BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.
BACKGROUND: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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.
Authors: Leonardo D'Aiuto; Kelly Williamson; Peter Dimitrion; James McNulty; Carla E Brown; Chanti Babu Dokuburra; Alexander J Nielsen; Wen Jing Lin; Paolo Piazza; Mark E Schurdak; Joel Wood; Robert H Yolken; Paul R Kinchington; David C Bloom; Vishwajit L Nimgaonkar Journal: Antiviral Res Date: 2017-03-23 Impact factor: 5.970
Authors: Inti Peredo; Anders Helldén; Nina Wolmer-Solberg; Anton Pohanka; Giuseppe Stragliotto; Afsar Rahbar; Lars Ståhle; Bo-Michael Bellander; Cecilia Söderberg-Nauclér Journal: BMJ Case Rep Date: 2015-12-15
Authors: James P Smith; Stephen Weller; Benjamin Johnson; Janet Nicotera; James M Luther; David W Haas Journal: Antimicrob Agents Chemother Date: 2009-12-28 Impact factor: 5.191
Authors: Jessica E Ericson; Martyn Gostelow; Julie Autmizguine; Christoph P Hornik; Reese H Clark; Daniel K Benjamin; P Brian Smith Journal: Pediatr Infect Dis J Date: 2017-04 Impact factor: 3.806
Authors: Anders Helldén; Ingegerd Odar-Cederlöf; Göran Nilsson; Susanne Sjöviker; Anders Söderström; Mia von Euler; Gunnar Ohlén; Ulf Bergman Journal: BMJ Open Date: 2013-04-11 Impact factor: 2.692