Toxicity of some broad-spectrum antibacterials in normal rat liver: the role of mitochondrial membrane permeability transition pore.

Ciprofloxacin (CIP) and Amoxycillin/Clavulanate (AC) are broad-spectrum antibiotics that are commonly administered for treatment of various bacterial infections. Studies have reported the antiproliferative and apoptotic activities of CIP in several cancer cell lines while AC has been implicated in drug-induced liver injury. We investigated the influence of CIP and AC on mitochondrial Permeability Transition (mPT) pore, ATPase activity, and cytochrome C release of normal Rat Liver Mitochondria (RLM) spectrophotometrically. In vitro, CIP and AC induced the opening of the mPT pore in a concentration-dependent manner with evidence of cytochrome C release maximally at 70 µg/ml by 13 and 10 folds, respectively. In vivo, CIP (100, 200 mg/kgbw) significantly induced mPT pore opening with induction folds of 2.4 and 2.6, respectively. However, low dose of AC (10 mg/kgbw) had no effect whatsoever on the mPT pore while higher dose (30 mg/kgbw) significantly induced pore opening by 3.4 folds. Similarly, CIP(100 mg/kgbw) and AC (30 mg/kgbw), significantly enhanced RLM ATPase activity, induced cytochrome C release and increased levels of RLM malondialdehyde generation and triggered the activation of caspases-9 and 3 in liver post-mitochondrial fraction. There were also significant (p<0.05) elevation in levels of serum aminotransferases and white blood cell count. Our results show that prolonged use of Ciprofloxacin and Amoxicillin Clavulanate could result in mitochondrial membrane breakdown via induction of opening of mPT pore leading to expulsion of cytochrome C, lipid peroxidation and decrease in energy content in healthy liver cells. These drugs should therefore be used with caution.

Drug-induced bile duct injury.

Drug-induced liver injury includes a spectrum of pathologies, some related to the mode of injury, some to the cell type primarily damaged. Among these, drug-induced bile duct injury is characterized by the destruction of the biliary epithelium following exposure to a drug. Most of the drugs associated with bile duct injury cause immune-mediated lesions to the epithelium of interlobular ducts. These share common histopathological features with primary biliary cholangitis, such as inflammation and necrosis at the expense of cholangiocytes and, if the insult persists, bile duct loss and biliary cirrhosis. Some drugs selectively target larger ducts. Such injury is often dose-dependent and thought to be the result of intrinsic drug toxicity. The histological changes resemble those seen in primary sclerosing cholangitis. This overview focuses on the clinical and pathological features of bile duct injury associated with drug treatment and on the immunological and biochemical effects that drugs exert on the biliary epithelium. This article is part of a Special Issue entitled: Cholangiocytes in Health and Disease edited by Jesus Banales, Marco Marzioni, Nicholas LaRusso and Peter Jansen.

The Role of Chronic Exposure to Amoxicillin/Clavulanic Acid on the Developmental Enamel Defects in Mice.

Amoxicillin used in early childhood may be associated with enamel hypomineralization. Our aim was to assess disturbances of amelogenesis in mice lower incisors induced by chronic administration of amoxicillin/clavulanic acid (AMC). Twenty-eight C57BL/6 male mice, of similar age, randomly divided into a control and 3 treatment groups (n = 7) received subcutaneous injection, once per day, for 60 days: 50, 100, and 150 mg/kg BW of AMC. Scanning electron microscopy/energy dispersive X-ray spectroscopy analysis in AMC treatment groups showed higher content in F and a decrease in P and Ca. Morphology changes ranged from scratched patterns, and small isolated pits-like enamel loss, to generalized demineralized enamel surface, giving a rough, foamy, scaly, or even cracked eggshell appearance to the affected areas. Histological analysis showed disturbances of maturation ameloblasts, which were less organized, with increased amounts of clear vacuoles in the cytoplasm and slightly more elongated and less condensed nucleus. Additionally, they were often detached from the enamel matrix. Transitional ameloblasts formed underlying the cysts of varied sizes. In conclusion, AMC dose-dependently affect ameloblast functions especially in the maturation phase, causing hypomineralized enamel formation with quantitative and/or qualitative defects.

Investigation of Oxidative Stress-Related Candidate Genes as Risk Factors for Drug-Induced Liver Injury due to Co-Amoxiclav.

The liver is susceptible to drug toxicity due to its vital role in xenobiotic metabolism and elimination. In addition to human leukocyte antigen (HLA) variants, which were previously determined as risk factors for drug-induced liver injury (DILI) due to co-amoxiclav, other non-HLA genes may contribute to hepatotoxicity risk. In this study, the association between DILI due to co-amoxiclav and several non-HLA genes was investigated. Association of variants in candidate genes (SOD2, GPX1, GSTM1, and GSTT1) with DILI due to various drugs was reported previously in other DILI cohorts. This study examined relevance in a co-amoxiclav-DILI cohort. One hundred sixty-five co-amoxiclav DILI cases were recruited from several European countries by two different studies (DILIGEN and iDILIC). A North-East England population group (n = 334) was used as the control group. PCR assays were used to genotype for the GSTM1 and GSTT1 null alleles with TaqMan SNP genotyping assays used for SOD2 (rs4880) and GPX1 (rs1050450). Fisher's exact test was used to assess differences in significance between cases and controls. None of the studied variants (SOD2 rs4880, GPX1 rs1050450, GSTM1 null allele, and GSTT1 null allele) was significantly associated with co-amoxiclav DILI compared with the control group. No significant differences between cases and controls were seen when combined SOD2/GPX1 genotypes and GST genotypes were considered. Despite the possible functional relevance and the previously reported contribution of the selected genes to DILI, our study failed to confirm associations between the selected genes and liver injury induced by co-amoxiclav.

HLA alleles influence the clinical signature of amoxicillin-clavulanate hepatotoxicity.

BACKGROUND AND AIM: The genotype-phenotype interaction in drug-induced liver injury (DILI) is a subject of growing interest. Previous studies have linked amoxicillin-clavulanate (AC) hepatotoxicity susceptibility to specific HLA alleles. In this study we aimed to examine potential associations between HLA class I and II alleles and AC DILI with regards to phenotypic characteristics, severity and time to onset in Spanish AC hepatotoxicity cases. METHODS: High resolution genotyping of HLA loci A, B, C, DRB1 and DQB1 was performed in 75 AC DILI cases and 885 controls. RESULTS: The distributions of class I alleles A*3002 (P/Pc = 2.6E-6/5E-5, OR 6.7) and B*1801 (P/Pc = 0.008/0.22, OR 2.9) were more frequently found in hepatocellular injury cases compared to controls. In addition, the presence of the class II allele combination DRB1*1501-DQB1*0602 (P/Pc = 5.1E-4/0.014, OR 3.0) was significantly increased in cholestatic/mixed cases. The A*3002 and/or B*1801 carriers were found to be younger (54 vs 65 years, P = 0.019) and were more frequently hospitalized than the DRB1*1501-DQB1*0602 carriers. No additional alleles outside those associated with liver injury patterns were found to affect potential severity as measured by Hy's Law criteria. The phenotype frequencies of B*1801 (P/Pc = 0.015/0.42, OR 5.2) and DRB1*0301-DQB1*0201 (P/Pc = 0.0026/0.07, OR 15) were increased in AC DILI cases with delayed onset compared to those corresponding to patients without delayed onset, while the opposite applied to DRB1*1302-DQB1*0604 (P/Pc = 0.005/0.13, OR 0.07). CONCLUSIONS: HLA class I and II alleles influence the AC DILI signature with regards to phenotypic expression, latency presentation and severity in Spanish patients.

Direct effect of intracanal medicaments on survival of stem cells of the apical papilla.

INTRODUCTION: Regenerative endodontic procedures are an alternative treatment for immature teeth with necrotic pulps. Typically, intracanal medicaments such as triple antibiotic paste (TAP) or double antibiotic paste (DAP) and calcium hydroxide (Ca[OH](2)) are used for disinfection. However, their effect on human stem cells of the apical papilla (SCAPs) is unknown. We hypothesized that intracanal medicaments at high concentrations are toxic to SCAPs. To test this hypothesis, a cell culture assay was used. METHODS: Briefly, SCAPs were cultured and subjected to either no drug treatment or various concentrations including TAP, DAP, modified TAP (ciprofloxacin, metronidazole and cefaclor), Augmentin (Champs Pharmacy, San Antonio, TX), or Ca(OH)(2). Viable stem cells counts were obtained using an automated method of detecting trypan blue dye at 3 days after treatment. RESULTS: All 4 antibiotics significantly reduced SCAP survival in a concentration-dependent fashion. Interestingly, Ca(OH)(2) was conducive with SCAP survival at all concentrations. CONCLUSIONS: Collectively, our data show that high concentrations of antibiotics have a detrimental effect on SCAP survival, whereas lower concentrations as well as Ca(OH)(2) at all tested concentrations are conducive with SCAP survival and proliferation. These studies highlight the clinically important point that intracanal medicaments must be used at concentrations that are bactericidal while having minimal effects on stem cell viability.

Tratamiento con amoxicilina-ácido clavulánico como causa de hepatotoxicidad con colestasis intrahepática / Amoxicillin-clavulanic acid therapy as cause of intrahepatic cholestasis

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