Intralesional acyclovir versus intralesional Hepatitis-B vaccine in treatment of resistant plantar warts: a randomized controlled trial.

Treating plantar warts is still a challenging problem with a long list of diverse treatment options that none of them seems to be definitive. To evaluate the effectiveness of intralesional acyclovir versus intralesional Hepatitis-B vaccine (HBV) in treatment of multiple resistant plantar warts. Forty-eight patients with resistant plantar warts completed the study with no dropouts. They were randomized into 3 groups; group(A) receiving intralesional HBV, group (B) receiving intralesional acyclovir and group (C) receiving intralesional saline as a control group over 5 biweekly sessions or until wart clearance. Clinical outcome was assessed through sequential digital lesion photographing upon each visit. Treatment related adverse reactions were recorded. 43.8%, 37.5% & 18.7% of Groups A, B &C respectively showed a complete response. pain was obvious in 100% and 56.3% of cases receiving intralesional acyclovir and HBV respectively. Up to the 6 month follow up period, none of the complete responders in all groups returned with a recurrence. Both acyclovir and HBV showed comparable efficacy and seem to be promising options for treating plantar warts being safe, affordable, and theoretically safe in immunocompromised cases.

Acyclovir extravasation in a newborn: a case report.

OBJECTIVE: Extravasation of infused drugs is not a rare problem in medical practice. Acyclovir is a vesicant and an antiviral medication commonly used for young children. In the present study, we presented a neonate with soft tissue damage due to acyclovir extravasation. CASE REPORT: A female newborn (Iranian, Asian) with gestational age 37+2 weeks and breech presentation was born by Cesarean delivery from a mother with a recent history of Herpes simplex virus (HSV) infection (Yas Women's Hospital, Tehran, Iran). Intravenous administration of acyclovir was initiated through a peripheral catheter inserted on the dorsal side of the left hand. A few minutes after the second dose, the patient showed a diffused firm swelling, local discoloration, and induration in the dorsum of the hand. The peripheral catheter was removed immediately. Hyaluronidase was injected subcutaneously in five different regions around the catheterization site. Intermittent limb elevation and cold compression (for 10 minutes) were applied. Serial follow-ups and examinations were performed hourly to check limb inflammation, ischemia, and compartment syndrome. The limb swelling and discoloration significantly improved 4 hours after the second dose of hyaluronidase. CONCLUSION: Early diagnosis of acyclovir extravasation and immediate management could prevent severe complications in neonates. Further studies are needed to suggest a standard approach and treatment protocol for acyclovir extravasation.

Clinical characteristics and outcomes of patients with Herpes Simplex Encephalitis in Vietnam: a retrospective study.

BACKGROUND: Herpes simplex encephalitis (HSE) is an important central nervous infection with severe neurological sequelae. The aim of this study was to describe clinical characteristic and outcomes of patients with HSE in Vietnam. METHODS: This was a retrospective study of 66 patients with herpes simplex encephalitis who admitted to the National Hospital for Tropical Diseases, Hanoi, Vietnam from 2018 to 2021. The detection of herpes simplex virus (HSV) in cerebrospinal fluid was made by the real-time PCR assay. We reported the clinical manifestation on admission and evaluated clinical outcomes at the hospital discharge by modified Rankin Scale (mRS). Multivariate logistic regression analysis was used to analyze the independent risk factors of severe outcomes. RESULTS: Of the 66 patients with laboratory confirmed HSE, the median age was 53 years (IQR 38-60) and 44 patients (69.7%) were male. The most common manifestations included fever (100%), followed by the consciousness disorder (95.5%). Other neurological manifestation were seizures (36.4%), memory disorders (31.8%), language disorders (19.7%) and behavioral disorders (13.6%). Conventional magnetic resonance imaging (MRI) showed 93.8% patients with temporal lobe lesions, followed by abnormalities in insula (50%), frontal lobe (34.4%) and 48.4% of patients had bilateral lesions. At discharge, 19 patients (28.8%) completely recovered, 15 patients (22.7%) had mild sequelae, 28 patients (42.4%) had moderate to severe sequelae. Severe neurological sequelae were memory disorders (55.8%), movement disorders (53.5%), language disorders (30.2%). Multivariate logistic regression analysis showed that Glasgow score decrement at admission, seizures, and time duration from onset of symptoms to the start of Acyclovir treatment > 4 days were independent factors associated with severe outcomes in HSE patients. CONCLUSION: Glasgow score decrement, seizures and delay treatment with Acyclovir were associated with the poor outcome of patients with HSE.

Harmol used for the treatment of herpes simplex virus induced keratitis.

Herpes simplex virus type 1 (HSV-1) infection of the eyes results in herpes simplex keratitis (HSK), which has led to vision loss and even blindness in patients. However, the rate of drug resistance in HSV is on the rise; therefore, new antiviral agents with sufficient safety profiles must be developed. At present, we assessed the anti-HSV-1 activity of 502 natural compounds and their ability to reduce the HSV-1-induced cytopathic effect. We chose harmol for further studies because it exhibited the highest antiviral activity. We found that harmol inhibited both HSV-1 F and HSV-1/153 (a clinical drug-resistant strain) replication, with an EC50 of 9.34 µM and 5.84 µM, respectively. Moreover, harmol reduced HSV-1 replication in corneal tissues and viral progeny production in tears, and also alleviated early corneal surface lesions related to HSK. For example, harmol treatment preserved corneal thickness and nerve density in HSK mice. Interestingly, harmol also showed a promising antiviral effect on HSV-1/153 induced HSK in mouse model. Furthermore, harmol combined with acyclovir (ACV) treatment showed a greater antiviral effect than either one alone in vitro. Therefore, harmol may be a promising therapeutic agent for managing HSK.

Clinical features of atypical presentations of mucocutaneous herpes simplex virus infection observed in immunosuppressed individuals. Part II: the knife-cut sign.

The knife-cut sign is a distinctive manifestation of herpes simplex virus (HSV) type 1 or HSV type 2 infection that has been described in at least 10 immunocompromised patients. It appears as an extremely painful linear erosion or fissure in an intertriginous area such as the body folds beneath the breast, or within the abdomen, or in the inguinal region. Also, concurrent HSV infection at other mucocutaneous sites, or viscera, or both have been observed. The patients had medical conditions (at least 9 patients) and/or immunosuppressive drug therapy (6 patients). The diagnosis of HSV infection was confirmed by viral culture (8 patients), biopsy (4 patients), direct fluorescence antibody testing (3 patients), immunohistochemistry staining (2 patients), polymerase chain reaction (2 patients), or Western blot serologic assay (1 patient). Knife-cut sign-associated HSV infection is potentially fatal; three patients died. However, clinical improvement or complete healing occurred in the patients who received oral valacyclovir (1 patient), or intravenous acyclovir (2 patients), or intravenous acyclovir followed by foscarnet (1 patient). In summary, HSV infection associated with a positive the knife-cut sign is a potentially fatal variant of HSV infection that occurs in the intertriginous areas of immunocompromised patients and usually requires intravenous antiviral therapy.

Clinical features of atypical presentations of mucocutaneous herpes simplex virus infection observed in immunosuppressed individuals. Part I: herpetic geometric glossitis.

Herpetic geometric glossitis is a unique morphologic variant of HSV (herpes simplex virus) type 1 infection on the dorsum of the tongue that presents as an extremely painful linear central lingual fissure with a branched pattern. in the center of the tongue; there is a branched pattern of fissures that extend bilaterally from the central linear fissure. Herpetic geometric glossitis has been reported in 11 patients; 8 of these individuals were immunocompromised. Medical conditions and immunosuppressive medication treatment (7 patients) or only medical disorders (3 patients) or neither (1 patient) were present. HSV type 1 infection was diagnosed by viral culture in (7 patients), Tzanck preparation (2 patients) or clinically (2 patients). Mucocutaneous HSV infection at non-lingual locations--including the lips, labial mucosa, face and chest--were observed in 5 patients. All patients' symptoms and lesions responded to treatment with oral antiviral therapy: acyclovir (9 patients), famciclovir (1 patient) or valacyclovir (1 patient). The lingual pain and dorsal tongue fissures completely resolved completely within two to 14 days. In summary, herpetic geometric glossitis is a unique HSV type 1 infection, usually in immunocompromised patients, that occurs on the dorsal tongue and responds completely after treatment with orally administered antiviral therapy.

Population pharmacokinetics and dose rationale for aciclovir in term and pre-term neonates with herpes.

Aciclovir is considered the first-line treatment against Herpes simplex virus (HSV) infections in new-borns and infants. As renal excretion is the major route of elimination, in renally-impaired patients, aciclovir doses are adjusted according to the degree of impairment. However, limited attention has been given to the implications of immature renal function or dysfunction due to the viral disease itself. The aim of this investigation was to characterize the pharmacokinetics of aciclovir taking into account maturation and disease processes in the neonatal population. Pharmacokinetic data obtained from 2 previously published clinical trials (n = 28) were analyzed using a nonlinear mixed effects modeling approach. Post-menstrual age (PMA) and creatinine clearance (CLCR) were assessed as descriptors of maturation and renal function. Simulation scenarios were also implemented to illustrate the use of pharmacokinetic data to extrapolate efficacy from adults. Aciclovir pharmacokinetics was described by a one-compartment model with first-order elimination. Body weight and diagnosis (systemic infection) were statistically significant covariates on the volume of distribution, whereas body weight, CLCR and PMA had a significant effect on clearance. Median clearance varied from 0.2 to 1.0 L/h in subjects with PMA <34 or ≥34 weeks, respectively. Population estimate for volume of distribution was 1.93 L with systemic infection increasing this value by almost 3-fold (2.67 times higher). A suitable model parameterization was identified, which discriminates the effects of developmental growth, maturation, and organ function. Exposure to aciclovir was found to increase with decreasing PMA and renal function (CLCR), suggesting different dosing requirement for pre-term neonates.

Acyclovir eco-geno-toxicity in freshwater organisms.

This study explores the eco-geno-toxic impact of Acyclovir (ACV), a widely used antiviral drug, on various freshwater organisms, given its increasing detection in surface waters. The research focused on non-target organisms, including the green alga Raphidocelis subcapitata, the rotifer Brachionus calyciflorus, the cladoceran crustacean Ceriodaphnia dubia, and the benthic ostracod Heterocypris incongruens, exposed to ACV to assess both acute and chronic toxicity. The results indicate that while acute toxicity occurs at environmentally not-relevant concentrations, a significant chronic toxicity for C. dubia (EC50 = 0.03 µg/L, NOEC = 0.02·10-2 µg/L), highlighted substantial environmental concern. Furthermore, DNA strand breaks and reactive oxygen species detected in C. dubia indicate significant increase at concentrations exceeding 200 µg/L. Regarding environmental risk, the authors identified chronic exposures to acyclovir causing inhibitory effects on reproduction in B. calyciflorus at hundreds of µg/L and hundredths of µg/L for C. dubia as environmentally relevant environmental concentrations. The study concludes by quantifying the toxic and genotoxic risks of ACV showing a chronic risk quotient higher than the critical value of 1and a genotoxic risk quotient reaching this threshold, highlighting the urgent need for a broader risk assessment of ACV for its significant implications for aquatic ecosystems.

Antiviral medications for preventing cytomegalovirus disease in solid organ transplant recipients.

BACKGROUND: The risk of cytomegalovirus (CMV) infection in solid organ transplant recipients has resulted in the frequent use of prophylaxis to prevent the clinical syndrome associated with CMV infection. This is an update of a review first published in 2005 and updated in 2008 and 2013. OBJECTIVES: To determine the benefits and harms of antiviral medications to prevent CMV disease and all-cause death in solid organ transplant recipients. SEARCH METHODS: We contacted the information specialist and searched the Cochrane Kidney and Transplant Register of Studies up to 5 February 2024 using search terms relevant to this review. Studies in the Register are identified through searches of CENTRAL, MEDLINE, and EMBASE, conference proceedings, the International Clinical Trials Registry Platform (ICTRP) Search Portal, and ClinicalTrials.gov. SELECTION CRITERIA: We included randomised controlled trials (RCTs) and quasi-RCTs comparing antiviral medications with placebo or no treatment, comparing different antiviral medications or different regimens of the same antiviral medications for CMV prophylaxis in recipients of any solid organ transplant. Studies examining pre-emptive therapy for CMV infection are studied in a separate review and were excluded from this review. DATA COLLECTION AND ANALYSIS: Two authors independently assessed study eligibility, risk of bias and extracted data. Summary estimates of effect were obtained using a random-effects model, and results were expressed as risk ratios (RR) and their 95% confidence intervals (CI) for dichotomous outcomes and mean difference (MD) and 95% CI for continuous outcomes. Confidence in the evidence was assessed using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach. MAIN RESULTS: This 2024 update found four new studies, bringing the total number of included studies to 41 (5054 participants). The risk of bias was high or unclear across most studies, with a low risk of bias for sequence generation (12), allocation concealment (12), blinding (11) and selective outcome reporting (9) in fewer studies. There is high-certainty evidence that prophylaxis with aciclovir, ganciclovir or valaciclovir compared with placebo or no treatment is more effective in preventing CMV disease (19 studies: RR 0.42, 95% CI 0.34 to 0.52), all-cause death (17 studies: RR 0.63, 95% CI 0.43 to 0.92), and CMV infection (17 studies: RR 0.61, 95% CI 0.48 to 0.77). There is moderate-certainty evidence that prophylaxis probably reduces death from CMV disease (7 studies: RR 0.26, 95% CI 0.08 to 0.78). Prophylaxis reduces the risk of herpes simplex and herpes zoster disease, bacterial and protozoal infections but probably makes little to no difference to fungal infection, acute rejection or graft loss. No apparent differences in adverse events with aciclovir, ganciclovir or valaciclovir compared with placebo or no treatment were found. There is high certainty evidence that ganciclovir, when compared with aciclovir, is more effective in preventing CMV disease (7 studies: RR 0.37, 95% CI 0.23 to 0.60). There may be little to no difference in any outcome between valganciclovir and IV ganciclovir compared with oral ganciclovir (low certainty evidence). The efficacy and adverse effects of valganciclovir or ganciclovir were probably no different to valaciclovir in three studies (moderate certainty evidence). There is moderate certainty evidence that extended duration prophylaxis probably reduces the risk of CMV disease compared with three months of therapy (2 studies: RR 0.20, 95% CI 0.12 to 0.35), with probably little to no difference in rates of adverse events. Low certainty evidence suggests that 450 mg/day valganciclovir compared with 900 mg/day valganciclovir results in little to no difference in all-cause death, CMV infection, acute rejection, and graft loss (no information on adverse events). Maribavir may increase CMV infection compared with ganciclovir (1 study: RR 1.34, 95% CI: 1.10 to 1.65; moderate certainty evidence); however, little to no difference between the two treatments were found for CMV disease, all-cause death, acute rejection, and adverse events at six months (low certainty evidence). AUTHORS' CONCLUSIONS: Prophylaxis with antiviral medications reduces CMV disease and CMV-associated death, compared with placebo or no treatment, in solid organ transplant recipients. These data support the continued routine use of antiviral prophylaxis in CMV-positive recipients and CMV-negative recipients of CMV-positive organ transplants.

Computational analysis of antiviral drugs using topological descriptors.

Many health challenges are attributed to viral infections, which represent significant concerns in public health. Among these infections, diseases such as herpes simplex virus (HSV), cytomegalovirus (CMV), and varicella-zoster virus (VZV) infections have garnered attention due to their prevalence and impact on human health. There are specific antiviral medications available for the treatment of these viral infections. Drugs like Cidofovir, Valacyclovir, and Acyclovir are commonly prescribed. These antiviral drugs are known for their efficacy against herpesviruses and related viral infections, leveraging their ability to inhibit viral DNA polymerase. A molecular descriptor is a numerical value that correlates with specific physicochemical properties of a molecular graph. This article explores the calculation of distance-based topological descriptors, including the Trinajstic, Mostar, Szeged, and PI descriptors for the aforementioned antiviral drugs. These descriptors provide insights into these drugs' structural and physicochemical characteristics, aiding in understanding their mechanism of action and the development of new therapeutic agents.

Efficient activation of peracetic acid by cobalt modified nitrogen-doped carbon nanotubes for drugs degradation: Performance and mechanism insight.

Peracetic acid (PAA) has garnered significant attention as a novel disinfectant owing to its remarkable oxidative capacity and minimal potential to generate byproducts. In this study, we prepared a novel catalyst, denoted as cobalt modified nitrogen-doped carbon nanotubes (Co@N-CNTs), and evaluated it for PAA activation. Modification with cobalt nanoparticles (∼4.8 nm) changed the morphology and structure of the carbon nanotubes, and greatly improved their ability to activate PAA. Co@N-CNTs/PAA catalytic system shows outstanding catalytic degradation ability of antiviral drugs. Under neutral conditions, with a dosage of 0.05 g/L Co@N-CNT-9.8 and 0.25 mM PAA, the removal efficiency of acyclovir (ACV) reached 98.3% within a mere 10 min. The primary reactive species responsible for effective pollutant degradation were identified as acetylperoxyl radicals (CH3C(O)OO•) and acetyloxyl radicals (CH3C(O)O•). In addition, density functional theory (DFT) proved that Co nanoparticles, as the main catalytic sites, were more likely to adsorb PAA and transfer more electrons than N-doped graphene. This study explored the feasibility of PAA degradation of antiviral drugs in sewage, and provided new insights for the application of heterogeneous catalytic PAA in environmental remediation.

Remission of HPV-Related Diseases by Antivirals for Herpesvirus: Clinical Cases and a Literature Review.

Epidemiological studies have shown that HPV-related diseases are the most prevalent sexually transmitted infections. In this context, this report will present various clinical cases demonstrating the effectiveness of Acyclovir (ACV) or its prodrug Valaciclovir (VCV), both acyclic guanosine analogs commonly used for the treatment of HHV-1 and HHV-2, for the treatment of HPV-related diseases. The report shows the remission of five cases of penile condyloma and a case of remission in a woman affected by cervical and vaginal condylomas and a vulvar giant condyloma acuminate of Buschke and Lowenstein. The literature review shows that ACV is effective in treating skin warts when administered orally, topically, and intralesionally, suggesting its therapeutic potential in other diseases associated with HPV. ACV was also used successfully as an adjuvant therapy for juvenile and adult forms of laryngeal papillomatosis, also known as recurrent respiratory papillomatosis, prolonging the patient's symptom-free periods. Although the prevention of HPV infections is certainly achieved with the HPV vaccine, ACV and VCV have shown to be effective even against genotypes not included in the current vaccine and can be helpful for those problematic clinical cases involving unvaccinated individuals, immunocompromised patients, people who live with HIV, or non-responders to the vaccine. We and others concluded that randomized clinical trials are necessary to determine the efficacy of ACV and VCV for HPV-related diseases.

Commercial human 3D corneal epithelial equivalents for modeling epithelial infection in herpes keratitis.

Herpes stromal keratitis is the leading cause of infectious blindness in the western world. Infection by HSV1 is most common, but VZV and hCMV also infect the cornea. Multiple models of HSV1 corneal infection exist, but none for VZV and hCMV because of their host specificity. Here, we used commercially available 3D human corneal epithelial equivalents (HCEE) to study infection by these herpesviruses. HCEE was infected by HSV-1 and hCMV without requiring scarification and resulted in spreading infections. Spread of HSV-1 infection was rapid, while that of hCMV was slow. In contrast, infections with VZV required damage to the HCEE and did not spread. Acyclovir dramatically reduced replication of HSV-1 in this model. We conclude that highly quality-controlled, readily available HCEE is a useful model to study human-restricted herpesvirus infection of the human corneal epithelium and for screening of antiviral drugs for treating HSK in an 3D model system.

[Clinical features of acyclovir encephalopathy without acute kidney injury].

INTRODUCTION: Few reports have described acyclovir (ACV) encephalopathy without acute kidney injury (AKI). OBJECTIVE: This study clarified the clinical features of ACV encephalopathy without AKI compared to that with AKI. METHODS: Creatinine (Cre) levels were measured on admission. After admission, Cre was measured in a timely manner for the first seven hospital days. The minimum Cre level in these measurements was then determined. ACV encephalopathy was defined when two criteria were met: 1) neurological symptoms appeared after valacyclovir (VACV) administration, and 2) neurological symptoms improved after VACV discontinuation. AKI was defined when the Cre level on admission was >1.5 times higher than the minimum Cre level. The subjects were divided into AKI and non-AKI groups based on these findings. RESULTS: Eighteen patients had ACV encephalopathy (5 males, mean age 81.3±5.5 years old). All patients were prescribed VACV 3,000 mg/day. The minimum Cre was 1.93±1.76 mg/dL. AKI occurred in 10 (56.6%) patients. VACV was discontinued in all patients, and emergency hemodialysis treatment was administered in 10 (55.6%) patients. All patients recovered. Compared to the AKI group, the non-AKI group had a lower history of taking a Ca-blocker (33.3% vs 80.0%, p=0.092), a lower rate of emergency dialysis (16.9% vs 70.0%, p=0.059) and a longer time to clinical improvement (3.67±1.86 vs 2.20±0.63 days, p=0.073). CONCLUSION: ACV encephalopathy without AKI is characterized by a low rate of emergency dialysis, which may be linked to a prolonged duration of symptoms.

Effect of acyclovir therapy on the outcome of mechanically ventilated patients with lower respiratory tract infection and detection of herpes simplex virus in bronchoalveolar lavage: protocol for a multicentre, randomised controlled trial (HerpMV).

INTRODUCTION: Herpes simplex virus (HSV) is frequently detected in the respiratory tract of mechanically ventilated patients and is associated with a worse outcome. The aim of this study is to determine whether antiviral therapy in HSV-positive patients improves outcome. METHODS AND ANALYSIS: Prospective, multicentre, open-label, randomised, controlled trial in parallel-group design. Adult, mechanically ventilated patients with pneumonia and HSV type 1 detected in bronchoalveolar lavage (≥105 copies/mL) are eligible for participation and will be randomly allocated (1:1) to receive acyclovir (10 mg/kg body weight every 8 hours) for 10 days (or until discharge from the intensive care unit if earlier) or no intervention (control group). The primary outcome is mortality measured at day 30 after randomisation (primary endpoint) and will be analysed with Cox mixed-effects model. Secondary endpoints include ventilator-free and vasopressor-free days up to day 30. A total of 710 patients will be included in the trial. ETHICS AND DISSEMINATION: The trial was approved by the responsible ethics committee and by Germany's Federal Institute for Drugs and Medical Devices. The clinical trial application was submitted under the new Clinical Trials Regulation through CTIS (The Clinical Trials Information System). In this process, only one ethics committee, whose name is unknown to the applicant, and Germany's Federal Institute for Drugs and Medical Devices are involved throughout the entire approval process. Results will be published in a journal indexed in MEDLINE and CTIS. With publication, de-identified, individual participant data will be made available to researchers. TRIAL REGISTRATION NUMBER: NCT06134492.

Combination of ganciclovir and trifluridine prevents drug-resistance emergence in HSV-1.

Ocular herpes simplex virus 1 (HSV-1) infections can lead to visual impairment. Long-term acyclovir (ACV) prophylaxis reduces the frequency of recurrences but is associated with drug resistance. Novel therapies are needed to treat drug-resistant HSV-1 infections. Here, we describe the effects of trifluridine (TFT) in combination with ACV or ganciclovir (GCV) on HSV-1 replication and drug-resistance emergence. Wild-type HSV-1 was grown under increasing doses of one antiviral (ACV, GCV, or TFT) or combinations thereof (ACV + TFT or GCV + TFT). Virus cultures were analyzed by Sanger sequencing and deep sequencing of the UL23 [thymidine kinase (TK)] and UL30 [DNA polymerase (DP)] genes. The phenotypes of novel mutations were determined by cytopathic effect reduction assays. TFT showed overall additive anti-HSV-1 activity with ACV and GCV. Five passages under ACV, GCV, or TFT drug pressure gave rise to resistance mutations, primarily in the TK. ACV + TFT and GCV + TFT combinatory pressure induced mutations in the TK and DP. The DP mutations were mainly located in terminal regions, outside segments that typically carry resistance mutations. TK mutations (R163H, A167T, and M231I) conferring resistance to all three nucleoside analogs (ACV, TFT, and GCV) emerged under ACV, TFT, ACV + TFT pressure and under GCV + TFT pressure initiated from suboptimal drug concentrations. However, higher doses of GCV and TFT prevented drug resistance in the resistance selection experiments. In summary, we identified novel mutations conferring resistance to nucleoside analogs, including TFT, and proposed that GCV + TFT combination therapy may be an effective strategy to prevent the development of drug resistance.

Serious neurological adverse events in immunocompetent children and adolescents caused by viral reactivation in the years following varicella vaccination.

Serious adverse events following vaccination include medical complications that require hospitalisation. The live varicella vaccine that was approved by the Food and Drug Administration in the United States in 1995 has an excellent safety record. Since the vaccine is a live virus, adverse events are more common in immunocompromised children who are vaccinated inadvertently. This review includes only serious adverse events in children considered to be immunocompetent. The serious adverse event called varicella vaccine meningitis was first reported in a hospitalised immunocompetent child in 2008. When we carried out a literature search, we found 15 cases of immunocompetent children and adolescents with varicella vaccine meningitis; the median age was 11 years. Eight of the children had received two varicella vaccinations. Most of the children also had a concomitant herpes zoster rash, although three did not. The children lived in the United States, Greece, Germany, Switzerland, and Japan. During our literature search, we found five additional cases of serious neurological events in immunocompetent children; these included 4 cases of progressive herpes zoster and one case of acute retinitis. Pulses of enteral corticosteroids as well as a lack of herpes simplex virus antibody may be risk factors for reactivation in immunocompetent children. All 20 children with adverse events were treated with acyclovir and recovered; 19 were hospitalised and one child was managed as an outpatient. Even though the number of neurological adverse events remains exceedingly low following varicella vaccination, we recommend documentation of those caused by the vaccine virus.

Valacyclovir or valganciclovir for cytomegalovirus prophylaxis: A randomized controlled trial in adult and pediatric kidney transplant recipients.

BACKGROUND: Valganciclovir (valG), a cytomegalovirus (CMV) prophylactic agent, has dose-limiting side effects. The tolerability and effectiveness of valacyclovir (valA) as CMV prophylaxis is unknown. METHODS: We conducted a randomized, open-label, single-center trial of valA versus valG for all posttransplant CMV prophylaxis in adult and pediatric kidney recipients. Participants were randomly assigned to receive valA or valG. Primary endpoints were the incidence of CMV viremia and side-effect related drug reduction with secondary assessment of incidence of EBV viremia. RESULTS: Of the 137 sequential kidney transplant recipients enrolled, 26 % were positive and negative for CMV antibody in donor and recipient respectively. The incidence of CMV viremia (4 of 71 [6 %]; 8 of 67 [12 %] P = 0.23), time to viremia (P = 0.16) and area under CMV viral load time curve (P = 0.19) were not significantly different. ValG participants were significantly more likely to require side-effect related dose reduction (15/71 [21 %] versus 1/66 [2 %] P = 0.0003). Leukopenia was the most common reason for valG dose reduction and granulocyte-colony stimulating factor was utilized for leukopenia recovery more frequently (25 % in valG vs 5 % in valA: P = 0.0007). Incidence of EBV viremia was not significantly different. CONCLUSIONS: ValA has significantly less dose-limiting side effects than valG. In our study population, a significant increase in CMV viremia was not observed, in adults and children after kidney transplant, compared to valG. TRIAL REGISTRATION NUMBER: NCT01329185.

Machine Learning Exploration of the Relationship Between Drugs and the Blood-Brain Barrier: Guiding Molecular Modification.

OBJECTIVE: This study aimed to improve the efficiency of pharmacotherapy for CNS diseases by optimizing the ability of drug molecules to penetrate the Blood-Brain Barrier (BBB). METHODS: We established qualitative and quantitative databases of the ADME properties of drugs and derived characteristic features of compounds with efficient BBB penetration. Using these insights, we developed four machine learning models to predict a drug's BBB permeability by assessing ADME properties and molecular topology. We then validated the models using the B3DB database. For acyclovir and ceftriaxone, we modified the Hydrogen Bond Donors and Acceptors, and evaluated the BBB permeability using the predictive model. RESULTS: The machine learning models performed well in predicting BBB permeability on both internal and external validation sets. Reducing the number of Hydrogen Bond Donors and Acceptors generally improves BBB permeability. Modification only enhanced BBB penetration in the case of acyclovir and not ceftriaxone. CONCLUSIONS: The machine learning models developed can accurately predict BBB permeability, and many drug molecules are likely to have increased BBB penetration if the number of Hydrogen Bond Donors and Acceptors are reduced. These findings suggest that molecular modifications can enhance the efficacy of CNS drugs and provide practical strategies for drug design and development. This is particularly relevant for improving drug penetration of the BBB.