valacyclovir and Body-Weight

Simotinib hydrochloride (SIM6802), which is a new epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI), is often prescribed for cancer patients with comorbidities and has serious adverse effects on gastrointestinal physiology. The drug-drug interactions (DDIs) between simotinib and other drugs in combination and the underlying mechanism of its gastrointestinal toxicity remain unclear. We hypothesized that the DDIs and the gastrointestinal toxicity of simotinib were related to its effects on the permeability of the intestine.. To determine the intestinal absorption capacity, pharmacokinetic studies and an in situ loop assay were used. The intestinal permeability was measured by a Caco-2 Transwell model. Real time PCR and Western blots were applied to detecting the expression changes of cell junction genes.. Our research demonstrated that simotinib upregulated the absorption of cefaclor, valaciclovir and acyclovir. The increase of non-selective absorption was caused by the low expression of cell junction gene afadin-6 and the increase in paracellular permeability in intestinal epithelial cells after simotinib treatment.. These findings revealed that simotinib upregulated intestinal absorption by increasing the paracellular permeability of intestinal epithelial cells. Our research provides theoretical bases for better formulation of EGFR-TKIs to alleviate adverse gastrointestinal effects and also provides guidance for clinical administration of simotinib.

Topics: Acyclovir; Anti-Infective Agents; Body Weight; Caco-2 Cells; Cefaclor; Dose-Response Relationship, Drug; Drug Interactions; Humans; Intestinal Absorption; Intestinal Mucosa; Microfilament Proteins; Permeability; Quinazolines; Spiro Compounds; Up-Regulation; Valacyclovir; Valine

Epstein-Barr virus (EBV) infection occurring in the postoperative period represents a significant risk for pediatric transplant recipients. It presents in various manners, including a mononucleosis-like syndrome, hepatitis, encephalopathy, or posttransplant lymphoproliferative disease (PTLD). Valacyclovir has in vitro activity against EBV. We sought to review our experience with valacyclovir on peripheral blood EBV viral loads among a group of EBV-infected patients after liver transplantation (OLT).. Twelve children of ages 6-36 months (median, 12 months), underwent OLT. Eight (66%) were EBV immunoglobulin (Ig)G seronegative at the time of the operation. Eight patients developed primary infection and 4 patients developed reactivation of a post primary infection. Valacyclovir was prescribed immediately to 3 patients when we detected an acute-primary EBV infection. Valacyclovir was prescribed for 2 patients who had primary EBV infections followed by PTLD. Three patients who had primary EBV infection were administered valacyclovir after they became chronically EBV PCR positive for more than 1 year. Four out of 12 cases (33%) were EBV seropositive at the time of OLT, and underwent postprimary EBV reactivation displaying chronic EBV carrier state for 8-10 months before valacyclovir treatment. Peripheral blood EBV viral loads were tested every 2 months. The primary outcome was the proportion of subjects with EBV viremia who had a >or=2 log 10 decrease in EBV copies/mL after valacyclovir treatment. The duration of valacyclovir treatment was a median of 10 months (range, 8-11 months). At the beginning of the treatment period the median level of EBV viral load was 1.1 x 10(4) (range, 1 x 10(4) to 1 x 10(7)). EBV virus was cleared in only 1 patient with primary acute EBV infection. EBV viral loads did not change in 7 of 12 patients and decreased only 1 log 10 (n = 2) or 2 log 10 (n = 2).. In this small, non-placebo-controlled study, valacyclovir treatment was not effective to decrease peripheral blood EBV viral loads.

Topics: Acute Disease; Acyclovir; Antiviral Agents; Body Weight; Child, Preschool; Chronic Disease; Epstein-Barr Virus Infections; Humans; Infant; Liver Function Tests; Liver Transplantation; Postoperative Complications; Recurrence; Retrospective Studies; Valacyclovir; Valine; Viral Load; Virus Activation

Herpes simplex virus type 1 (HSV-1) is an important pathogen related to epilepsy. We have shown previously that corneal inoculation of mice with HSV-1 causes acute spontaneous behavioral and electrophysiological seizures and increases hippocampal excitability and kainite-induced seizure susceptibility. In this study, we aimed to determine whether early-life HSV-1 infection in mice might cause short- and long-term enhanced susceptibility to pentylenetetrazol (PTZ)-induced seizures and to evaluate whether early antiviral drug therapy was effectively ameliorating this deficit. Seizure threshold was calculated by the latency of onset of the myoclonic jerk, generalized clonus, and maximal tonic-clonic convulsion. We demonstrate that the localization of viral antigens was predominantly within the bilateral temporal areas (amygdala, piriform, and entorhinal cortex) of HSV-1-infected mice. We also present evidence that mice of all HSV-1-infected groups had a shorter latency and higher severity to PTZ-induced seizures than in age-matched, mock-infected controls. Treatment of HSV-1-infected mice with valacyclovir, a potent inhibitor of HSV-1 replication, produced a dose-dependent decrease in the signs of neurological deficits, pathological damages, and PTZ-induced seizure severity. Our results are consistent with the hypothesis that early-life HSV-1 infection leads to persistent enhancement of neuronal excitability in limbic circuits, which could result in an overall increased propensity to induce seizures later in life. Additionally, prompt optimal antiviral therapy effectively decreases seizure susceptibility in HSV-1-infected mice by limiting the level of viral replication and inflammatory response induced by virus. The present study provides not only experimental evidence, but also a new therapeutic strategy in HSV-1-associated human epilepsy.

Topics: Acyclovir; Animals; Antiviral Agents; Behavior, Animal; Body Weight; Disease Susceptibility; Dose-Response Relationship, Drug; Drug Interactions; Electroencephalography; Electromyography; Herpes Simplex; Herpesvirus 1, Human; Hippocampus; Immunohistochemistry; Infections; Male; Mice; Mice, Inbred BALB C; Pentylenetetrazole; Reaction Time; Seizures; Staining and Labeling; Time Factors; Valacyclovir; Valine; Virus Latency

Famciclovir (FCV) and valaciclovir (VACV) have previously been shown to be potent inhibitors of herpes simplex virus type 1 (HSV-1) in a murine cutaneous model. In the present study, mice were inoculated in the skin of the left ear pinna with herpes simplex virus (HSV) type 1. Antiviral therapy was started on different days postinoculation (p.i.), terminating at the end of day 10 p.i. The compounds were administered twice daily by oral gavage at 50 mg/kg of body weight/dose. Mice were sampled on day 5 p.i., during the acute phase of the infection, and the titers of infectious virus in the target tissues (ear, brain stem, and trigeminal ganglia) were determined. At 2 to 3 months p.i., the ipsilateral and contralateral trigeminal and cervical dorsal root ganglia were explanted, and four different methods were used to detect latent HSV. The methods were (i) conventional explant culture for 5 days followed by homogenization, (ii) long-term culture (up to 73 days) of whole ganglia, followed by homogenization, (iii) dissociation by enzymatic disaggregation and an infectious center assay, and (iv) in situ hybridization to detect latency-associated transcripts (LATs). The conventional explant culture method was the least sensitive method, while in situ staining for LAT was the most sensitive, and all mice, including those treated from early times with FCV, were shown to be latently infected. Significantly less latent virus was detected by all four methods, however, in ganglia obtained from mice that had been treated with FCV in comparison with the amount detected in ganglia from mice that had been treated with VACV. However, in no case was latency completely eliminated.

Topics: 2-Aminopurine; Acyclovir; Animals; Antiviral Agents; Body Weight; Brain; Cell Culture Techniques; Dermatitis; Ear; Famciclovir; Female; Herpes Simplex; Herpesvirus 1, Human; In Situ Hybridization; Mice; Mice, Inbred BALB C; Neurons; Trigeminal Ganglion; Valacyclovir; Valine; Virus Latency