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      Acyclovir Neurotoxicity in a Peritoneal Dialysis Patient: Report of a Case and Review of the Pharmacokinetics of Acyclovir

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          Abstract

          Patient: Male, 80

          Final Diagnosis: Neurotoxicity due acyclovir

          Symptoms: Confusion • hallucination

          Medication: Acyclovir

          Clinical Procedure: —

          Specialty: Nephrology

          Objective:

          Unusual clinical course

          Background:

          The elderly population in the United States and the world is rapidly increasing. With aging, immunity and kidney function decrease, thus predisposing people to viral illnesses for which there is no effective prophylaxis. Herpes zoster afflicts the elderly and other immunocompromised patients, like those with end-stage renal disease, transplant recipients, and cancer patients, causing significant morbidity and sometimes mortality. Treating herpes zoster becomes problematic when the regular pharmacokinetics of the antiviral drugs are disturbed.

          Case Report:

          An 83-year-old African American man with end-stage kidney disease (ESRD) and on chronic peritoneal dialysis (PD) developed herpes zoster, for which he received the manufacturer-recommended intravenous dose of acyclovir. Shortly after taking the medication, he developed confusion, disorientation, and visual hallucinations. He was switched from PD to hemodialysis (HD), with successful recovery. Examination of the cerebrospinal fluid for meningitis and imaging studies of the head were negative. Serum levels of acyclovir were elevated.

          Conclusions:

          Even when the acyclovir dose is properly adjusted for kidney function based on the current manufacturer’s recommendations, it can cause neurotoxicity. Here, we discuss the pharmacokinetics of acyclovir and make some recommendations with regard to dose adjustment in patients with ESRD.

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          Most cited references29

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          History, pharmacokinetics, and pharmacology of acyclovir.

          A screening program for antiviral drugs begun at Burroughs Wellcome in the 1960s resulted in the discovery of acyclovir in 1974. Preclinical investigation brought the drug to clinical trials in 1977 and the first form of the drug (topical) was available to physicians in 1982. Activity of acyclovir is greatest against herpes 1 and herpes 2, less against varicella zoster, still less against Epstein-Barr, and very little against cytomegalovirus. Acyclovir is an antiviral agent only after it is phosphorylated in infected cells by a viral-induced thymidine kinase. Acyclovir monophosphate is phosphorylated to diphosphate and triphosphate forms by cellular enzymes in the infected host cell where the drug is concentrated. Acyclovir triphosphate inactivates viral deoxyribonucleic acid polymerase. Acyclovir incorporation into the growing viral deoxyribonucleic acid chain causes its termination. The antiviral process has relatively little effect on normal, uninfected cells. An important toxic effect of acyclovir is its potential to cause obstructive nephropathy. The drug is excreted primarily by the kidney, which may require smaller doses in patients with decreased kidney function. Oral dosages of acyclovir as recommended for herpes simplex are probably not adequate for varicella zoster infections.
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            High serum concentrations of the acyclovir main metabolite 9-carboxymethoxymethylguanine in renal failure patients with acyclovir-related neuropsychiatric side effects: an observational study.

            Acyclovir (ACV) has been used for over two decades to treat herpes virus infections. Serious neurological adverse side effects have occurred during ACV treatment in patients with renal failure, but the cause of the symptoms remains unknown. We hypothesized that increased concentrations of the ACV main metabolite 9-carboxymethoxymethylguanine (CMMG) correlated to these symptoms. We conducted an observational study from 1991 to mid 1999 based on samples sent for analysis of ACV concentration from various hospital departments in Sweden. Patients with neuropsychiatric symptoms (NS+, n=49) were compared with patients without symptoms (NS-, n=44). ACV and CMMG concentrations were analysed by HPLC. Medical records were analysed for symptoms and compared with pertinent cases identified from Medline. The serum CMMG levels were significantly higher in the NS+ group (mean=34.1 micro mol/l, 95% confidence interval 23.4-46.1) compared with the NS- group (mean=4.7 micro mol/l, 95% confidence interval 3.3-6.6; P<0.001). CMMG was the strongest predictor in a receiver-operating characteristics curve analysis (ROC), based on 77 patients, of ACV-related neuropsychiatric symptoms. The ROC curve for CMMG demonstrated that neuropsychiatric symptoms could be predicted with a sensitivity of 91% and a specificity of 93% with the use of a cut-off value of 10.8 micro mol/l of CMMG. Thirty-five of 49 patients in the NS+ group showed levels exceeding this concentration compared with only three of 44 of patients in the NS- group (P<0.001). ACV exposure, ACV concentration, creatinine clearance and creatinine concentration were weaker but statistically significant predictors. Haemodialysis reduced CMMG and ACV levels and relieved the symptoms. The determination of CMMG levels in serum may be a useful tool in supporting the diagnosis of ACV-associated neuropsychiatric symptoms. Furthermore, the monitoring of CMMG levels may prevent the emergence of symptoms.
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              Clinical pharmacokinetics of acyclovir.

              O L Laskin (1983)
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                Author and article information

                Journal
                Am J Case Rep
                Am J Case Rep
                amjcaserep
                The American Journal of Case Reports
                International Scientific Literature, Inc.
                1941-5923
                2018
                09 December 2018
                : 19
                : 1459-1462
                Affiliations
                [1 ]Nephrology Section, Jerry L Pettis Veterans Memorial Medical Center, Loma Linda, CA, U.S.A.
                [2 ]Pharmacy Section, Jerry L Pettis Veterans Memorial Medical Center, Loma Linda, CA, U.S.A.
                Author notes

                Authors’ Contribution:

                [A]

                Study Design

                [B]

                Data Collection

                [C]

                Statistical Analysis

                [D]

                Data Interpretation

                [E]

                Manuscript Preparation

                [F]

                Literature Search

                [G]

                Funds Collection

                Conflict of interest: None declared

                Corresponding Author: Seyed-Ali Sadjadi, e-mail: sadjadia@ 123456yahoo.com
                Article
                911520
                10.12659/AJCR.911520
                6298245
                30531673
                09fb9135-2edb-4851-a2e3-c6fcc13e3510
                © Am J Case Rep, 2018

                This work is licensed under Creative Common Attribution-NonCommercial-NoDerivatives 4.0 International ( CC BY-NC-ND 4.0)

                History
                : 04 June 2018
                : 07 September 2018
                Categories
                Articles

                acyclovir,dialysis,neurotoxicity syndromes
                acyclovir, dialysis, neurotoxicity syndromes

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