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Journal of the American Pharmacists... 2024Herpes encephalitis, a rare yet potentially fatal viral infection, is treated exclusively with acyclovir, the sole antiviral medication used for this condition.... (Review)
Review
BACKGROUND
Herpes encephalitis, a rare yet potentially fatal viral infection, is treated exclusively with acyclovir, the sole antiviral medication used for this condition. Acyclovir recommended dose is 10 mg/kg/dose intravenous every 8 hours; however, it is unclear what body weight should be utilized in obese patients. Using the ideal body weight may result in subtherapeutic ineffective concentrations, while utilizing the actual body weight might result in acyclovir induced adverse effects, either nephrotoxicity or neurotoxicity or both.
OBJECTIVE
The objective of this scoping review is to explore existing evidence regarding acyclovir dosing for obese patients afflicted with herpes encephalitis.
METHODS
MEDLINE, EMBASE, Scopus, Web of Science, and CINAHL databases were searched on 26 May 2023, with no language restrictions. Two independent reviewers utilized the Covidence software to carry out the screening and selection of the articles. A total of 22 articles were included in the current review.
RESULTS
The prevalence of acyclovir-associated nephrotoxicity ranged from 13% to 21%, while the prevalence of neurotoxicity was not clearly defined. However, there is lack of evidence regarding what may arise from subtherapeutic concentrations. An approach has been suggested to help clinicians to give the most appropriate acyclovir dose to herpes encephalitis patients. Patients with normal kidney function could receive the normal doses based on actual weight if normal weight and based on adjusted body weight if obese. On the other hand, if the patients are experiencing augmented renal clearance, they could receive up to the maximum recommended doses.
CONCLUSION
Overall, there is a lack of consistency on which body weight to use to calculate acyclovir dose in obese patients. So it is recommended that further studies compare the concentration of intravenous acyclovir between obese and nonobese patients and relating the resultant concentration with patient outcomes.
Topics: Humans; Acyclovir; Antiviral Agents; Body Weight; Dose-Response Relationship, Drug; Encephalitis, Herpes Simplex; Obesity
PubMed: 38364888
DOI: 10.1016/j.japh.2024.02.013 -
Survey of Ophthalmology 2024Acute retinal necrosis is a progressive intraocular inflammatory syndrome characterized by diffuse necrotizing retinitis that can lead to a poor visual outcome, mainly... (Meta-Analysis)
Meta-Analysis Review
Acute retinal necrosis is a progressive intraocular inflammatory syndrome characterized by diffuse necrotizing retinitis that can lead to a poor visual outcome, mainly from retinal detachment. The antiviral treatment approach for acute retinal necrosis varies as there are no established guidelines. We summarize the outcomes of acute retinal necrosis with available antiviral treatments. Electronic searches were conducted in PubMed/MEDLINE, EMBASE, Scopus, and Google Scholar for interventional and observational studies. Meta-analysis was performed to evaluate the pooled proportion of the predefined selected outcomes. This study was registered in PROSPERO (CRD42022320987). Thirty-four studies with a total of 963 participants and 1,090 eyes were included in the final analysis. The estimated varicella-zoster virus and herpes simplex virus polymerase chain reaction-positive cases were 63% (95% CI: 55-71%) and 35% (95% CI: 28-42%), respectively. The 3 main antiviral treatment approaches identified were oral antivirals alone, intravenous antivirals alone, and a combination of systemic (oral or intravenous) and intravitreal antivirals. The overall pooled estimated proportions of visual acuity improvement, recurrence, and retinal detachment were 37% (95% CI: 27-47%), 14% (95% CI: 8-21%), and 43% (95% CI: 38-50%), respectively. Patients treated with systemic and intravitreal antivirals showed a trend towards better visual outcomes than those treated with systemic antivirals (oral or intravenous) alone, even though this analysis was not statistically significant (test for subgroup differences P = 0.83).
Topics: Humans; Retinal Necrosis Syndrome, Acute; Antiviral Agents; Acyclovir; Eye Infections, Viral; Retinal Detachment; Retrospective Studies
PubMed: 37774799
DOI: 10.1016/j.survophthal.2023.09.004 -
Biomedicine & Pharmacotherapy =... Dec 2022To obtain information on the serum concentrations of acyclovir and its metabolite in routine health care with respect to the renal function.
OBJECTIVE
To obtain information on the serum concentrations of acyclovir and its metabolite in routine health care with respect to the renal function.
METHODS
This prospective study analyzed data from 27 patients receiving acyclovir intravenously between June 2019 and October 2021. Patients were divided into two subgroups according to the estimated glomerular filtration rate. Serum concentrations of acyclovir and its metabolite 9-(carboxymethoxymethyl) guanine were mainly analyzed on day 5 after the initiation of treatment before the morning dose (trough concentration) and 30 min after the end of the infusion (peak concentration).
RESULTS
Trough acyclovir concentrations ranged from 0.8 to 7.6 mg/L and peak concentrations from 6.3 to 25.7 mg/L, and trough metabolite concentrations ranged from 0.12 to 2.30 mg/L and peak concentrations from 0.47 to 2.70 mg/L, respectively. The ratio of trough metabolite and acyclovir concentrations ranged from 0.07 to 0.63 and the ratio of peak concentrations from 0.03 to 0.24. Patients in the subgroup with reduced renal function were significantly older, smaller, and of lower body weight and received significantly lower doses of acyclovir.
CONCLUSIONS
A 10-fold difference in the weight-adjusted apparent clearance of acyclovir was observed between patients. This wide interindividual variability in acyclovir pharmacokinetics can lead not only to toxicity but also to suboptimal acyclovir concentrations in severe infections. Therefore, therapeutic monitoring of serum concentrations of acyclovir and its metabolite may be important for optimizing pharmacotherapy, especially in patients with severe clinical conditions.
Topics: Humans; Acyclovir; Guanine; Prospective Studies; Antiviral Agents; Glomerular Filtration Rate
PubMed: 36228373
DOI: 10.1016/j.biopha.2022.113852 -
BMC Ophthalmology Apr 2015This objective of the review and analysis is to demonstrate that acyclovir (ACV) 3% ophthalmic ointment is superior to idoxuridine (IDU) in treating herpetic keratitis... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
This objective of the review and analysis is to demonstrate that acyclovir (ACV) 3% ophthalmic ointment is superior to idoxuridine (IDU) in treating herpetic keratitis (HK) presenting as dendritic and geographic ulcer sub-types.
DATA SOURCES
Publications in human subjects were identified by searching the Ovid MEDLINE database through April 2011, combining medical subject headings (MESH) "Keratitis, Herpetic/" AND "Acyclovir/" limiting by the key words "topical" OR "ointment" and also restricted to MESH "Administration, Topical/" OR "Ointments/". The results were cross checked with the references used in the Cochrane Database Syst Rev. 1:1-134, 2009 and GlaxoSmithKline clinical documents related to acyclovir.
STUDY SELECTION
Randomized, double-masked studies in subjects diagnosed with HK with head to head comparator arms of ACV ophthalmic ointment and topical IDU that had actual or calculable healing rates at Day seven.
DATA EXTRACTION
Data independently extracted from identified articles by two authors of this manuscript.
DATA SYNTHESIS
Data from seven randomized, controlled trials (RCT) evaluating 432 subjects that met inclusion criteria (214 were treated with ACV and 218 were treated with IDU) and had Day seven healing rates calculable. All sub-classified lesions were identified as either dendritic ulcers (n = 185) or geographic ulcers (n = 35). The Cochran-Mantel-Haenszel (CMH) method in Biometrics 10:417-51, 1954 and JNCI 22:719-48, 1959, controlling for study, was performed as the primary analysis using SAS v9. Homogeneity was assessed using Breslow-Day-Tarone (BDT) test in IARC 1:1-32, 1980 and Biometrika 72:91-5, 1985. The analysis was performed with outliers removed to assess their impact.
RESULTS
ACV showed statistically significant greater odds of healing HK at Day seven in all subjects (Odds Ratio 3.95, 95% CI2.60, 6.00, p < 0.0001), in dendritic ulcers (Odds Ratio 4.22, 95% CI: 2.14, 8.32; p < 0.0001) and geographic ulcers (Odds Ratio 5.31, 95% CI: 1.09, 25.93; p = 0.0244).
CONCLUSION
ACV 3% ophthalmic ointment is a valuable intervention for dendritic and geographic corneal ulcers. ACV and IDU were generally well tolerated in the studies reviewed.
Topics: Acyclovir; Antiviral Agents; Follow-Up Studies; Humans; Idoxuridine; Keratitis, Herpetic; Ointments; Time Factors; Treatment Outcome
PubMed: 25928630
DOI: 10.1186/s12886-015-0022-2 -
The Cochrane Database of Systematic... Dec 2016Infectious mononucleosis (IM) is a clinical syndrome, usually caused by the Epstein Barr virus (EPV), characterised by lymphadenopathy, fever and sore throat. Most cases... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Infectious mononucleosis (IM) is a clinical syndrome, usually caused by the Epstein Barr virus (EPV), characterised by lymphadenopathy, fever and sore throat. Most cases of symptomatic IM occur in older teenagers or young adults. Usually IM is a benign self-limiting illness and requires only symptomatic treatment. However, occasionally the disease course can be complicated or prolonged and lead to decreased productivity in terms of school or work. Antiviral medications have been used to treat IM, but the use of antivirals for IM is controversial. They may be effective by preventing viral replication which helps to keep the virus inactive. However, there are no guidelines for antivirals in IM.
OBJECTIVES
To assess the effects of antiviral therapy for infectious mononucleosis (IM).
SEARCH METHODS
We searched the Cochrane Central Register of Controlled Trials (CENTRAL, Issue 3, March 2016), which contains the Cochrane Acute Respiratory Infections (ARI) Group's Specialised Register, MEDLINE (1946 to 15 April 2016), Embase (1974 to 15 April 2016), CINAHL (1981 to 15 April 2016), LILACS (1982 to 15 April 2016) and Web of Science (1955 to 15 April 2016). We searched the World Health Organization (WHO) International Clinical Trials Registry Platform and ClinicalTrials.gov for completed and ongoing trials.
SELECTION CRITERIA
We included randomised controlled trials (RCTs) comparing antivirals versus placebo or no treatment in IM. We included trials of immunocompetent participants of any age or sex with clinical and laboratory-confirmed diagnosis of IM, who had symptoms for up to 14 days. Our primary outcomes were time to clinical recovery and adverse events and side effects of medication. Secondary outcomes included duration of abnormal clinical examination, complications, viral shedding, health-related quality of life, days missing from school or work and economic outcomes.
DATA COLLECTION AND ANALYSIS
Two review authors independently assessed studies for inclusion, assessed the included studies' risk of bias and extracted data using a customised data extraction sheet. We used the GRADE criteria to rate the quality of the evidence. We pooled heterogeneous data where possible, and presented the results narratively where we could not statistically combine data.
MAIN RESULTS
We included seven RCTs with a total of 333 participants in our review. Three trials studied hospitalised patients, two trials were conducted in an outpatient setting, while the trial setting was unclear in two studies. Participants' ages ranged from two years to young adults. The type of antiviral, administration route, and treatment duration varied between the trials. The antivirals in the included studies were acyclovir, valomaciclovir and valacyclovir. Follow-up varied from 20 days to six months. The diagnosis of IM was based on clinical symptoms and laboratory parameters.The risk of bias for all included studies was either unclear or high risk of bias. The quality of evidence was graded as very low for all outcomes and so the results should be interpreted with caution. There were statistically significant improvements in the treatment group for two of the 12 outcomes. These improvements may be of limited clinical significance.There was a mean reduction in 'time to clinical recovery as assessed by physician' of five days in the treatment group but with wide confidence intervals (CIs) (95% CI -8.04 to -1.08; two studies, 87 participants). Prospective studies indicate that clinical signs and symptoms may take one month or more to resolve and that fatigue may be persistent in approximately 10% of patients at six-month follow-up, so this may not be a clinically meaningful result.Trial results for the outcome 'adverse events and side effects of medication' were reported narratively in only five studies. In some reports authors were unsure whether an adverse event was related to medication or complication of disease. These results could not be pooled due to the potential for double counting results but overall, the majority of trials reporting this outcome did not find any significant difference between treatment and control groups.There was a mean reduction in 'duration of lymphadenopathy' of nine days (95% CI -11.75 to -6.14, two studies, 61 participants) in favour of the treatment group.In terms of viral shedding, the overall effect from six studies was that viral shedding was suppressed while on antiviral treatment, but this effect was not sustained when treatment stopped.For all other outcomes there was no statistically significant difference between antiviral treatment and control groups.
AUTHORS' CONCLUSIONS
The effectiveness of antiviral agents (acyclovir, valomaciclovir and valacyclovir) in acute IM is uncertain. The quality of the evidence is very low. The majority of included studies were at unclear or high risk of bias and so questions remain about the effectiveness of this intervention. Although two of the 12 outcomes have results that favour treatment over control, the quality of the evidence of these results is very low and may not be clinically meaningful. Alongside the lack of evidence of effectiveness, decision makers need to consider the potential adverse events and possible associated costs, and antiviral resistance. Further research in this area is warranted.
Topics: Acute Disease; Acyclovir; Adolescent; Adult; Antiviral Agents; Child; Child, Preschool; Female; Guanine; Humans; Infectious Mononucleosis; Male; Randomized Controlled Trials as Topic; Valacyclovir; Valine; Young Adult
PubMed: 27933614
DOI: 10.1002/14651858.CD011487.pub2 -
Cleveland Clinic Journal of Medicine Sep 2015
Topics: Acyclovir; Aged; Antiviral Agents; Diagnosis, Differential; Glucocorticoids; Herpes Zoster; Herpesvirus 3, Human; Humans; Male; Neuralgia; Treatment Outcome; Virus Activation
PubMed: 26366954
DOI: 10.3949/ccjm.82a.14173 -
AAPS PharmSciTech Oct 2020Currently, pharmaceutical research is directed wide range for developing new drugs for oral administration to target disease. Acyclovir formulation is having common...
Currently, pharmaceutical research is directed wide range for developing new drugs for oral administration to target disease. Acyclovir formulation is having common issues of short half-life and poor permeability, causing messy treatment which results in patient incompliance. The present study formulates a lipid polymeric hybrid nanoparticles for antiviral acyclovir (ACV) agent with Phospholipon® 90G (lecithin), chitosan, and polyethylene glycol (PEG) to improve controlled release of the drugs. The study focused on the encapsulation of the ACV in lipid polymeric particle and their sustained delivery. The formulation developed for the self-assembly of chitosan and lecithin to form a shell encapsulating acyclovir, followed by PEGylation. Optimisation was performed via Box-Behnken Design (BBD), forming nanoparticles with size of 187.7 ± 3.75 nm, 83.81 ± 1.93% drug-entrapped efficiency (EE), and + 37.7 ± 1.16 mV zeta potential. Scanning electron microscopy and transmission electron microscopy images displayed spherical nanoparticles formation. Encapsulation of ACV and complexity with other physical parameters are confirmed through analysis using Fourier transform infrared spectroscopy, differential scanning calorimetry, and X-ray diffraction. Nanoparticle produced was capable of achieving 24-h sustained release in vitro on gastric and intestinal environments. Ex vivo study proved the improvement of acyclovir's apparent permeability from 2 × 10 to 6.46 × 10 cm s. Acyclovir new formulation was achieved to be stable up to 60 days for controlled release of the drugs. Graphical abstract.
Topics: Acyclovir; Animals; Antiviral Agents; Chitosan; Delayed-Action Preparations; Drug Compounding; Drug Stability; Intestinal Absorption; Lecithins; Lipids; Nanoparticles; Particle Size; Polyethylene Glycols; Rabbits
PubMed: 33057878
DOI: 10.1208/s12249-020-01810-0 -
Journal of Virology Jun 2022Understanding the molecular mechanisms of herpes simplex virus 1 (HSV-1) latent infection and reactivation in neurons requires the use of model systems. Establishing a...
Understanding the molecular mechanisms of herpes simplex virus 1 (HSV-1) latent infection and reactivation in neurons requires the use of model systems. Establishing a quiescent infection in cultured neurons is problematic, as any infectious virus released can superinfect the cultures. Previous studies have used the viral DNA replication inhibitor acyclovir to prevent superinfection and promote latency establishment. Data from these previous models have shown that reactivation is biphasic, with an initial phase I expression of all classes of lytic genes, which occurs independently of histone demethylase activity and viral DNA replication but is dependent on the cell stress protein DLK. Here, we describe a new model system using HSV-1 Stayput-GFP, a reporter virus that is defective for cell-to-cell spread and establishes latent infections without the need for acyclovir. The establishment of a latent state requires a longer time frame than previous models using DNA replication inhibitors. This results in a decreased ability of the virus to reactivate using established inducers, and as such, a combination of reactivation triggers is required. Using this system, we demonstrate that biphasic reactivation occurs even when latency is established in the absence of acyclovir. Importantly, phase I lytic gene expression still occurs in a histone demethylase and viral DNA replication-independent manner and requires DLK activity. These data demonstrate that the two waves of viral gene expression following HSV-1 reactivation are independent of secondary infection and not unique to systems that require acyclovir to promote latency establishment. Herpes simplex virus-1 (HSV-1) enters a latent infection in neurons and periodically reactivates. Reactivation manifests as a variety of clinical symptoms. Studying latency and reactivation is invaluable, allowing the molecular mechanisms behind both processes to be targeted by therapeutics that reduce the clinical consequences. Here, we describe a novel model system using a cell-to-cell spread-defective HSV-1, known as Stayput-GFP, which allows for the study of latency and reactivation at the single neuron level. We anticipate this new model system will be an incredibly valuable tool for studying the establishment and reactivation of HSV-1 latent infection . Using this model, we find that initial reactivation events are dependent on cellular stress kinase DLK but independent of histone demethylase activity and viral DNA replication. Our data therefore further validate the essential role of DLK in mediating a wave of lytic gene expression unique to reactivation.
Topics: Acyclovir; Antiviral Agents; DNA Replication; DNA, Viral; Herpes Simplex; Herpesvirus 1, Human; Histone Demethylases; Humans; Latent Infection; MAP Kinase Kinase Kinases; Virus Activation; Virus Latency; Virus Replication
PubMed: 35608347
DOI: 10.1128/jvi.00508-22 -
Biomedical Chromatography : BMC Apr 2022A novel MS-based analytical method for simultaneous analysis of the antiviral drugs acyclovir, its metabolite 9-carboxymethoxymethylguanine, ganciclovir, and penciclovir...
A novel MS-based analytical method for simultaneous analysis of the antiviral drugs acyclovir, its metabolite 9-carboxymethoxymethylguanine, ganciclovir, and penciclovir in human serum is described. These antiviral drugs are active against herpes virus infections. Acyclovir and penciclovir are regarded as safe and effective medicines with mild side effects such as headache and gastrointestinal discomfort, and ganciclovir is regarded as more toxic and is known to cause, for example, bone marrow suppression. Acyclovir's main metabolite 9-carboxymethoxymethylguanine is a presumptive neurotoxin and should be monitored in patients with impaired renal function or in cases with neurotoxic symptoms. A sample was prepared using protein precipitation with 1% formic acid in methanol containing isotopically labeled internal standard. Chromatographic separation on a biphenyl column and mass spectrometric detection were performed in multiple reaction monitoring (MRM) mode on a Xevo TQ-S micro with ESI in positive ion mode, within 3 min. Inter-day assay accuracies for the quality controls varied between 95 and 104% and intra-day assay between 93 and 105%. Inter-day and intra-day assay imprecision for the quality controls ranged between 1.4 and 4.2% and 1.7 and 6.5% respectively. The lower limit of quantification for all four substances was 0.156 μmol/L. It is an accurate and reproducible method for therapeutic drug monitoring.
Topics: Acyclovir; Chromatography, Liquid; Ganciclovir; Guanine; Humans; Reproducibility of Results; Tandem Mass Spectrometry
PubMed: 34981553
DOI: 10.1002/bmc.5315 -
Scientific Reports Jul 2021Herpes simplex virus is among the most prevalent sexually transmitted infections. Acyclovir is a potent, selective inhibitor of herpes viruses and it is indicated for...
Herpes simplex virus is among the most prevalent sexually transmitted infections. Acyclovir is a potent, selective inhibitor of herpes viruses and it is indicated for the treatment and management of recurrent cold sores on the lips and face, genital herpes, among other diseases. The problem of the oral bioavailability of acyclovir is limited because of the low permeability across the gastrointestinal membrane. The use of nanoparticles of pseudoboehmite as a drug delivery system in vitro assays is a promising approach to further the permeability of acyclovir release. Here we report the synthesis of high purity pseudoboehmite from aluminium nitrate and ammonium hydroxide containing nanoparticles, using the sol-gel method, as a drug delivery system to improve the systemic bioavailability of acyclovir. The presence of pseudoboehmite nanoparticles were verified by infrared spectroscopy, transmission electron microscopy, and X-ray diffraction techniques. In vivo tests were performed with Wistar rats to compare the release of acyclovir, with and without the addition of pseudoboehmite. The administration of acyclovir with the addition of pseudoboehmite increased the drug content by 4.6 times in the plasma of Wistar rats after 4 h administration. We determined that the toxicity of pseudoboehmite is low up to 10 mg/mL, in gel and the dried pseudoboehmite nanoparticles.
Topics: Acyclovir; Administration, Oral; Aluminum Hydroxide; Aluminum Oxide; Animals; Antiviral Agents; Biological Availability; Caco-2 Cells; Cell Survival; Drug Delivery Systems; Drug Liberation; Herpes Simplex; Humans; Models, Animal; Nanogels; Rats; Rats, Wistar; Simplexvirus
PubMed: 34326377
DOI: 10.1038/s41598-021-94325-y