ABSTRACT
<p><b>OBJECTIVE</b>To evaluate the acute and sub-chronic toxicity of intravenously administered tetrandrine (TET) in female BALB/c mice.</p><p><b>METHODS</b>The median lethal dose (LD) of intravenously administered TET was calculated in mice using Dixon's up-and-down method. In the acute toxicity study, mice were intravenously administered with TET at a single dose of 20, 100, 180, 260 and 340 mg/kg, respectively and were evaluated at 14 days after administration. In the sub-acute toxicity study, mice were intravenously administered various doses of TET (30, 90 and 150 mg/kg) each day for 14 consecutive days. Clinical symptoms, mortality, body weight, serum biochemistry, organ weight and histopathology were examined at the end of the experiment, as well as after a 1-week recovery period.</p><p><b>RESULT</b>LDwas found to be 444.67±35.76 mg/kg. In the acute toxicity study, no statistically signifificant differences in body weight, blood biochemistry, or organ histology were observed between the administration and control groups when mice were intravenously administered with single dose at 20, 100, 180, 260 and 340 mg/kg of TET (P >0.05). In the sub-acute toxicity study, no signifificant changes in body weight, biochemistry and organ histology were observed with up to 90 mg/kg of TET compared with the control group (P >0.05), however, in the 150 mg/kg administered group, TET induced transient toxicity to liver, lungs and kidneys, but withdrawal of TET can lead to reversal of the pathological conditions.</p><p><b>CONCLUSIONS</b>The overall fifindings of this study indicate that TET is relatively non-toxic from a single dose of 20, 100, 180, 260 or 340 mg/kg, and that up to 90 mg/kg daily for 14 consecutive days can be considered a safe application dose.</p>
Subject(s)
Animals , Female , Administration, Intravenous , Benzylisoquinolines , Toxicity , Body Weight , Mice, Inbred BALB C , Organ Specificity , Toxicity Tests, Acute , Toxicity Tests, ChronicABSTRACT
<p><b>BACKGROUND</b>The most critical mechanism governing drug resistance in Candida albicans (C. albicans) involves efflux pumps, the functionality of which largely depends on energy metabolism. Alcohol dehydrogenase I (ADH1) plays an important role in intracellular energy metabolism. The aim of this study was to explore the relationship between ADH1 and drug resistance in C. albicans.</p><p><b>METHODS</b>Twenty clinical C. albicans samples isolated from individual patients diagnosed with vulvovaginal candidiasis, and two C. albicans strains obtained from a single parental source (the fuconazole (FLC)-sensitive strain CA-1S and the FLC-resistant strain CA-16(R)) were included in our study. In accordance with the Clinical and Laboratory Standards Institute (CLSI) M27-A3 guidelines, we used the microdilution method to examine the FLC minimum inhibitory concentrations (MICs) and real-time reverse transcription polymerase chain reaction (RT-PCR) to measure the mRNA expression levels of ADH1 and the azole resistance genes CDR1, CDR2, MDR1, FLU1 and ERG11 in all the isolates.</p><p><b>RESULTS</b>A highly significant positive correlation between the mRNA levels of ADH1 and the MICs (rs = 0.921, P = 0.000), as well as positive correlations between the mRNA level of ADH1 and those of CDR1, CDR2 and FLU1 (rs of 0.704, 0.772 and 0.779, respectively, P < 0.01), were observed in the 20 clinical C. albicans samples. The relative expression of ADH1 was upregulated 10.63- to 17.61-fold in all of the drug-resistant isolates. No correlations were found between the mRNA levels of ADH1 and those of MDR1 or ERG11 (P > 0.05). The mRNA levels of the examined drug resistance genes were higher in the CA-16(R) strain than in CA-1(S), and the mRNA levels of ADH1 in CA-16(R) were 11.64-fold higher than those in CA-1(S) (P < 0.05).</p><p><b>CONCLUSIONS</b>These results suggest that high levels of ADH1 transcription are implicated in FLC resistance in C. albicans and that the mRNA expression levels of ADH1 are positively correlated with those of CDR1, CDR2 and FLU1.</p>