established whether this toxic mechanism contributes to the therapeutic actions or side-effects of feverfew obtained domestically and used as a self-medication, but it is intriguing that the toxic feature is absent from the commercially available dried leaves. Pharmacology Group, Kings College London, London SW3 6LX, UK; and Department of Chemistry, University of Nottingham
RICHARD BARSBY UMIT SALAN DAVID W. KNIGHT J. ROBIN S. HOULT
Berry MI. Feverfew faces the future. Pharm J 1984; 232: 611-14. Johnson ES, Kadam NP, Hylands DM, Hylands PJ. Efficacy of feverfew as prophylactic treatment of migraine. Br Med J 1985; 291: 569-73. 3. Murphy JJ, Heptinstall S, Mitchell JRA. Randomised double-blind placebocontrolled trial of feverfew in migraine prevention. Lancet 1988; ii: 189-92. 4. Glover V, Sandler M. Can the vascular and neurogenic theories of migraine finally be reconciled? Trends Pharmacol Sci 1989; 10: 1-3. 5. Saxena PR, Ferran MD. 5-HT1-like receptor agonists and the pathophysiology of migraine. Trends Pharmacol Sci 1989; 10: 200-04. 6. Begley MJ, Hewlett MJ, Knight DW. Revised structures for guaianolide &agr;-methylenebutyrolactones from feverfew. Phytochemistry 1989; 28: 940-43. 7. Groenewegen WA, Knight DW, Heptinstall S. Compounds extracted from feverfew that have anti-secretory activity contain an &agr;-methylene butyrolactone unit. J Pharm Pharmacol 1986; 38: 709-12. 1. 2.
Mfermentans (incognitus) seems to be susceptible to doxycycline, tetracycline, and ciprofloxacin but resistant to erythromycin.4 In another previously healthy young man with fever, malaise, weight loss, diarrhoea, and extensive tissue necrosis of liver and spleen, M fermentans (incognitus) was concentrated at the advancing margins of the necrotising lesions.5 After treatment with 300 mg recovered and has doxycycline per day orally for 6 weeks, he fully remained disease-free for more than a year.5 Recent interest in mycoplasma has also focused on a possible role as co-factor for disease progression in AIDS6 and M fermentens (incognitus) has been implicated in AID S-associated nephropathy.7 The Chief, Navy Bureau of Medicine and
Surgery, Washington, DC,
Clinical Investigation Program sponsored this report no 84-16-1968-291. Departments of Internal Medicine
(Infectious Disease Division), Laboratory (Pathology Division), and Clinical Investigation, Naval Hospital, San Diego, California 92134, USA; and Department of Infectious and Parasitic Disease-Pathology, Armed Forces Institute of Pathology, Washington, DC
HARRY J. BEECHAM, III SHYH C. Lo DREW E. LEWIS STEWART W. COMER KENNETH J. RILEY EDWARD C. OLDFIELD, III
SC, Lawson MS, Newton PB III, et al. Association of the virus-like infectious agent originally reported in patients with AIDS with acute fatal disease in previously healthy non-AIDS patients. Am J Trop Med Hyg 1989; 41: 364-76. 2. Lo SC, Shih JWK, Newton PB III, et al. Virus-like infectious agent (VLIA) is a novel pathogenic mycoplasma: Mycoplasma incognitus. Am J Trop Med Hyg 1989; 41: 586-600. 3. Lo SC, Dawson MS, Wong DM, et al. Identification of Mycoplasma incognitus infection in patients with AIDS: an immunohistochemical, in-situ hybridization and ultrastructural study. Am J Trop Med Hyg 1989; 41: 601-16. 4. Hayes MM, Wear DJ, Lo S-C. In vitro antimicrobial susceptibility testing for the newly identified AIDS-associated myocplasma—Mycoplasma fermentans (incognitos strain). Arch Pathol Lab Med 1991; 115: 464-66. 5. Lo S-C, Buchholz CL, Wear DJ, Hohm RC, Marty AM. Histopathology and doxycyline treatment in a previously healthy non-AIDS patient systematically infected by Mycoplasma fermentans (incognitus strain) Mod Pathol (in press). 6. Editorial. Mycoplasma and AIDS—what connection? Lancet 1991; 337: 20-22. 7. Bauer FA, Wear DJ, Angritt P, Lo SC. Mycoplasma fermentans (incognitus strain) infection in the kidneys of patients with acquired immunodeficiency syndrome and associated nephropathy: a light microscopic, immunohistochemical, and ultrastructural study. Human Pathol 1991; 22: 63-69. 1. Lo
Inhibitory effects of chloroform extracts of fresh feverfew leaves on rings of rabbit aorta contracted by cumulative doses of serotonin (5-HT). (.) responses under control conditions, (0) 20 min and (A) 40 min after addition of 100 gglml feverfew Mean values from 3-8 tests at each serotonin dose are shown Inset: Cumulative doses (ranging from 10’’to 10-4 mol/I) were applied to an aortic ring preparation before (upper), during (middle) and after (lower) 100 Ilg/ml feverfew extract. Relaxations of the tissue after completing additions of serotonin were obtained by repeatedly washing with fresh Krebs solution. Typical of four similar experiments.
sesquiterpene a-methylene butyrolactone parthenolide,’’ purified from the crude extracts, but
Irreversible inhibition of vascular reactivity by feverfew SIR,-Extracts of feverfew(Tanacetum parthenium) have been taken orally for centuries for various conditions including arthritis and fever, and there is now clinical evidence showing prophylactic benefit in migraine.2,3 In view of the considerable interest in possible roles of changes in vascular reactivity and the contributions of serotonin to the pathogenesis of migraine,4,5 we have studied the actions of crude extracts of feverfew on the responses of isolated rings of rabbit aorta in vitro. Rings of 2 mm thickness were cut from the thoracic aorta of New Zealand White rabbits and suspended under 2 g tension in 3 ml tissue baths containing well oxygenated Krebs solution. Contractions to various agonists including serotonin, phenylephrine, the thromboxane A2 mimetic U46619, and
angiotensin II were recorded isometrically. Treatment of aortic rings with 25-200 ltg/ml feverfew extract (prepared by steeping fresh leaves in chloroform and evaporating solvent to yield a viscous dark brown-green residue, which was then dissolved in methanol) led to a progressive and time-dependent inhibition of responses to all the contractile agonists. The figure shows data for serotonin. Similar results were obtained for phenylephrine, U46619, and angiotensin, all of which act on smooth muscle through independent receptors. Thus the inhibitory effects of feverfew are non-specific, and may result from interference with post-receptor contractile mechanisms. The inhibition was also irreversible (see inset to figure), implying a long-lasting toxic effect on the tissue. We also found that addition of feverfew extract to precontracted rings caused a gradual loss of tone, after which the rings were refractory to further stimulation by any of the contractile agonists (confirming the irreversible nature of the inhibitory feverfew action). Similar results were obtained with the
were not seen
when
extracts were
prepared from dried feverfew leaves (of unknown age) obtained commercially from a health-food shop. Extracts of the dried leaves did not inhibit aortic contractility, and by chemical highperformance liquid chromatography did not contain parthenolide or other a-methylenelactones. Our results show that fresh leaves of feverfew contain compounds that have a non-specific inhibitory and potentially toxic action on vascular smooth muscle. This might arise by a Michael-type addition reaction between the activated a-methylene butyrolactone function of the parthenolide and other sesquiterpenes present in the feverfew and essential sulphydryl groups in the vascular smooth muscle.7 It remains to be established whether this toxic mechanism contributes to the therapeutic actions or side-effects of feverfew obtained domestically and used as a self-medication, but it is intriguing that the toxic feature is absent from the commercially available dried leaves. Pharmacology Group, Kings College London, London SW3 6LX, UK; and Department of Chemistry, University of Nottingham
RICHARD BARSBY UMIT SALAN DAVID W. KNIGHT J. ROBIN S. HOULT
Berry MI. Feverfew faces the future. Pharm J 1984; 232: 611-14. Johnson ES, Kadam NP, Hylands DM, Hylands PJ. Efficacy of feverfew as prophylactic treatment of migraine. Br Med J 1985; 291: 569-73. 3. Murphy JJ, Heptinstall S, Mitchell JRA. Randomised double-blind placebocontrolled trial of feverfew in migraine prevention. Lancet 1988; ii: 189-92. 4. Glover V, Sandler M. Can the vascular and neurogenic theories of migraine finally be reconciled? Trends Pharmacol Sci 1989; 10: 1-3. 5. Saxena PR, Ferran MD. 5-HT1-like receptor agonists and the pathophysiology of migraine. Trends Pharmacol Sci 1989; 10: 200-04. 6. Begley MJ, Hewlett MJ, Knight DW. Revised structures for guaianolide &agr;-methylenebutyrolactones from feverfew. Phytochemistry 1989; 28: 940-43. 7. Groenewegen WA, Knight DW, Heptinstall S. Compounds extracted from feverfew that have anti-secretory activity contain an &agr;-methylene butyrolactone unit. J Pharm Pharmacol 1986; 38: 709-12. 1. 2.
