- Email: [email protected]
Zidovudine (AZT)
957
weeks) to 19 AIDS patients; most patients gained weight and showed some improvement in other clinical features.3 Absorption of the drug was satisfactory and blood levels which were inhibitory to HIV were
achieved; the half-life in the circulation
was
1 h. Glucuronidation accounts for of the excretion of the drug. Zidovudine crosses the blood-brain barrier (cerebrospinal fluid levels reach 50-60% of plasma levels4.5), which is an important requirement in view of the ability ofHIV to grow in the central nervous system. Some improvement of T-cell function was indicated by increased numbers of circulating helper-inducer (CD4 cells and restoration of cutaneous delayed-type hypersensitivity reactions in patients who had previously been
approximately most
+)
anergic.3 Zidovudine
(AZT)
3’-azido-3’-deoxythymidine (zidovudine, azidothymidine, AZT) has now been licensed for use for the management of serious manifestations of human immunodeficiency virus (HIV) infections in patients with acquired immunodeficiency syndrome (AIDS) or AIDS-related complex (ARC). The drug will be distributed to different countries in proportion to the numbers of AIDS cases reported to WHO; in the UK, regional health authorities have received supplies related to the local frequency of patients. Zidovudine was synthesised in 1964 by Horwitz and colleagues;1 in 1985, Mitsuya et aP reported that HIV replication was inhibited by concentrations in the range 50-500 nmol/1. As with other 2’, 3’dideoxynucleoside analogues, zidovudine acts as chain-terminator in DNA synthesis. Substitution of the 3’-hydroxy group in thymidine by an azido group
produces azidothymidine. Phosphorylation by cellular thymidine kinase to produce azidothymidine monophosphate and subsequent conversion to the triphosphate, by other kinases, leads to insertion of the compound into the developing chain of viral DNA. The presence of the 3’-azido group prevents the formation of further 5’-3’ phosphodiester linkages and, consequently, DNA synthesis is halted. Differences in susceptibility between the RNAdependent DNA polymerase of HIV and mammalian DNA polymerase alpha is probably a major reason for the selective antiviral action of zidovudine. However the toxic effects of the drug, which may limit its use, are probably the result of a non-specific effect on cellular DNA polymerase. In a 6-week phase I trial conducted by Yarchoan and colleagues in the USA, zidovudine was administered intravenously (2 weeks) and then orally (4 1. Horwitz
JP, Chua J, Noel
M. Nucleosides V. The
monomesylates
&bgr;-D-lyxofuranosyl) thymine. J Org Chem 1964; 29:
of
1-(2’-deoxy-
2076-78.
2. Mitsuya
H, Weinhold KJ, Furman PA, et al. 3’ azido-3’-deoxythymidine (BW A509U): an antiviral agent that inhibits the infectivity and cytopathic effect of human T-lymphotropic virus type 111/lymphadenopathy-associatedvirusinvitro. Proc Natl Acad Sci USA 1985; 82: 7096-100.
A multicentre randomised, double-blind, placebocontrolled trial of zidovudine in AIDS patients who had recently recovered from Pneumocystis carinii pneumonia and in patients with ARC was initiated in February, 1986, also in the USA. 282 patients were enrolled, with nearly equal numbers in each arm. Interim analysis of the results after 6 months revealed a highly significant reduction in mortality in the patients receiving zidovudine (1death vs 19 in the placebo group), and these findings led to the abandonment of the placebo arm of the trial on ethical grounds. Since then the drug has been prescribed extensively in the USA on a compassionate use basis. Yarchoan and Broder4 reported continuous administration of zidovudine to AIDS patients for as long as 18 months. Some patients with ARC or Kaposi’s sarcoma, who had only mildly abnormal immunological and bone-marrow function at the start of therapy, had sustained increases in CD4 + cell numbers. Others, with AIDS, had a late decrease in CD4 + cells and secondary infections with Pneumocystis carinii. These follow-up studies appear to confirm the findings of the phase II study which indicated that zidovudine will extend the lifeexpectancy of AIDS sufferers. In a small study of patients with HIV-associated dementia, peripheral neuropathy, or both, 6 of 7 individuals had some improvement of symptoms as assessed by clinical
examination, neuropsychometric testing, nerveor emission conduction studies, positron tomography.4,s Serious toxicity has been observed during the treatment of HIV-infected patients with zidovudine. Anaemia necessitating blood transfusion, leucopenia, and specifically neutropenia have frequently led to reduction in dosage or discontinuation of the drug. An increase in the red-cell mean corpuscular volume is 3. Yarchoan R, Klecker RW, Weinhold KJ, et al. Administration of 3’-azido-3’deoxythymidine, an inhibitor of HTLV-III LAV replication, to patients with AIDS or AIDS-related complex. Lancet 1986; i: 575-80. 4. Yarchoan R, Broder S. Development of antiretroviral therapy for the acquired immunodeficiency syndrome and related disorders: a progress report. N Engl J Med 1987; 316: 557-64. 5. Yarchoan R, Berg G, Brouwers P, et al. Response of human-immunodeficiencyvirus-associated neurological disease to 3’-azido-3’-deoxythymidine. Lancet 1987; i: 132-35
958
often an early sign of these toxic effects.6 This bone-marrow toxicity does not usually cause thrombocytopenia ; some patients have even had increases in circulating platelets during zidovudine therapy. Approximately half the recipients of the drug have reported headaches and some have experienced nausea and vomiting. There have also been reports of more serious central nervous system toxicity. In one case a patient with headache and confusion progressed to unresponsiveness and focal seizures 48 h after starting treatment;7 in another, zidovudine therapy was associated with the development of acute Wernicke’s encephalopathy in an AIDS patient with none of the known risk factors for that condition.8 A report that acyclovir can potentiate the action of azidothymidine in vitro9 has led to the initiation of trials of combination therapy, but a recorded case of apparent neurotoxicity of acyclovir in a patient receiving zidovudine emphasises the need for caution with this approach. Another route to combination therapy is hinted at in the in-vitro findings of Mitchell and
colleagues.10 The antiviral effects of zidovudine in vivo have been confirmed by the reduction of circulating HIV antigen during treatment.l1 Reduction or cessation of zidovudine has, however, led to an immediate return of circulating antigen, and the renewed antigenaemia has often been associated with the onset of opportunistic infections. For this reason it is important to realise that once zidovudine treatment is started it will probably be needed for long periods, if not for life. The potential toxicity of zidovudine in patients with the less severe manifestations of HIV infection, such as persistent generalised lymphadenopathy, is unknown and the results of further trials are awaited. Until the safety of the drug has been more extensively evaluated, extreme caution should be exercised by practitioners considering its use in these groups or in symptomless carriers of the virus. The myelotoxic effects seen in patients with AIDS and ARC, if they also occur in those with less severe disease, might be sufficient to impose additional stress on the immune system and precipitate disease. Thus zidovudine represents an important development in measures to counter the effects of HIV infection. Other potent and possibly less toxic substances are now under evaluation and one of these, 2’,3’-dideoxycytidine, is being assessed in a phase I
Non-convulsive Status
Epilepticus
THE term status epilepticus (etat de mal epileptique), coined in 1824 to refer to repeated grand mal seizures, soon became widely used. More recently, however, it has been gradually appreciated that other seizure types may occur, and complex classifications have been devised.1 Status epilepticus, for the purposes of the International Classification of Seizure Type, is present "whenever a seizure persists for a sufficient length of time or is repeated sufficently frequently enough to produce a fixed and enduring epileptic condition".It may be divided into convulsive and non-convulsive forms. Convulsive status may be subdivided into generalised tonic clonic (synonym: grand mal) status, and simple partial status (synonym: epilepsia partialis continua). The former is of course the most common form of status epilepticus; it is usually easily recognised and is an important medical emergency, requiring urgent and expert management. Simple partial status is the second most common form of status, and again is usually easy to diagnose, although management may be difficult. Whilst the convulsive forms of status cause little confusion, either nosologically or clinically, the same can not be said of non-convulsive status. Non-convulsive status epilepticus is nevertheless an important syndrome and one with which many physicians are unfamiliar. Three criteria are usually given for the diagnosis of non-convulsive status:3-5 the presence of continuous
prolonged epileptic symptoms, electroencephalographic (EEG) abnormalties consistent with the diagnosis, and a prompt response to treatment. All three criteria are not invariably met, however. Non-convulsive status may conveniently be into subdivided generalised absence status (synonyms: petit mal status, spike wave stupor, epilepsia minor continua, minor epileptic status) and complex partial status (synonyms: psychomotor status, temporal lobe status). The patient with absence status presents with altered consciousness (ranging from simple inattentiveness to stupor), often accompanied by mild clonic movements of the eyelids, face, or hands or simple automatism. The diagnosis is definitively established by EEG, which shows continuous or at least frequent spike wave activity, classically regular 3 Hz activity but more commonly 2-3 Hz irregular spike wave or polyspike wave or
.
study.4 6. Yarchoan R, Broder S. Strategies for the pharmacologic intervention against HTLV-111/LAV. In Broder S, ed. AIDS: modern concepts and therapeutic challenges New York: Marcel Dekker, 1987: 335-60. 7. Hagler DN, Frame PT. Azidothymidine neurotoxicity. Lancet 1986; ii: 1392-93. 8. Davtyan D, Vinters H. Wemicke’s encephalopathy in AIDS patient treated with zidovudine. Lancet 1987; i: 919-20. 9. Mitsuya H, Matsukura M, Broder S. Rapid in vitro systems for assessing activity of agents against HTLV-III/LAV. In: Broder S, ed. AIDS modem concepts and therapeutic challenges. New York: Marcel Dekker, 1987: 303-33. 10. Mitchell WM, Montefiori DC, Robinson WE Jr, Strayer DR, Carter WA. Mismatched double-stranded RNA (Ampligen) reduces concentration of zidovudine (azidothymidine) required for in-vitro inhibition of human immunodeficiency virus. Lancet 1987; i: 890-92. 11. Chaisson RE, Allain J-P, Leuther M, Volberding PA Significant changes in HIV antigen level in the serum of patients treated with azidothymidine. N Engl J Med 1986; 315: 1610-11.
disturbances. The status may continue for hours days, during which time the patient may be more 1. Gastaut H. Classification of status
or or
epilepticus. In: Rose FC, ed. Research progress in 1983 8-13. 2. Gastaut H. Clinical and EEG classification of epileptic seizures. Epilepsia 1970; 11: 102-13. 3. Doose H. Nonconvulsive status epilepticus in children: clinical aspects and classification. In: Delgado-Escueta AV, Wasterlain CG, Treiman DM, Porter RJ, eds. Advances in neurology no 34: status epilepticus. New York: Raven, 1983: 83-92. 4. Porter RJ, Penry JK Pent mal status In: Delgado-Escueta AV, et al, eds. Advances in neurology no 34 status epilepticus. New York: Raven, 1983: 61-67. 5. Stores G. Nonconvulsive status epilepticus in children. In: Pedley TA, Meldrum BS, eds. Recent advances in epilepsy 3. Edinburgh. Churchill Livingstone, 1986. 295-310.
epilepsy. Bath: Pitman,
weeks) to 19 AIDS patients; most patients gained weight and showed some improvement in other clinical features.3 Absorption of the drug was satisfactory and blood levels which were inhibitory to HIV were
achieved; the half-life in the circulation
was
1 h. Glucuronidation accounts for of the excretion of the drug. Zidovudine crosses the blood-brain barrier (cerebrospinal fluid levels reach 50-60% of plasma levels4.5), which is an important requirement in view of the ability ofHIV to grow in the central nervous system. Some improvement of T-cell function was indicated by increased numbers of circulating helper-inducer (CD4 cells and restoration of cutaneous delayed-type hypersensitivity reactions in patients who had previously been
approximately most
+)
anergic.3 Zidovudine
(AZT)
3’-azido-3’-deoxythymidine (zidovudine, azidothymidine, AZT) has now been licensed for use for the management of serious manifestations of human immunodeficiency virus (HIV) infections in patients with acquired immunodeficiency syndrome (AIDS) or AIDS-related complex (ARC). The drug will be distributed to different countries in proportion to the numbers of AIDS cases reported to WHO; in the UK, regional health authorities have received supplies related to the local frequency of patients. Zidovudine was synthesised in 1964 by Horwitz and colleagues;1 in 1985, Mitsuya et aP reported that HIV replication was inhibited by concentrations in the range 50-500 nmol/1. As with other 2’, 3’dideoxynucleoside analogues, zidovudine acts as chain-terminator in DNA synthesis. Substitution of the 3’-hydroxy group in thymidine by an azido group
produces azidothymidine. Phosphorylation by cellular thymidine kinase to produce azidothymidine monophosphate and subsequent conversion to the triphosphate, by other kinases, leads to insertion of the compound into the developing chain of viral DNA. The presence of the 3’-azido group prevents the formation of further 5’-3’ phosphodiester linkages and, consequently, DNA synthesis is halted. Differences in susceptibility between the RNAdependent DNA polymerase of HIV and mammalian DNA polymerase alpha is probably a major reason for the selective antiviral action of zidovudine. However the toxic effects of the drug, which may limit its use, are probably the result of a non-specific effect on cellular DNA polymerase. In a 6-week phase I trial conducted by Yarchoan and colleagues in the USA, zidovudine was administered intravenously (2 weeks) and then orally (4 1. Horwitz
JP, Chua J, Noel
M. Nucleosides V. The
monomesylates
&bgr;-D-lyxofuranosyl) thymine. J Org Chem 1964; 29:
of
1-(2’-deoxy-
2076-78.
2. Mitsuya
H, Weinhold KJ, Furman PA, et al. 3’ azido-3’-deoxythymidine (BW A509U): an antiviral agent that inhibits the infectivity and cytopathic effect of human T-lymphotropic virus type 111/lymphadenopathy-associatedvirusinvitro. Proc Natl Acad Sci USA 1985; 82: 7096-100.
A multicentre randomised, double-blind, placebocontrolled trial of zidovudine in AIDS patients who had recently recovered from Pneumocystis carinii pneumonia and in patients with ARC was initiated in February, 1986, also in the USA. 282 patients were enrolled, with nearly equal numbers in each arm. Interim analysis of the results after 6 months revealed a highly significant reduction in mortality in the patients receiving zidovudine (1death vs 19 in the placebo group), and these findings led to the abandonment of the placebo arm of the trial on ethical grounds. Since then the drug has been prescribed extensively in the USA on a compassionate use basis. Yarchoan and Broder4 reported continuous administration of zidovudine to AIDS patients for as long as 18 months. Some patients with ARC or Kaposi’s sarcoma, who had only mildly abnormal immunological and bone-marrow function at the start of therapy, had sustained increases in CD4 + cell numbers. Others, with AIDS, had a late decrease in CD4 + cells and secondary infections with Pneumocystis carinii. These follow-up studies appear to confirm the findings of the phase II study which indicated that zidovudine will extend the lifeexpectancy of AIDS sufferers. In a small study of patients with HIV-associated dementia, peripheral neuropathy, or both, 6 of 7 individuals had some improvement of symptoms as assessed by clinical
examination, neuropsychometric testing, nerveor emission conduction studies, positron tomography.4,s Serious toxicity has been observed during the treatment of HIV-infected patients with zidovudine. Anaemia necessitating blood transfusion, leucopenia, and specifically neutropenia have frequently led to reduction in dosage or discontinuation of the drug. An increase in the red-cell mean corpuscular volume is 3. Yarchoan R, Klecker RW, Weinhold KJ, et al. Administration of 3’-azido-3’deoxythymidine, an inhibitor of HTLV-III LAV replication, to patients with AIDS or AIDS-related complex. Lancet 1986; i: 575-80. 4. Yarchoan R, Broder S. Development of antiretroviral therapy for the acquired immunodeficiency syndrome and related disorders: a progress report. N Engl J Med 1987; 316: 557-64. 5. Yarchoan R, Berg G, Brouwers P, et al. Response of human-immunodeficiencyvirus-associated neurological disease to 3’-azido-3’-deoxythymidine. Lancet 1987; i: 132-35
958
often an early sign of these toxic effects.6 This bone-marrow toxicity does not usually cause thrombocytopenia ; some patients have even had increases in circulating platelets during zidovudine therapy. Approximately half the recipients of the drug have reported headaches and some have experienced nausea and vomiting. There have also been reports of more serious central nervous system toxicity. In one case a patient with headache and confusion progressed to unresponsiveness and focal seizures 48 h after starting treatment;7 in another, zidovudine therapy was associated with the development of acute Wernicke’s encephalopathy in an AIDS patient with none of the known risk factors for that condition.8 A report that acyclovir can potentiate the action of azidothymidine in vitro9 has led to the initiation of trials of combination therapy, but a recorded case of apparent neurotoxicity of acyclovir in a patient receiving zidovudine emphasises the need for caution with this approach. Another route to combination therapy is hinted at in the in-vitro findings of Mitchell and
colleagues.10 The antiviral effects of zidovudine in vivo have been confirmed by the reduction of circulating HIV antigen during treatment.l1 Reduction or cessation of zidovudine has, however, led to an immediate return of circulating antigen, and the renewed antigenaemia has often been associated with the onset of opportunistic infections. For this reason it is important to realise that once zidovudine treatment is started it will probably be needed for long periods, if not for life. The potential toxicity of zidovudine in patients with the less severe manifestations of HIV infection, such as persistent generalised lymphadenopathy, is unknown and the results of further trials are awaited. Until the safety of the drug has been more extensively evaluated, extreme caution should be exercised by practitioners considering its use in these groups or in symptomless carriers of the virus. The myelotoxic effects seen in patients with AIDS and ARC, if they also occur in those with less severe disease, might be sufficient to impose additional stress on the immune system and precipitate disease. Thus zidovudine represents an important development in measures to counter the effects of HIV infection. Other potent and possibly less toxic substances are now under evaluation and one of these, 2’,3’-dideoxycytidine, is being assessed in a phase I
Non-convulsive Status
Epilepticus
THE term status epilepticus (etat de mal epileptique), coined in 1824 to refer to repeated grand mal seizures, soon became widely used. More recently, however, it has been gradually appreciated that other seizure types may occur, and complex classifications have been devised.1 Status epilepticus, for the purposes of the International Classification of Seizure Type, is present "whenever a seizure persists for a sufficient length of time or is repeated sufficently frequently enough to produce a fixed and enduring epileptic condition".It may be divided into convulsive and non-convulsive forms. Convulsive status may be subdivided into generalised tonic clonic (synonym: grand mal) status, and simple partial status (synonym: epilepsia partialis continua). The former is of course the most common form of status epilepticus; it is usually easily recognised and is an important medical emergency, requiring urgent and expert management. Simple partial status is the second most common form of status, and again is usually easy to diagnose, although management may be difficult. Whilst the convulsive forms of status cause little confusion, either nosologically or clinically, the same can not be said of non-convulsive status. Non-convulsive status epilepticus is nevertheless an important syndrome and one with which many physicians are unfamiliar. Three criteria are usually given for the diagnosis of non-convulsive status:3-5 the presence of continuous
prolonged epileptic symptoms, electroencephalographic (EEG) abnormalties consistent with the diagnosis, and a prompt response to treatment. All three criteria are not invariably met, however. Non-convulsive status may conveniently be into subdivided generalised absence status (synonyms: petit mal status, spike wave stupor, epilepsia minor continua, minor epileptic status) and complex partial status (synonyms: psychomotor status, temporal lobe status). The patient with absence status presents with altered consciousness (ranging from simple inattentiveness to stupor), often accompanied by mild clonic movements of the eyelids, face, or hands or simple automatism. The diagnosis is definitively established by EEG, which shows continuous or at least frequent spike wave activity, classically regular 3 Hz activity but more commonly 2-3 Hz irregular spike wave or polyspike wave or
.
study.4 6. Yarchoan R, Broder S. Strategies for the pharmacologic intervention against HTLV-111/LAV. In Broder S, ed. AIDS: modern concepts and therapeutic challenges New York: Marcel Dekker, 1987: 335-60. 7. Hagler DN, Frame PT. Azidothymidine neurotoxicity. Lancet 1986; ii: 1392-93. 8. Davtyan D, Vinters H. Wemicke’s encephalopathy in AIDS patient treated with zidovudine. Lancet 1987; i: 919-20. 9. Mitsuya H, Matsukura M, Broder S. Rapid in vitro systems for assessing activity of agents against HTLV-III/LAV. In: Broder S, ed. AIDS modem concepts and therapeutic challenges. New York: Marcel Dekker, 1987: 303-33. 10. Mitchell WM, Montefiori DC, Robinson WE Jr, Strayer DR, Carter WA. Mismatched double-stranded RNA (Ampligen) reduces concentration of zidovudine (azidothymidine) required for in-vitro inhibition of human immunodeficiency virus. Lancet 1987; i: 890-92. 11. Chaisson RE, Allain J-P, Leuther M, Volberding PA Significant changes in HIV antigen level in the serum of patients treated with azidothymidine. N Engl J Med 1986; 315: 1610-11.
disturbances. The status may continue for hours days, during which time the patient may be more 1. Gastaut H. Classification of status
or or
epilepticus. In: Rose FC, ed. Research progress in 1983 8-13. 2. Gastaut H. Clinical and EEG classification of epileptic seizures. Epilepsia 1970; 11: 102-13. 3. Doose H. Nonconvulsive status epilepticus in children: clinical aspects and classification. In: Delgado-Escueta AV, Wasterlain CG, Treiman DM, Porter RJ, eds. Advances in neurology no 34: status epilepticus. New York: Raven, 1983: 83-92. 4. Porter RJ, Penry JK Pent mal status In: Delgado-Escueta AV, et al, eds. Advances in neurology no 34 status epilepticus. New York: Raven, 1983: 61-67. 5. Stores G. Nonconvulsive status epilepticus in children. In: Pedley TA, Meldrum BS, eds. Recent advances in epilepsy 3. Edinburgh. Churchill Livingstone, 1986. 295-310.
epilepsy. Bath: Pitman,