Understanding adefovir pharmacokinetics as a component of a transporter phenotyping cocktail.

PURPOSE: Adefovir (as dipivoxil) was selected as a probe drug in a previous transporter cocktail phenotyping study to assess renal organic anion transporter 1 (OAT1), with renal clearance (CLR) as the primary parameter describing renal elimination. An approximately 20% higher systemic exposure of adefovir was observed when combined with other cocktail components (metformin, sitagliptin, pitavastatin, and digoxin) compared to sole administration. The present evaluation applied a population pharmacokinetic (popPK) modeling approach to describe adefovir pharmacokinetics as a cocktail component in more detail. METHODS: Data from 24 healthy subjects were reanalyzed. After establishing a base model, covariate effects, including the impact of co-administered drugs, were assessed using forward inclusion then backward elimination. RESULTS: A one-compartment model with first-order absorption (including lag time) and a combination of nonlinear renal and linear nonrenal elimination best described the data. A significantly higher apparent bioavailability (73.6% vs. 59.0%) and a lower apparent absorption rate constant (2.29 h-1 vs. 5.18 h-1) were identified in the combined period compared to the sole administration period, while no difference was seen in renal elimination. The population estimate for the Michaelis-Menten constant (Km) of the nonlinear renal elimination was 170 nmol/L, exceeding the observed range of adefovir plasma maximum concentration, while the maximum rate (Vmax) of nonlinear renal elimination was 2.40 µmol/h at the median absolute estimated glomerular filtration rate of 105 mL/min. CONCLUSION: The popPK modeling approach indicated that the co-administration primarily affected the apparent absorption and/or prodrug conversion of adefovir dipivoxil, resulting in the minor drug-drug interaction observed for adefovir as a victim. However, renal elimination remained unaffected. The high Km value suggests that assessing renal OAT1 activity by CLR has no relevant misspecification error with the cocktail doses used.

Therapeutic Effects of GGsTop® Gel in a Mouse Model of 5-Fluorouracil-induced Oral Mucositis With Reduced White Blood Cells.

BACKGROUND/AIM: In order to produce an animal model for oral mucositis induced by anticancer drugs, it is necessary to maintain an immunosuppressive state. We determined the optimal dose and frequency of 5-fluorouracil for a model mouse production. In addition, we used this model to investigate the effect of GGsTop® gelation on the therapeutic effect of oral mucositis. MATERIALS AND METHODS: Changes in body weight and white blood cell count were measured to determine the optimal dosing schedule. The therapeutic effect of GGsTop® gel using chitosan was evaluated by observing changes in the ulcer area for three weeks and measuring collagen and glutathione concentrations in oral mucosal tissue. RESULTS: The optimal dose and frequency of 5-fluorouracil were found to be 50 mg/kg every four days. It was revealed that the therapeutic effect of GGsTop® was enhanced by gelation. CONCLUSION: GGsTop® gel is suggested to be a promising formulation for the treatment of oral mucositis.

Pharmacokinetic/pharmacodynamic modeling of drug interactions at the P2Y12 receptor between selatogrel and oral P2Y12 antagonists.

Selatogrel is a potent and reversible P2Y12 receptor antagonist developed for subcutaneous self-administration by patients with suspected acute myocardial infarction. After single-dose emergency treatment with selatogrel, patients are switched to long-term treatment with oral P2Y12 receptor antagonists. Selatogrel shows rapid onset and offset of inhibition of platelet aggregation (IPA) to overcome the critical initial time after acute myocardial infarction. Long-term benefit is provided by oral P2Y12 receptor antagonists such as clopidogrel, prasugrel, and ticagrelor. A population pharmacokinetic (PK)/pharmacodynamic (PD) model based on data from 545 subjects in 4 phase I and 2 phase II studies well described the effect of selatogrel on IPA alone and in combination with clopidogrel, prasugrel, and ticagrelor. The PK of selatogrel were described by a three-compartment model. The PD model included a receptor-pool compartment to which all drugs can bind concurrently, reversibly or irreversibly, depending on their mode of action. Furthermore, ticagrelor and its active metabolite can bind to the selatogrel-receptor complex allosterically, releasing selatogrel from the binding site. The model provided a framework for predicting the effect on IPA of selatogrel followed by reversibly and irreversibly binding oral P2Y12 receptor antagonists for sustained effects. Determining the timepoint for switching from emergency to maintenance treatment is critical to achieve sufficient IPA at all times. Simulations based on the interaction model showed that loading doses of clopidogrel and prasugrel administered 15 h and 4.5 h after selatogrel, respectively, provide sustained IPA with clinically negligible drug interaction. Study Highlights WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC? Selatogrel is a potent reversible P2Y12 receptor antagonist developed for subcutaneous self-administration by patients in case of suspected acute myocardial infarction. Transition to oral P2Y12 receptor antagonists without drug interaction and sufficient inhibition of platelet aggregation must be assured at all times. WHAT QUESTION DID THIS STUDY ADDRESS? The pharmacokinetic/pharmacodynamic model semimechanistically describes the effect of selatogrel on platelet inhibition alone and in combination with the oral P2Y12 receptor antagonists clopidogrel, prasugrel, and ticagrelor. WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE? Model-based simulations showed that loading doses of clopidogrel and prasugrel can be administered from 15 h and 4.5 h after selatogrel, respectively. HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE? These results support guiding the clinical transition from selatogrel emergency treatment to oral maintenance therapy in a safe and efficacious way.

Initial Experience Treating HPV-Related Laryngeal Diseases with Oral Brincidofovir: A Pilot Study.

OBJECTIVE: To determine if brincidofovir, an oral analog of cidofovir that achieves high tissue levels of the active metabolite with low systemic toxicity, has an observable effect on HPV-related disease of the larynx. METHODS: Two patients with laryngeal recurrent respiratory papillomatosis (one each of genotypes 6 and 11) and 1 with recurring aryepiglottic fold carcinoma in situ (genotype 16) received oral brincidofovir according to protocol. Close-range videoendoscopic examinations were done during and after the study period to observe disease behavior in the absence of other interventions, and after subsequent surgical intervention. Disease character and magnitude of recurrence for each patient were compared to their patterns prior to brincidofovir. RESULTS: Brincidofovir reduced papilloma burden in 1 patient and markedly attenuated the rate and magnitude of recurrence in both. After surgical intervention, Patient 1 remains disease-free at 10 years (7 years from last intervention) and Patient 2 has no symptoms at 8 years. Patient 3 with recurring carcinoma in situ has required less frequent resections and specimens show reduced degrees of dysplasia present only in islands amid normal mucosa at 8 years (currently no evidence of disease at 21 months from last intervention). CONCLUSION: Brincidofovir appears to attenuate HPV disease of the larynx in this small pilot study, though further investigation is required because of the highly variable nature of the disease and potential confounding factors.

Insights from In Vitro and Clinical Data to Guide Transition from the Novel P2Y12 Antagonist Selatogrel to Clopidogrel, Prasugrel, and Ticagrelor.

Reduced pharmacodynamic (PD) effects of irreversible oral P2Y12 receptor antagonists have been reported when administered during cangrelor infusion. Therefore, the PD interaction liability of the novel P2Y12 receptor antagonist selatogrel with irreversible (i.e., clopidogrel, prasugrel) and reversible (i.e., ticagrelor) oral P2Y12 receptor antagonists was investigated in vitro and in healthy subjects. In vitro, selatogrel reduced the effects of clopidogrel and prasugrel in a concentration-dependent manner, while additive effects were observed for the combination of selatogrel and ticagrelor. Accordingly, a single-center, randomized, double-blind, two-way crossover study was conducted consisting of six groups. In each group (N = 12), an open-label loading dose of 300 or 600 mg clopidogrel, 60 mg prasugrel, or 180 mg ticagrelor was administered 30 minutes (i.e., at t max of selatogrel) or 12 hours after a single subcutaneous dose of 16 mg selatogrel or placebo. Inhibition of platelet aggregation (IPA) was assessed at various time points up to 48 hours. Reduced IPA was determined when clopidogrel or prasugrel was administered 30 minutes after selatogrel (∼40 and 70% lower IPA, respectively, at 24 hours postdosing). However, when administering prasugrel 12 hours after selatogrel, IPA was not impacted (>90% IPA) and in the case of clopidogrel reduced effects were partially mitigated. Similar IPA was determined for ticagrelor when administered 30 minutes after selatogrel or placebo. In conclusion, reduced IPA was observed for clopidogrel and prasugrel when administered after selatogrel, which can be mitigated by applying an appropriate time interval. No PD interaction with ticagrelor was observed.

Internal dosimetry studies of 170Tm-EDTMP complex, as a bone pain palliation agent, in human tissues based on animal data.

Radiopharmaceuticals with therapeutic applications are designed to deliver high doses of radiation to target organs with minimizing unwanted radiation to healthy tissues. Owing to the potential of targeted radiotherapy to treat a wide range of malignancies, 170Tm -EDTMP was developed for possible therapeutic applications. This study describes absorbed dose prediction of 170Tm-EDTMP in human organs after animal injection which is determined via medical internal radiation dose (MIRD) and MCNP-4C code methods. It was estimated that a 1-MBq administration of 170Tm-EDTMP into the human body would result in an absorbed dose of 37.9 mGy (MIRD method) and 38.02 mGy (MCNP-4C code) in the bone surface after 60 days post injection. Highest and lowest difference between MIRD and MCNP results are for lung and bone surface respectively. Finally, the results show that there is a good agreement between MIRD method and MCNP-4C simulation code for absorbed dose estimation.

Orally Bioavailable Small-Molecule CD73 Inhibitor (OP-5244) Reverses Immunosuppression through Blockade of Adenosine Production.

The adenosinergic pathway represents an attractive new therapeutic approach in cancer immunotherapy. In this pathway, ecto-5-nucleotidase CD73 has the unique function of regulating production of immunosuppressive adenosine (ADO) through the hydrolysis of AMP. CD73 is overexpressed in many cancers, resulting in elevated levels of ADO that correspond to poor patient prognosis. Therefore, reducing the level of ADO via inhibition of CD73 is a potential strategy for treating cancers. Based on the binding mode of adenosine 5'-(α,ß-methylene)diphosphate (AOPCP) with human CD73, we designed a series of novel monophosphonate small-molecule CD73 inhibitors. Among them, OP-5244 (35) proved to be a highly potent and orally bioavailable CD73 inhibitor. In preclinical studies, 35 completely inhibited ADO production in both human cancer cells and CD8+ T cells. Furthermore, 35 lowered the ratio of ADO/AMP significantly and reversed immunosuppression in mouse models, indicating its potential as an in vivo tool compound for further development.

Selatogrel, a novel P2Y12 inhibitor: a review of the pharmacology and clinical development.

INTRODUCTION: Platelet P2Y12 inhibitors have a key role in reducing thrombotic complications in patients undergoing percutaneous coronary intervention (PCI) and those with acute coronary syndrome (ACS). Clopidogrel, prasugrel and ticagrelor are widely prescribed oral P2Y12 receptor antagonists, but numerous clinical and pharmacological factors can lead to impaired gastrointestinal absorption resulting in reduced antithrombotic protection. These observations underscore the need for novel compounds or routes of administration that enable more favorable pharmacokinetic and pharmacodynamic profiles while reducing the risk for thrombotic complications. AREAS COVERED: Selatogrel, formerly known as ACT-246475, is a novel, potent, reversible, and selective non-thienopyridine antagonist of the P2Y12 receptor developed for subcutaneous administration. Results from preclinical, Phase 1 and 2 studies have shown selatogrel to have rapid absorption and sustained and reversible platelet P2Y12 inhibitory effects with a larger therapeutic window compared to the oral P2Y12 inhibitors. Such findings make selatogrel a promising agent to be tested in phase 3 studies. EXPERT OPINION: Advantages of subcutaneous administration of selatogrel are fast onset of action, easy administration and the fecal excretion not requiring dose adjustment based on renal function. These characteristics may translate into an advantage in the peri-procedural setting and in emergency and/or unconscious patients. Selatogrel may represent a viable alternative to intravenous P2Y12 inhibition (i.e. cangrelor), although some aspects need to be further clarified, including side effects, how to switch to oral P2Y12 inhibitor and the association with concomitant drugs.

Effect of Rifampin-Mediated OATP1B1 and OATP1B3 Transporter Inhibition on the Pharmacokinetics of the P2Y12 Receptor Antagonist Selatogrel.

In vitro studies have indicated that the P2Y12 receptor antagonist selatogrel is a substrate of organic anion-transporting-polypeptide (OATP)1B1 and OATP1B3 that are known to mediate hepatic uptake. Selatogrel is primarily eliminated via the biliary route. Therefore, the study aim was to investigate the effect of rifampin-mediated OATP1B1 and OATP1B3 inhibition on the pharmacokinetics (PK) of selatogrel. This was a randomized, double-blind, placebo-controlled, two-period, crossover study in 14 healthy subjects. In each period, a single subcutaneous dose of 4 mg selatogrel was administered, either immediately after a single intravenous 30 minutes infusion of 600 mg rifampin or after placebo. Plasma samples were collected for 36 hours and analyzed using a validated liquid chromatography-tandem mass spectrometry method. PK parameters of selatogrel were calculated using noncompartmental analysis. The effect of rifampin was explored based on geometric mean peak plasma concentration (Cmax ) and area under the concentration curve from zero to infinity (AUC0-∞ ) ratios and for time of maximum plasma concentration (Tmax ) by Wilcoxon signed rank test. In addition, the safety and tolerability of the study treatments were evaluated. The geometric mean ratios of Cmax and AUC0-∞ were 1.19 (90% confidence interval (CI) 1.11-1.28) and 1.43 (90% CI 1.36-1.51), respectively, indicating a minor selatogrel exposure increase when administered after an infusion of rifampin compared with placebo. Rifampin administration did not affect terminal half-life (t½ ) or Tmax of selatogrel. All study treatments were safe and well-tolerated. A single dose of 600 mg rifampin, a potent OATP1B1/1B3 inhibitor, did not impact the PK of selatogrel to a clinically relevant extent suggesting that OATP1B1 and OATP1B3 transporters do not play a major role in the elimination of selatogrel.

Oral brincidofovir decreases the incidence of HHV-6B viremia after allogeneic HCT.

Human herpesvirus 6B (HHV-6B) frequently reactivates after allogeneic hematopoietic cell transplantation (HCT). There are no randomized studies of antiviral treatments to prevent HHV-6B reactivation. Brincidofovir has high in vitro activity against HHV-6B and other DNA viruses, but its in vivo activity for HHV-6B has not been demonstrated. We performed a post hoc analysis of a randomized controlled trial of twice-weekly oral brincidofovir for cytomegalovirus prophylaxis after allogeneic HCT to study the effect of brincidofovir on HHV-6B reactivation. We included patients randomized within 2 weeks of HCT and who received at least 6 consecutive doses of study drug after randomization. We tested plasma for HHV-6B through week 6 post-HCT. The cohort consisted of 92 patients receiving brincidofovir and 61 receiving placebo. The cumulative incidence of HHV-6B plasma detection through day 42 post-HCT was significantly lower among patients receiving brincidofovir (14.2%) compared with placebo (32.4%; log-rank, 0.019). In an adjusted Cox model, brincidofovir exposure remained associated with a lower hazard for HHV-6B plasma detection (hazard ratio, 0.40; 95% confidence interval, 0.20-0.80). In conclusion, brincidofovir prophylaxis reduced HHV-6B reactivation after allogeneic HCT in a post hoc analysis of a randomized controlled trial. These data support the study of intravenous brincidofovir for HHV-6B prophylaxis.

Hydrophilic polyphosphoester-conjugated fluorinated chlorin as an entirely biodegradable nano-photosensitizer for reliable and efficient photodynamic therapy.

An entirely biodegradable nano-photosensitizer platform (PPE-FP2) was fabricated by conjugating the photosensitizer TFPC to hydrophilic polyphosphoesters (PPEs) for efficiently liberating photosensitizers at the tumor site. The complete biodegradability of PPE-FP2 avoided residual nanoparticles in vivo after therapy, realizing reliable and effective photodynamic therapy.

Absorption, distribution, metabolism and excretion of the P2Y12 receptor antagonist selatogrel after subcutaneous administration in healthy subjects.

The P2Y12 receptor antagonist selatogrel which exhibits rapid inhibition of platelet aggregation following subcutaneous administration is in development for the treatment of acute myocardial infarction.This human ADME study was performed in six healthy male subjects to determine the routes of elimination and to identify/quantify the metabolites of selatogrel at a therapeutically relevant dose of 16 mg [14C]-radiolabelled selatogrel.The median tmax and t1/2 of selatogrel was 0.75 h and 4.7 h, respectively. It was safe and well tolerated based on adverse event, ECG, vital sign and laboratory data.Geometric mean total recovery of [14C]-radioactivity was 94.9% of which 92.5% was recovered in faeces and 2.4% in urine.Selatogrel was the most abundant entity in each matrix. In plasma, no major metabolite was identified. In excreta, the glucuronide M21 (14.7% of radioactivity) and the mono-oxidized A1 (6.2%) were the most abundant metabolites in urine and faeces, respectively.Overall, none of the metabolic pathways contributed to a relevant extent to the overall elimination of selatogrel, i.e. by more than 25% as defined per regulatory guidance. Hence, no pharmacokinetic interaction studies with inhibitors or inducers of drug-metabolizing enzymes are warranted for clinical development of selatogrel.

Low-dose adefovir dipivoxil-induced hypophosphatemia osteomalacia in five chronic hepatitis B virus-infected patients. Is low-dose adefovir dipivoxil-induced nephrotoxicity completely reversible?

Adefovir dipivoxil (ADV) is one of the most important nucleostide analogues currently in use for the treatment of chronic hepatitis B virus (HBV) infection. Low-dose ADV-induced nephrotoxicity in most cases was reported to be reversible after the discontinuation of ADV or by decreasing the dose of ADV. In our study, we have 5 documented cases of low-dose ADV-induced hypophosphatemia osteomalacia with or without Fanconi syndrome which were diagnosed in our hospital between 2010 and 2017. Three patients were observed to have a full recovery after the discontinuation of ADV. Two patients had persistently elevated urine ß2-microglobulin levels and out of these two patients, one patient had persistent hypophosphatemia after the cessation of ADV. These cases illustrated that the use of low-dose ADV increased the risk of nephrotoxicity, and in some patients, low-dose ADV-induced nephrotoxicity was not completely reversible. Patients of East Asian origin, especially those with a low body mass index, were prone to a relatively higher risk of developing low-dose ADV-induced nephrotoxicity; therefore, it was worth paying attention to the side effects caused by low-dose ADV.

The different effects of adefovir dipivoxil and telbivudine on the prognosis of hepatitis b virus-related hepatocellular carcinoma patients after curative resection.

Numerous studies suggested that antiviral therapy could reduce the recurrence in hepatocellular carcinoma (HCC) patients after hepatectomy. The impact of nucleotide and nucleoside analogues on prognosis of chronic hepatitis B (CHB) related HCC remains to be explored. We aimed to investigate the role of the telbivudine and adefovir dipivoxil on the prognosis of CHB-related HCC patients after hepatectomy.One hundred eighty-eight CHB-related patients who received hepatectomy from February 2010 to February 2017 were divided into telbivudine (LdT) and adefovir dipivoxil (ADV) groups. The characteristics and survival information of both groups were retrospectively compared and analyzed.One hundred eleven and 77 patients received telbivudine and adefovir dipivoxil monotherapy, respectively. Alanine aminotransferase (ALT), total bilirubin level, status of hepatitis B e antigen (HBeAg), serum HBV-DNA level were compared between groups. OS and DFS in ADV-treatment group were significantly better than it in LdT-treatment group (P < .05). In the subgroups analysis, we found that ADV treatment was significantly associated with better DFS and OS among patients with cirrhosis, HBeAg-negative patients, or those with detectable HBV-DNA.CHB-related HCC patients receiving long-term ADV-treatment had a better OS and DFS than patients receiving LdT-treatment after hepatectomy.

Diethyl [(3-phenoxy-2-oxo-4-phenyl-azetidin-1-yl)-phenyl-methyl]-phosphonate as a potent anticancer agent in chemo-differentiation therapy of acute promyelocytic leukemia.

Organophosphonates are a group of chemical agents which have high bioactivity. In the present study, we aimed to investigate the anticancer activity of the synthesized ß-lactam derivatives of α-amino phosphonates on solid tumor and human leukemic cell lines. The results show that one of these compounds, Diethyl [(3-phenoxy-2-oxo-4-phenyl-azetidine-1-yl)-phenyl-methyl]-phosphonate, is a potent anticancer agent which especially shows anti-leukemic activity. Flow cytometry study showed that this chemical agent causes the G1 phase cell cycle arrest and consequently apoptosis in NB4 cell line as an acute promyelocytic leukemia model. In fact, this agent induces cell differentiation and apoptosis, at low and high concentrations, respectively. Its combination with All-Trans Retinoic Acid shows a higher percentage of cells in the terminal differentiation stage. This evidence suggested that diethyl phosphonate might be a proper candidate for chemo-differentiation therapy in acute promyelocytic leukemia and even in other types of acute myeloid leukemia.

A Randomized, Double-Blind, Placebo-Controlled Phase 3 Trial of Oral Brincidofovir for Cytomegalovirus Prophylaxis in Allogeneic Hematopoietic Cell Transplantation.

Cytomegalovirus (CMV) infection is a common complication of allogeneic hematopoietic cell transplantation (HCT). In this trial, we randomized adult CMV-seropositive HCT recipients without CMV viremia at screening 2:1 to receive brincidofovir or placebo until week 14 post-HCT. Randomization was stratified by center and risk of CMV infection. Patients were assessed weekly through week 15 and every third week thereafter through week 24 post-HCT. Patients who developed clinically significant CMV infection (CS-CMVi; CMV viremia requiring preemptive therapy or CMV disease) discontinued the study drug and began anti-CMV treatment. The primary endpoint was the proportion of patients with CS-CMVi through week 24 post-HCT; patients who discontinued the trial or with missing data were imputed as primary endpoint events. Between August 2013 and June 2015, 452 patients were randomized at a median of 15 days after HCT and received study drug. The proportion of patients who developed CS-CMVi or were imputed as having a primary endpoint event through week 24 was similar between brincidofovir-treated patients and placebo recipients (155 of 303 [51.2%] versus 78 of 149 [52.3%]; odds ratio, .95 [95% confidence interval, .64 to 1.41]; P = .805); fewer brincidofovir recipients developed CMV viremia through week 14 compared with placebo recipients (41.6%; P < .001). Serious adverse events were more frequent among brincidofovir recipients (57.1% versus 37.6%), driven by acute graft-versus-host disease (32.3% versus 6.0%) and diarrhea (6.9% versus 2.7%). Week 24 all-cause mortality was 15.5% among brincidofovir recipients and 10.1% among placebo recipients. Brincidofovir did not reduce CS-CMVi by week 24 post-HCT and was associated with gastrointestinal toxicity.

Clinical Pharmacology of the Reversible and Potent P2Y12 Receptor Antagonist ACT-246475 After Single Subcutaneous Administration in Healthy Male Subjects.

ACT-246475 is a selective and reversible P2Y12 receptor antagonist inducing inhibition of platelet aggregation (IPA). A randomized, double-blind, placebo-controlled, parallel-design study was performed to investigate the safety, tolerability, pharmacokinetics, and pharmacodynamics of escalating single subcutaneous doses of ACT-246475 (1, 2, 4, 8, 16, or 32 mg) in healthy male subjects (N = 8 per dose, 3:1 active:placebo ratio). Pharmacodynamic effects were assessed based on maximum platelet aggregation and P2Y12 reaction units using light transmission aggregometry and VerifyNow® assays, respectively. ACT-246475 was safe and well tolerated up to 32 mg based on adverse event data and absence of clinically relevant changes in hematology, biochemistry, vital signs, and electrocardiogram variables. Median time to reach maximum plasma concentration was 0.5-0.75 hours, and geometric mean terminal half-life ranged from 1.3 to 9.2 hours across the tested dose range. Exposure to ACT-246475 was dose proportional across all dose groups. The maximal %IPA was reached within 30 minutes after subcutaneous administration of ACT-246475. A dose-dependent duration and extent of effect were observed based on area under the effect curve and maximum effect data. Similar results were observed for maximum platelet aggregation and P2Y12 reaction units. The %IPA was ≥85% at doses ≥2 mg. This level of %IPA was extended to at least 12 hours in the 32-mg dose group. The safety and pharmacokinetic/pharmacokinetic profile with quick onset and adequate duration of IPA support further investigation in patients with coronary artery disease.

Therapeutic Effect of GGsTop, Selective Gamma-glutamyl Transpeptidase Inhibitor, on a Mouse Model of 5-Fluorouracil-induced Oral Mucositis.

BACKGROUND: Oral mucositis (OM) induced by cancer chemotherapy has a high incidence and serious symptoms, which often force chemotherapy to be stopped. GGsTop is a newly-discovered gamma-glutamyl transpeptidase (GGT) inhibitor. Previous research suggested that inhibition of GGT suppressed reactive oxygen species and induced the production of collagen and elastin. We hypothesized that GGsTop could safely treat OM. MATERIALS AND METHODS: A mouse model of OM was treated with GGsTop and ulcer area, weight, and white blood cell count were determined. The treatment effect was also evaluated by hematoxylin-eosin and collagen staining. RESULTS: The therapeutic effect of GGsTop was better than that of an existing drug and may be safely used in combination with chemotherapy. Furthermore, GGsTop promoted collagen production in oral mucosa. CONCLUSION: GGsTop treated OM quickly and safely. GGsTop is highly valuable for use as a treatment for OM.