Safety assessment of So-cheong-ryong-tang: subchronic toxicity study in Crl:CD Sprague Dawley rats.

So-cheong-ryong-tang, an oriental herbal formula, is used in Korea for treating pulmonary disorders, including asthma, bronchitis and allergic diseases. The objective of the present study was to investigate the potential adverse effects, if any, of subchronic administration of So-cheong-ryong-tang aqueous extract (SCRT) in male and female rats. In the present study, 0, 1,000, 2,000 and 5,000 mg/kg/day of SCRT was administered to Crl:CD Sprague Dawley rats (10/gender/group) for 13 weeks via oral gavage. Administration of the SCRT did not result in any mortality. There were no clinical or ophthalmological signs, changes in urinalysis, body weight, food consumption, gross findings, hematology, serum biochemistry, organ weight or histopathology attributable to the administration of SCRT. Any alterations noted were incidental and consistent with those historically observed in the age and strain of rats used in the present study. Based on the results of the present study, the no observed adverse effect level for SCRT under the present experimental conditions was determined to be 5,000 mg/kg/day, the highest dose assessed, for both genders.

Carcinogenicity study of CKD-501, a novel dual peroxisome proliferator-activated receptors α and γ agonist, following oral administration to Sprague Dawley rats for 94-101 weeks.

CKD-501 is a peroxisome proliferator-activated receptor (PPAR) agonist. The current study was conducted in Sprague Dawley (SD) rats for 94-101 weeks to investigate the carcinogenic potential of CKD-501. 60 males received 0, 0.03, 0.12, or 1.0mg/kg/day, which was changed after 66 weeks to 0.24 mg/kg/day due to increased mortality, while 60 females received 0, 0.03, 0.06, or 0.12 mg/kg/day throughout the study period. After switching the dosage, no significant changes in the survival rates were observed. Non-neoplastic lesions such as bladder transitional cell hyperplasia and a diminished corpus luteum were observed in females administered 0.12 mg/kg/day and the right chamber dilation and left ventricular hypertrophy were increased dose dependently in both males and females. Non-neoplastic lesions such as bone marrow hypoplasia and fat cell proliferation and neoplastic lesions such as lipomas and liposarcomas observed in males and/or females were considered expected pharmacological effects for this compound. Compared to rosiglitazone, CKD-501 had a 4.4-fold higher margin of safety for tumor induction and did not cause bladder carcinoma as was observed with pioglitazone.

Blockade of hERG K(+) channel by antimalarial drug, primaquine.

Lengthening of the Q-T interval and proarrhythmia are adverse effects associated with antimalarial agents. Also, lengthening of the Q-T interval is a definite outcome when patients are administered with an overdose of primaquine. Inhibition of potassium current I (Kr) and resultant QT prolongation is suggested as the reason behind drug-induced arrhythmias. The present study investigated the molecular mechanisms of voltage-dependent inhibition of human Ether-a-go-go Related Gene (hERG) delayed rectifier K(+) channels expressed in HEK-293 cells by primaquine. Primaquine inhibited hERG current in a concentration-dependent manner with the half-maximal inhibitory concentration (IC(50)) of 21.5 microM. The voltage-dependent inhibition of hERG current resulted in the activation curve to be shifted to a negative voltage after primaquine exposure in a dose-dependent manner. Blockade of hERG by primaquine was also found to be time-dependent, occurring rather rapidly. Blockade of wild-type hERG channel by primaquine was similar to those of both the S6 residue hERG mutants (F656A and Y652A) and the pore region mutants (T623A). In conclusion, these results indicate that primaquine preferentially inhibits the hERG potassium channel, but blockade of hERG channel by primaquine may not be related to the S6 residue or the pore region, but may be induced through other pathways such as binding other region or effect by drug binding receptor which indicates a need for further exploration.