- Email: [email protected]
SUSCEPTIBILITY OF HUMAN HERPESVIRUS 6 TO ACYCLOVIR AND GANCICLOVIR
382 successes led Merck to claim, in 1884, that this "should be sufficient to ensure for cocaine a lasting position as a valuable article of medicine". Freud had taken up the idea in 1882 and used it on his friend von Fleischl, who had become addicted to morphine while using it as an analgesic, following a thumb
remedy.2 Further use
amputation.4 In the 1890s cocaine
was
widely used in the treatment of opioid
habituation5 although the results were said to be poor.6 Over the next decade attitudes shifted so that cocaine was described as "not
only useless, but in the highest degree dangerous".7 This change of opinion is exemplified by Jennings, who, in 1890, recommended the administration of fluid extract of coca as the dose of morphine was reduced.s But, by 1909, he felt compelled to write that giving cocaine to morphine addicts was "like playing with fIre".9 History of Science Department, Exeter College,
MICHAEL
Oxford OX1 3DP
J. CLARKE
1. Freud S, Byck R, eds. Cocaine papers. New York: Meridan, 1975. 2. Bentley WH. Erythroxyoin coca in the opium and alcohol habits. Ther Gaz 1880; 1: 253-54. 3. Merck E. Coca and its salts. Pharm J 1884; 15: 425. 4. Jones E. Sigmund Freud: life and work, vol 1. London: Hogarth Press, 1953 89-101. 5. Matthison J. The treatment of the morphine disease. Proc Soc Study Inebriety 1892; 33: 1. 6. Drury H. Morphinomania. Dublin J Med Sci 1899; 107: 321. 7. Chaldecott J. The use of cocaine in the morphia habit: a warning. Lancet 1907; ii: 811. 8. Jennings O. On the cure of the morphia habit. London: Bailliere Tindall & Cox, 1890: 99. 9. Jennings O. The morphine habit and its voluntary renunciation. London: Baillière Tindall & Cox, 1909: 28.
point determination by CPE was confirmed by western blot analysis of extracts of infected cultures with a human serum containing a high titre of antibodies for several HHV-6 polypeptides (Russler SK, Tapper MA, Liepins A, Carrigan DR, unpublished). Ganciclovir was highly effective in inhibiting the induction of viral CPE with IDso of about 2 fllTIolfl (table). In contrast, acyclovir was much less active against the virus, with only the highest concentration showing an antiviral effect. The approximate ID 50 of acyclovir was 100 Eunol/1. Although high, this IDso for acyclovir is within the limits reached in the plasma of patients during aggressive antiviral therapy. Treatment of HHV-6 infection has not been thought necessary. Roseola, a common childhood illness associated with HHV-6 infection, is generally benign and self-limited. Nevertheless, in the setting of severe immunocompromise such as haematological malignancy and its treatment, organ transplantation, or AIDS, this virus may need to be controlled, especially in children infected wih the human immunodeficiency virus, where common childhood infections can be severe or fatal.5 Our results show that the pattern of susceptibility of HHV-6 to antiviral agents resembles that of cytomegalovirus (CMV) in that it is strikingly inhibited by ganciclovir but is resistant to the antiviral effects of acyclovir.6 HHV-6 is therefore likely to be a betaherpesvirus and may have other characteristics in common with CMV. Because of the serious myelosuppressive side-effects of ganciclovir, it will be difficult to justify treating HHV-6 infection with this drug unless a life threatening infection is encountered. In view of our results, high-dose acyclovir may be a viable and less toxic alternative. Division of Infectious
Diseases,
SUSCEPTIBILITY OF HUMAN HERPESVIRUS 6 TO ACYCLOVIR AND GANCICLOVIR
Department of Medicine, Medical College of Wisconsin
SIR,-Human herpesvirus-6 (HHV-6) has been isolated from the peripheral blood of patients with immunocompromising conditions such as leukaemia, lymphoma, and AIDS,1 and from normal children with roseola.2 Several normal adults with a
Department of Pathology, Medical College of Wisconsin,
of
and
malaise, syndrome consisting lymphadenopathy, fatigue, together with serological evidence of acute HHV-6 infection, have been described,3and a self-limiting febrile illness has been observed in renal alllograft patients in association with HHV-6 infection.4 However, it is not yet clear under what circumstances, if any, HHV-6 infection should be treated. We report a study of in vitro susceptibility of HHV-6 to two anti-herpesvirus chemotherapeutic agents, acyclovir and ganciclovir. Normal peripheral blood mononuclear cells (PBMC) were purified by Ficoll-Hypaque density gradient centrifugation, phytohaemagglutinin (PHA) stimulated, resuspended in culture medium containing 10% fetal bovine serum and 10 U/ml recombinant DNA derived human interleukin-2, and cultured in small dishes. Acyclovir and ganciclovir were added to replicate sets of six dishes each to give final concentrations about the same as those clinically achievable in plasma. Each dish was then infected with 100 tissue culture infectious doses (TCID) of HHV-6 (KF strain). Appropriate infected, uninfected, and drug-negative controls were included. The infected dishes were then examined for the appearance of characteristic viral cytopathic effects (CPE). EndINHIBITION OF CPE INDUCTION BY HHV-6 IN PHA-STIMULATED PERIPHERAL BLOOD MONONUCLEAR CELLS BY GANCICLOVIR AND ACYCLOVIR
*Measured on 13th
day after infection.
Milwaukee, Wisconsin 53226, USA
SUSAN K. RUSSLER
MARK A. TAPPER DONALD R. CARRIGAN
SZ, Ablashi DV, Makham PD et al., Isolation of a new virus, HBLV, in patients with lymphopmliferative disorders. Science 1986; 234: 596-601. 2. Yamanishi K, Okuno T, Shiraki K, et al. Identification of human herpesvirus-6 as a causal agent for exanthem subitum. Lancet 1988; i: 1065-67. 3. Niederman JC, Liu CR, Kaplan MH, Brown NA. Clinical and serological features of human herpesvirus-6 infection in three adults. Lancet 1988; ii: 817-19. 4. Morris DJ, Littler E, Arrand JR, et al. Human herpesvirus 6 infection in renal-transplant recipients. N Engl J Med 1989; 320: 1560-61. 5. Falloon J, Eddy J, Wiener L, Pizzo PA. Human immunodeficiency virus infection in children. J Pediatr 1989; 114: 1-30. 6. Elion G. History, mechanism of actioon, spectrum and selectivity of nucleoside analogs. In: Mills J, Corey L, eds. Antiviral chemotherapy. New York: Elsevier, 1. Salahuddin
1986: 118-37.
PHOTODYNAMIC THERAPY
SIR,-Your July 8 editorial discusses photodynamic therapy (PDT) in the treatment of malignant primary brain tumours. Less 1 attention has been given to haemodynamic reactions during PDT We report a 30-year-old woman who underwent combined surgical and photodynamic treatments of a glioblastoma grade IV located in the left temporobasal region. In our institution, PDT is two days after the resection of the tumour and tissue sensitisation of the tumour bed with haematoporphyrin (HPD). During resection the patient was anaesthetised with diazepam, fentanyl, and pancuronium bromide and was hyperventilated mechanically (PaC02 28-33 mm Hg). The operation passed without complications and the postoperative period was uneventful. Two days later the patient had intraoperative PDT, anaesthetised as before. During craniotomy we noticed no major haemodynamic changes. Blood pressure (BP) and heart-rate (HR) remained stable before start of PDT (systolic BP 100-120 mm Hg, HR 90-100/ min). During administration of PDT with an argon-dye laser (200 J/cm total dose), a sudden rise in systolic blood pressure (up to 220 mm Hg) occurred without changes in HR. Despite the use of vasodilators (isoflurane, less than 05 vol%, nitroglycerin, urapidil) to avoid major bleeding, systolic blood pressure remained between 200 and 220 mm Hg until the end of PDT, when blood pressure fell to pre-PDT values, without further administration of vasodilators.
applied
remedy.2 Further use
amputation.4 In the 1890s cocaine
was
widely used in the treatment of opioid
habituation5 although the results were said to be poor.6 Over the next decade attitudes shifted so that cocaine was described as "not
only useless, but in the highest degree dangerous".7 This change of opinion is exemplified by Jennings, who, in 1890, recommended the administration of fluid extract of coca as the dose of morphine was reduced.s But, by 1909, he felt compelled to write that giving cocaine to morphine addicts was "like playing with fIre".9 History of Science Department, Exeter College,
MICHAEL
Oxford OX1 3DP
J. CLARKE
1. Freud S, Byck R, eds. Cocaine papers. New York: Meridan, 1975. 2. Bentley WH. Erythroxyoin coca in the opium and alcohol habits. Ther Gaz 1880; 1: 253-54. 3. Merck E. Coca and its salts. Pharm J 1884; 15: 425. 4. Jones E. Sigmund Freud: life and work, vol 1. London: Hogarth Press, 1953 89-101. 5. Matthison J. The treatment of the morphine disease. Proc Soc Study Inebriety 1892; 33: 1. 6. Drury H. Morphinomania. Dublin J Med Sci 1899; 107: 321. 7. Chaldecott J. The use of cocaine in the morphia habit: a warning. Lancet 1907; ii: 811. 8. Jennings O. On the cure of the morphia habit. London: Bailliere Tindall & Cox, 1890: 99. 9. Jennings O. The morphine habit and its voluntary renunciation. London: Baillière Tindall & Cox, 1909: 28.
point determination by CPE was confirmed by western blot analysis of extracts of infected cultures with a human serum containing a high titre of antibodies for several HHV-6 polypeptides (Russler SK, Tapper MA, Liepins A, Carrigan DR, unpublished). Ganciclovir was highly effective in inhibiting the induction of viral CPE with IDso of about 2 fllTIolfl (table). In contrast, acyclovir was much less active against the virus, with only the highest concentration showing an antiviral effect. The approximate ID 50 of acyclovir was 100 Eunol/1. Although high, this IDso for acyclovir is within the limits reached in the plasma of patients during aggressive antiviral therapy. Treatment of HHV-6 infection has not been thought necessary. Roseola, a common childhood illness associated with HHV-6 infection, is generally benign and self-limited. Nevertheless, in the setting of severe immunocompromise such as haematological malignancy and its treatment, organ transplantation, or AIDS, this virus may need to be controlled, especially in children infected wih the human immunodeficiency virus, where common childhood infections can be severe or fatal.5 Our results show that the pattern of susceptibility of HHV-6 to antiviral agents resembles that of cytomegalovirus (CMV) in that it is strikingly inhibited by ganciclovir but is resistant to the antiviral effects of acyclovir.6 HHV-6 is therefore likely to be a betaherpesvirus and may have other characteristics in common with CMV. Because of the serious myelosuppressive side-effects of ganciclovir, it will be difficult to justify treating HHV-6 infection with this drug unless a life threatening infection is encountered. In view of our results, high-dose acyclovir may be a viable and less toxic alternative. Division of Infectious
Diseases,
SUSCEPTIBILITY OF HUMAN HERPESVIRUS 6 TO ACYCLOVIR AND GANCICLOVIR
Department of Medicine, Medical College of Wisconsin
SIR,-Human herpesvirus-6 (HHV-6) has been isolated from the peripheral blood of patients with immunocompromising conditions such as leukaemia, lymphoma, and AIDS,1 and from normal children with roseola.2 Several normal adults with a
Department of Pathology, Medical College of Wisconsin,
of
and
malaise, syndrome consisting lymphadenopathy, fatigue, together with serological evidence of acute HHV-6 infection, have been described,3and a self-limiting febrile illness has been observed in renal alllograft patients in association with HHV-6 infection.4 However, it is not yet clear under what circumstances, if any, HHV-6 infection should be treated. We report a study of in vitro susceptibility of HHV-6 to two anti-herpesvirus chemotherapeutic agents, acyclovir and ganciclovir. Normal peripheral blood mononuclear cells (PBMC) were purified by Ficoll-Hypaque density gradient centrifugation, phytohaemagglutinin (PHA) stimulated, resuspended in culture medium containing 10% fetal bovine serum and 10 U/ml recombinant DNA derived human interleukin-2, and cultured in small dishes. Acyclovir and ganciclovir were added to replicate sets of six dishes each to give final concentrations about the same as those clinically achievable in plasma. Each dish was then infected with 100 tissue culture infectious doses (TCID) of HHV-6 (KF strain). Appropriate infected, uninfected, and drug-negative controls were included. The infected dishes were then examined for the appearance of characteristic viral cytopathic effects (CPE). EndINHIBITION OF CPE INDUCTION BY HHV-6 IN PHA-STIMULATED PERIPHERAL BLOOD MONONUCLEAR CELLS BY GANCICLOVIR AND ACYCLOVIR
*Measured on 13th
day after infection.
Milwaukee, Wisconsin 53226, USA
SUSAN K. RUSSLER
MARK A. TAPPER DONALD R. CARRIGAN
SZ, Ablashi DV, Makham PD et al., Isolation of a new virus, HBLV, in patients with lymphopmliferative disorders. Science 1986; 234: 596-601. 2. Yamanishi K, Okuno T, Shiraki K, et al. Identification of human herpesvirus-6 as a causal agent for exanthem subitum. Lancet 1988; i: 1065-67. 3. Niederman JC, Liu CR, Kaplan MH, Brown NA. Clinical and serological features of human herpesvirus-6 infection in three adults. Lancet 1988; ii: 817-19. 4. Morris DJ, Littler E, Arrand JR, et al. Human herpesvirus 6 infection in renal-transplant recipients. N Engl J Med 1989; 320: 1560-61. 5. Falloon J, Eddy J, Wiener L, Pizzo PA. Human immunodeficiency virus infection in children. J Pediatr 1989; 114: 1-30. 6. Elion G. History, mechanism of actioon, spectrum and selectivity of nucleoside analogs. In: Mills J, Corey L, eds. Antiviral chemotherapy. New York: Elsevier, 1. Salahuddin
1986: 118-37.
PHOTODYNAMIC THERAPY
SIR,-Your July 8 editorial discusses photodynamic therapy (PDT) in the treatment of malignant primary brain tumours. Less 1 attention has been given to haemodynamic reactions during PDT We report a 30-year-old woman who underwent combined surgical and photodynamic treatments of a glioblastoma grade IV located in the left temporobasal region. In our institution, PDT is two days after the resection of the tumour and tissue sensitisation of the tumour bed with haematoporphyrin (HPD). During resection the patient was anaesthetised with diazepam, fentanyl, and pancuronium bromide and was hyperventilated mechanically (PaC02 28-33 mm Hg). The operation passed without complications and the postoperative period was uneventful. Two days later the patient had intraoperative PDT, anaesthetised as before. During craniotomy we noticed no major haemodynamic changes. Blood pressure (BP) and heart-rate (HR) remained stable before start of PDT (systolic BP 100-120 mm Hg, HR 90-100/ min). During administration of PDT with an argon-dye laser (200 J/cm total dose), a sudden rise in systolic blood pressure (up to 220 mm Hg) occurred without changes in HR. Despite the use of vasodilators (isoflurane, less than 05 vol%, nitroglycerin, urapidil) to avoid major bleeding, systolic blood pressure remained between 200 and 220 mm Hg until the end of PDT, when blood pressure fell to pre-PDT values, without further administration of vasodilators.
applied