Mariko Asahi

Modulation of mdr1a and CYP3A gene expression in the intestine and liver as possible cause of changes in the cyclosporin A disposition kinetics by dexamethasone

We investigated the effect of dexamethasone (DEX) on the disposition kinetics of cyclosporin A (CyA) and the mechanism of this drug interaction. Rats were treated with DEX (1 or 75mg/kg per day, i.p.) once a day for 1-7 days, and the blood concentration of CyA was measured after an i.v. or p.o. dose of CyA (10mg/kg) at 1.5hr after the last DEX treatment. In rats treated with a low dose of DEX (1mg/kg), the blood concentration of CyA after i.v. administration was unchanged compared with that of untreated rats, whereas the blood concentration after oral administration was significantly decreased, and this decrease was dependent on the duration of DEX administration. The total clearance (CL(tot)) of CyA was unchanged, but the bioavailability was significantly decreased to about one-third of that in DEX-untreated rats after 7 days of DEX treatment. At this time, the expression of mdr1a mRNA and P-gp in the liver and intestine was increased, whereas CYP3A2 was unaffected at both the mRNA and protein levels. In rats treated with a high dose of DEX (75mg/kg), the blood concentration of CyA was significantly decreased after both i.v. and p.o. administrations compared with those of untreated rats. The bioavailability of CyA was decreased, and the CL(tot) was significantly increased. The P-gp and CYP3A2 in the liver and intestine were increased at both the mRNA and protein levels. Our results indicate that the drug interaction between CyA and DEX is a consequence of modulation of P-gp and CYP3A2 gene expression by DEX, with differential dose-dependence.

Gosha-jinki-gan reduced oxaliplatin-induced hypersensitivity to cold sensation and its effect would be related to suppression of the expression of TRPM8 and TRPA1 in rats.

Peripheral neuropathy is a common side effect of the chemotherapeutic agent oxaliplatin (Oxp), and is associated with hypersensitivity to cold sensation in the acute stage. Recently, gosha-jinki-gan (GJG), a Japanese herbal medicine, was reported to improve Oxp-induced cold hypersensitivity. However, the mechanism for this effect was not elucidated. We hypothesized that the effect of GJG on Oxp-induced cold hypersensitivity may be associated with the expression of the transient receptor potential melastatin 8 (TRPM8) and transient receptor potential ankyrin 1 (TRPA1) channels, which are cold-gated ion channels. To assess this hypothesis, we examined alteration of the withdrawal response to cold stimulation following coadministration of GJG and Oxp in rats, and the relationship between this altered withdrawal response and the expression of TRPM8 and TRPA1 mRNA in the dorsal root ganglia (DRG). Assessment of cold hypersensitivity was performed at 4 and 10°C using a cold plate. Compared with Oxp administration alone, coadministration of GJG (oral dose: 1 g/kg/day for 12 days) and Oxp (intraperitoneal dose: 4 mg/kg twice a week) significantly reduced the withdrawal response to cold stimulation. On the 12th day of drug administration, the L4–L6 DRG were removed and the expression of TRPM8 and TRPA1 mRNA was determined using RT-PCR. The expression of TRPM8 and TRPA1 in the DRG of rats that were coadministered GJG and Oxp decreased significantly compared with that in the rats administered Oxp alone. These results suggest that coadministration of GJG may improve Oxp-induced cold hypersensitivity by suppressing the overexpression of TRPM8 and TRPA1 mRNA.

Causative agent of vascular pain among photodegradation products of dacarbazine.

The photodegradation products of the anticancer drug, dacarbazine, cause adverse reactions including local venous pain when injected intravenously. In this study, we attempted to identify which of these products is responsible. We synthesized or purchased five photodegradation products of dacarbazine (dimethylamine, 5‐diazoimidazole‐4‐carboxamide (Diazo‐IC), 4‐carbamoylimidazolium‐5‐olate, 5‐carbamoyl‐2‐(4‐carbamoylimidazol‐5‐ylazo) imidazolium‐5‐olate and 2‐azahypoxanthine) and examined the pain reaction induced by their intraperitoneal administration in mice using an abdominal stretching or constriction assay. Only Diazo‐IC clearly induced pain reaction in mice in a dose‐dependent manner, the other products caused no pain reaction. The threshold concentration for pain reaction in mice was estimated to be about 0.1 mg mL−1. While diclofenac sodium significantly reduced acetic‐acid‐induced pain reaction in mice, it did not influence those induced by Diazo‐IC. This result suggests that the mechanism of Diazo‐IC‐induced pain is different from that of acetic‐acid‐induced inflammatory pain. Dacarbazine itself produced marked relaxation of rat thoracic aorta strips in a concentration‐dependent manner, but there was no difference between the activity of dacarbazine and its photo‐exposed solution, so constriction or relaxation of blood vessels is unlikely to be a factor in the pain reaction. In conclusion, Diazo‐IC generated by photodegradation of dacarbazine solution causes the side‐effect of venous pain. Dacarbazine solution that has turned pink should not be used, because Diazo‐IC is an intermediate in the formation of the reddish product, 5‐carbamoyl‐2‐(4‐carbamoylimidazol‐5‐ylazo) imidazolium‐5‐olate. Drip infusion preparations of dacarbazine should be shielded from light.

Study of Effect of Pharmacotherapy on ADL in Patients with Parkinson's Disease Based on Medical Report.

The control of drug use for Parkinsons disease is very important for both the QOL and ADL of patients. Nowadays, patients with Parkinsons disease are treated with the concomitant use with L-dopa, dopamine receptor agonists and norepinephrine receptor agonists. However, these drugs elicit some adverse effects. Therefore, we tried to search for the effects and adverse effects, based on patient histories. As a result of our investigations, most patients broke out with tremors and were administered anticholinergic drugs, while a few patients were treated with L-dopa as the first drug of choice. Avoid the administration of L-dopa at first seemed to help prevent the onset of Wearing-off or On-off phenomenon. Gastric mucosal cytoprotective drugs appeared to be effective for preventing of gastric symptoms due to drugs for Parkinsons disease. Moreover, we found that mental symptoms only rarely occurred after the readministration of anticholinergic drugs. We must be careful to treat patients with brain infarction after the onset of mental symptoms. These results are valuable for helping to improve the treatment of Parkinsons disease, and may also help in performing further studies on the use of new drugs.

A Clinical Pharmacy Practice for Fourth-year Undergraduates Given by Pharmacist. Development of One-month Curriculum and the Evaluation.

We participated in the development of a one-month curriculum for clinical pharmacy training for fourth-year undergraduates studying at Kanazawa University. Students learned about 81 diseases and the drug therapy through integrating an up-to-date electronic textbook. The pharmacists surveyed the education problem offered at the university by giving the lectures and attending a conference on drug therpy.