Biomedical subjects
D Brigden
Publications and source records attributed to D Brigden.
Use of interferon in the management of patients with subacute sclerosing panencephalitis.
Six patients (five male, one female) with subacute sclerosing panencephalitis were treated with purified lymphoblastoid interferon, using a combination of intravenous and lumbar intrathecal routes. The first symptoms of the disorder occurred between seven and 16 years of age, and the length of the illness before treatment varied from 1 1/2 to 12 months. All six patients were in the first clinical stage of the disorder. After a limited period of follow-up there has been no clinical improvement. Nil or low levels of interferon were found in CSF two hours after intravenous injection, but CSF levels of interferon were maintained for at least 24 hours after intrathecal injections. Side-effects of interferon included pyrexial reactions, especially after high-dose intravenous therapy (six), lethargy (four), a transient rise in blood pressure (two) and a reduction in platelet count (six). Staphylococcus epidermidis was grown from the CSF of one patient.
The clinical pharmacology of acyclovir and its prodrugs.
Acyclovir (Zovirax) is a highly specific antiherpes virus agent. Extensive investigations of the pharmacokinetics in man have shown it to have a useful half-life of about three hours and to be largely excreted unchanged in the urine. Crystaluria can be avoided provided the patient is well hydrated and attention is paid to the dosing instructions especially in patients with renal failure. In vitro ED50s (the drug concentration inhibiting virus replication by 50%) bear some general relevance to effective plasma levels in man. A new prodrug of acyclovir, 2-amino-9-[2-hydroxyethoxy methyl]-9H-purine (A515U), which is converted to acyclovir by xanthine oxidase is rapidly absorbed from the human gut and converted to acyclovir. This prodrug provides the opportunity to design regimes that are more convenient for the patient and may be more effective than acyclovir itself in the therapy of the less sensitive herpes viruses (e.g. Epstein-Barr virus and the Cytomegalovirus).
Acyclovir: an update of the clinical applications of this antiherpes agent.
This paper reviews the clinical evaluation of acyclovir in the treatment of herpes-virus infections, predominantly those due to herpes simplex and varicella-zoster viruses. Intravenous, oral and topical acyclovir have been reported to be effective in the therapy of a wide variety of established herpes simplex virus infections and the systemic drug has been shown to be capable of suppressing reactivation of that virus. Although acyclovir has less activity against varicella-zoster virus, infections caused by this agent are also susceptible to intravenous and possibly oral therapy. Clinical efficacy against Epstein-Barr virus and cytomegalovirus infections has not been demonstrated but several studies are currently in progress. Limited evidence of in vivo activity against hepatitis B virus also requires further evaluation. Continued studies on tolerance of the drug in clinical use has confirmed the early promise of this selective antiviral, whilst initial concern about the development of widespread resistance has not been borne out in practice.
Oral acyclovir prophylaxis against herpes simplex virus in non-Hodgkin lymphoma and acute lymphoblastic leukaemia patients receiving remission induction chemotherapy. A randomised double blind, placebo controlled trial.
Forty-one patients receiving remission induction chemotherapy with vincristine, adriamycin and prednisolone (VAP) for high grade lymphoma or acute lymphoblastic leukaemia were entered into a double blind, placebo controlled trial of oral acyclovir prophylaxis against herpes simplex virus (HSV) infection. The dose of acyclovir was 200 mg four times daily for the duration of chemotherapy (six weeks). Of the 40 evaluable patients, 20 were randomised to each arm. Prophylactic oral acyclovir significantly reduced the incidence of clinical HSV infection from 60% on placebo to 5% acyclovir (P less than 0.001), and the incidence of viral isolates from 70% on placebo to 5% on acyclovir (P less than 0.001).
Acyclovir prophylaxis against herpes virus infections in severely immunocompromised patients: randomised double blind trial.
Twenty patients undergoing allogeneic bone marrow transplantation and 39 patients receiving remission induction chemotherapy for acute leukaemia were entered into a double blind, placebo controlled stratified trial of acyclovir prophylaxis against herpes group virus infections. Within the transplant group intravenous acyclovir 5 mg/kg twice daily given throughout the period of granulocytopenia completely prevented oropharyngeal herpes simplex virus infection compared with a 50% incidence in the placebo arm (p = 0.033). The acyclovir group also had fewer days of fever during the trial and a shorter duration of leukopenia, possibly because of the prevention of herpes simplex virus infections. There was a high incidence of herpes infections after the trial in patients who received either acyclovir or placebo. In the non-transplant group there was also a significant reduction of herpes simplex virus infection in the oropharynx and oesophagus (two out of 19 patients as compared with 10 out of 20; p = 0.018). Herpes simplex virus was isolated in the acyclovir arm within a day after starting the trial in one patient, and the other failure was due to a virus with reduced sensitivity to acyclovir in a patient who had had several previous courses of the drug. The incidence of herpes infections after stopping treatment was low. The influence of acyclovir on excretion of Epstein-Barr virus in saliva in either group was inconclusive. One patient (transplant group) developed a cytomegalovirus infection while receiving acyclovir. Acyclovir provides effective prophylaxis against oropharyngeal and oesophageal herpes simplex virus infection in severely immunocompromised seropositive (greater than or equal to 1/8) patients. In patients given bone marrow transplants this may have the additional benefit of reducing the time to recovery of an adequate blood count and the number of days of fever.
Interferon in acute and chronic viral infections.
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The mechanism of action, pharmacokinetics and toxicity of acyclovir--a review.
Acyclovir (ACV) has a novel, highly selective biological activity which results in the inhibition of herpesvirus replication at concentrations 300-3000-fold lower than those that will inhibit mammalian cellular functions. Subacute and chronic studies in animals indicate that the drug is relatively non-toxic, poses no special risks to pregnancy or the foetus and does not induce detectable oncogenic or genetic changes. In man, acyclovir has a plasma half-life of approximately three hours, is widely distributed throughout the body tissues and is rapidly cleared, mainly as unchanged drug, through the kidneys. Provided that the product (Zovirax) is used according to the manufacturers' instructions, the risk of significant toxic effects is low.
The present and future for acyclovir.
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Renal function after acyclovir intravenous injection.
Plasma urea or creatinine was noted to be raised in 58 of 354 patients treated with intravenous acyclovir. This occurred after intravenous bolus injection of high dosages of acyclovir but the risk was considerably reduced by slow intravenous infusion of the same dosage over one hour, with adequate hydration of the patient and adjustment of dosage in patients with preexisting impaired renal function. Animal studies indicate that the impairment of renal function associated with high bolus injections of acyclovir is due to crystal formation in the renal tubules and/or the collecting ducts, and that the crystals are removed after cessation of treatment. The special problems involved in the treatment of patients with herpes encephalitis necessitating limited fluid intake and the possible interaction with other nephrotoxic drugs are discussed.
Treatment of erythema multiforme secondary to herpes simplex by prophylactic topical acyclovir.
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Acyclovir - a review of the preclinical and early clinical data of a new antiherpes drug.
A review of the literature on acyclovir (Zovirax), a new antiherpes drug, with particular activity against herpes simplex virus types I and II and also against varicella-zoster, Epstein-Barr, cytomegalo and herpes B viruses, is presented. The article deals with 'in vitro' and 'in vivo' efficacy in animals, animal toxicity, latency and resistance, the mechanism of action and early clinical experience.
Human pharmacokinetics of acyclovir (an antiviral agent) following rapid intravenous injection.
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Parenteral acyclovir therapy for herpesvirus infections in man.
Acyclovir is a new antiviral agent which is highly active against herpesviruses in vitro and in laboratory animals. Twenty-three cancer patients with cutaneous and/or systemic herpes zoster or herpes simplex infections were treated with parenteral acyclovir. All had received previous specific treatment for their malignant disease and ten had undergone bone-marrow transplantation. The drug seemed to arrest the progress of the infections and was most effective when given early. Although two patients showed transient increases in blood-urea, possibly the result of acyclovir, the drug was remarkably non-toxic in the doses used.
Acycloguanosine for viral pneumonia.
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Immunological aspects of candidal vaginitis.
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Antilymphocyte globulin in the treatment of advanced Sézary syndrome.
Two patients with Sézary syndrome, refractory to conventional treatment, were given cyclophosphamide and antilymphocyte globulin (A.L.G) Both patients showed improvement. One patient subsequently died from widespread varicella and the other relapsed later. It is concluded that A.L.G. may be effective in this condition.