Effects and Mode of Action of Oleic Acid and Tween 80 on Skin Permeation of Disulfiram.

Oral disulfiram (DSF) has been used clinically for alcohol dependence and recently has been found to have antitumor activity. A transdermal delivery system would be useful for maintaining drug concentration and reducing the frequency of administration of DSF for cancer treatment. Penetrating the stratum corneum (SC) barrier is a challenge to the transdermal delivery of DSF. Therefore, we investigated the promoting effects and mechanism of action of the combination of oleic acid (OA) and Tween 80 on the skin permeation of DSF. Hairless mouse skin was exposed to OA and Tween 80, combined in various ratios (1 : 0, 2 : 1, 1 : 1, 1 : 2, and 0 : 1). A permeation experiment was performed, and total internal reflection IR spectroscopic measurements, differential scanning calorimetry, and synchrotron radiation X-ray diffraction measurements were taken of the SC with each applied formulation. The combination of OA and Tween 80 further enhanced the absorption-promoting effect of DSF, compared with individual application. The peak of the CH2 inverse symmetric stretching vibration near the skin surface temperature was shifted by a high frequency due to the application of OA, and DSF solubility increased in response to Tween 80. We believe that the increased fluidity of the intercellular lipids due to OA and the increased solubility of DSF due to Tween 80 promoted the absorption of DSF. Our study clarifies the detailed mechanism of action of the skin permeation and promoting effect of DSF through the combined use of OA and Tween 80, contributing to the development of a transdermal preparation of DSF.

Varicella-zoster virus-associated meningitis, encephalitis, and myelitis with sporadic skin blisters: A case report.

BACKGROUND: Varicella-zoster virus (VZV) generally causes chickenpox at first infection in childhood and then establishes latent infection in the dorsal root ganglia of the spinal cord or other nerves. Virus reactivation owing to an impaired immune system causes inflammation along spinal nerves from the affected spinal segment, leading to skin manifestations (herpes zoster). Viremia and subsequent hematogenous transmission and nerve axonal transport of the virus may lead to meningitis, encephalitis, and myelitis. One such case is described in this study. CASE SUMMARY: A 64-year-old man presented with dysuria, pyrexia, and progressive disturbance in consciousness. He had signs of meningeal irritation, and cerebrospinal fluid (CSF) analysis revealed marked pleocytosis with mononuclear predominance and a CSF/serum glucose ratio of 0.64. Head magnetic resonance imaging revealed hyperintense areas in the frontal lobes. He had four isolated blisters with papules and halos on his right chest, right lumbar region, and left scapular region. Infected giant cells were detected using the Tzanck test. Degenerated epidermal cells with intranuclear inclusion bodies and ballooning degeneration were present on skin biopsy. Serum VZV antibody titers suggested previous infection, and the CSF tested positive for VZV-DNA. He developed paraplegia, decreased temperature perception in the legs, urinary retention, and fecal incontinence. The patient was diagnosed with meningitis, encephalitis, and myelitis and was treated with acyclovir for 23 days and prednisolone for 14 days. Despite gradual improvement, the urinary retention and gait disturbances persisted as sequelae. CONCLUSION: VZV reactivation should be considered in differential diagnoses of patients with sporadic blisters and unexplained central nervous system symptoms.

In vitro inhibition of CYP2C9-mediated warfarin 7-hydroxylation by iguratimod: possible mechanism of iguratimod-warfarin interaction.

Iguratimod is a novel disease-modifying antirheumatic drug. A blue letter (safety advisory) for drug interaction between iguratimod and warfarin was issued by the Ministry of Health, Labour and Welfare of Japan in May 2013. Iguratimod may affect warfarin metabolism catalyzed by CYP. However, it is not clear whether iguratimod inhibits warfarin oxidation. This study was performed to investigate the effects of iguratimod on warfarin 7-hydroxylation with human liver microsomes (HLMs) and recombinant CYP enzymes. Iguratimod concentration-dependently inhibited R,S-warfarin 7-hydroxylase activity of HLMs with an IC50 value of 15.2 µM. The inhibitory effect was examined with S-warfarin and R-warfarin to determine which enantiomer was more potently inhibited by iguratimod. Iguratimod potently inhibited the S-warfarin 7-hydroxylase activity of HLMs with an IC50 value of 14.1 µM, but showed only slight inhibition of R-warfarin 7-hydroxylation. Furthermore, iguratimod inhibited the S-warfarin 7-hydroxylase activity of recombinant CYP2C9.1 (rCYP2C9.1) and rCYP2C9.3 in a concentration-dependent manner with IC50 values of 10.8 and 20.1 µM, respectively. Kinetic analysis of the inhibition of S-warfarin 7-hydroxylation by iguratimod indicated competitive-type inhibition for HLMs and rCYP2C9.1 but mixed-type inhibition for rCYP2C9.3. The Ki values for HLMs, rCYP2C9.1, and rCYP2C9.3 were 6.74, 4.23, and 14.2 µM, respectively. Iguratimod did not exert metabolism-dependent inhibition of S-warfarin 7-hydroxylation. These results indicated that iguratimod is a potent direct inhibitor of CYP2C9-mediated warfarin 7-hydroxylation and that its inhibitory effect on CYP2C9.1 was more sensitive than that on CYP2C9.3.