Development of polymer film dosage forms of lidocaine for buccal administration: II. Comparison of preparation methods

In previous studies, we prepared film dosage forms of lidocaine (LC) with hydroxypropylcellulose (HPC) as a film base using the solvent evaporation (SE) method. However, from the viewpoint of environmental issues, a reduction in organic solvent use in pharmaceutical and other industries is required. In this study, we prepared the LC films by direct compression of the physical mixture (DCPM method) and direct compression of the spray dried powder (DCSD method). Magnesium stearate, which was required as a lubricant for direct compression, showed no effect on the LC release rate. The LC release rate (%/h) was independent of the compression pressure, but a higher pressure was preferable to easily remove the film from the punches. An increase in the film weight decreased the LC release rate expressed in %/h, whereas no significant effect of film weight was observed on the LC release rate from unit surface area expressed in mg/h/cm(2). The LC release rate (%/h) was independent of the LC content, suggesting that the LC release rate (mg/h) can be quantitatively controlled by changing the LC content in the formulation. The LC release rate and penetration rate were affected by the preparation method; that is, DCPM method < DCSD method < SE method. The LC penetration rates through excised hamster oral mucosa were linearly correlated to the release rate of un-ionized LC, which was estimated by the LC release rate multiplied by the un-ionized fraction of LC for the HPC film dosage form.     

Cationic charge determines the distribution of liposomes between the vascular and extravascular compartments of tumors

Tumor vessels possess unique physiological features that might be exploited for improving drug delivery. In the present study, we investigate the possibility of modifying polyethylene glycol-ylated liposome cationic charge of polyethylene glycol coated liposomes to optimize delivery to tumor vessels using biodistribution studies and intravital microscopy. The majority of liposomes accumulated in the liver, and increasing charge resulted in lower retention in the spleen and blood. Although overall tumor uptake was not affected by charge in the biodistribution studies, intravital microscopy showed that increasing the charge content from 10 to 50 mol % doubled the accumulation of liposomes in tumor vessels, suggesting a change in intratumor distribution; no significant effect of charge on interstitial accumulation could be detected, possibly attributable to spatial heterogeneity. Increased vascular accumulation of cationic liposomes was similar in two different tumor types and sites. Our results suggest that optimizing physicochemical properties of liposomes that exploit physiological features of tumors and control the intratumor distribution of these drug carriers should improve vascular-specific delivery.     

Enhanced elimination of tissue methylmercury in Parachlorella beijerinckii-fed mice

To investigate the influence of Chlorella (Parachlorella beijerinckii) on the excretion and tissue accumulation of methylmercury (MeHg), we orally administered 5 mg/kg of MeHg chloride (4 mg Hg/kg) to female C57BL/6N mice (aged 10 weeks). The mice were housed in metabolism cages to collect urine and feces for 3 weeks with diets containing 0%, 5%, or 10% P. beijerinckii powder (BP) in a basal diet (CE-2). The lowered blood Hg levels in the 5% and 10% BP groups became significant compared to those of the control group (0% BP) as early as day 7. During the 21 days of testing, significant increases in the cumulative Hg eliminations into urine (5% BP) and feces (5% and 10% BP) were found in the BP groups. Twenty-one days after administration, the organ Hg levels in both BP groups tended to decrease compared to that of the control group. The reduction of Hg levels in the kidney and brain were significant, whereas that in the liver was not. Although tissue Hg levels are known to be closely related to glutathione (GSH) metabolism, no difference was found in GSH levels in the blood or organs between the control group and the 10% BP group. These results suggest that continuous BP intake accelerates the excretion of MeHg and subsequently decreases tissue Hg levels in mice, with no alteration of GSH metabolism. We should conduct further research to elucidate details regarding the mechanism of BP-induced enhancement of MeHg excretion.     

Prevalences of lifetime histories of self-cutting and suicidal ideation in Japanese adolescents: differences by age

We examined differences in the prevalence of a lifetime history of self-cutting and suicidal ideation by age among junior and senior high-school students. Histories of self-cutting and suicidal ideation were reported by 9.9% and 40.4% of the students. Among early teens, females were more likely to report suicidal ideation than males, and among late teens, females were more likely than males to report self-cutting.     

A case of relapsed acute myeloid leukemia with brain white matter lesions

Lesions of the central nervous system (CNS) in acute myeloid leukemia (AML) have a wide range of causes. Apart from infection, virus, fungus and bacteria have to be excluded. Other causes including involvement of leukemia, toxic encephalopathies induced by chemotherapy and radiation therapy, and vascular lesions must be diagnosed differentially for advanced treatment or follow-up. While ultimate diagnosis rests on the collection of cerebrospinal fluid, it is not enough for essential diagnosis. Imaging techniques such as head MRI are powerful tools for diagnosis of intracranial organic lesions, especially in this setting involving leukemia, progressive multifocal leukoencephalopathy (PML) by JC virus infection and treatment-related disseminated necrotizing leukoencephalopathy. A 50-year-old man with AML, who relapsed three times,progressed to an acute consciousness disturbance and was complicated with multiple CNS lesions. He presented with a vesicle formation on his skin, which was pathologically diagnosed as virus infection 1 week after CNS lesions appeared. He was considered to have systemic herpes infection. In this case, considered judgment with multiple approaches would be needed for diagnosis in some cases of AML with the CNS infiltration shadow.     

The effects of arginine and selective inducible nitric oxide synthase inhibitor on pathophysiology of sepsis in a CLP model

BACKGROUND: Sepsis is an arginine-deficient state and is associated with overproduction of nitric oxide (NO) by inducible nitric oxide synthase (iNOS). It has been indicated that low plasma levels of arginine are related to high mortality rates in sepsis. Arginine, however, is also known to be a precursor of NO. Therefore, administration of arginine in septic patients remains controversial. We examined the effects of co-administration of arginine and aminoguanidine, a selective iNOS inhibitor, on sepsis, using rat models. METHOD: Sepsis was induced in rats by cecal ligation and puncture (CLP). Effects of separate and combined administration of arginine and aminoguanidine were investigated by comparing plasma levels of arginine, expressions of heme oxygenase (HO)-1 and HO-2 in liver and lung, and nitrite + nitrate (NOx) excretion in urine, as well as neuroendocrine responses in urine in the early phase of sepsis. Seven-day survival rates were also examined. RESULTS: A combination of arginine and aminoguanidine recovered the plasma level of arginine at 6 h post-CLP, decreased expression of HO-1 in liver and lung at 24 h post-CLP, decreased urinary excretion of epinephrine, norepinephrine, dopamine, and 17-hydroxycorticosteroid in the first 24 h post-CLP, and increased 7-d survival. CONCLUSION: It is demonstrated that administration of arginine together with the selective iNOS inhibitor in the early phase of sepsis restores plasma arginine, reduces oxidative stress by probably maintaining NO derived from constitutive NOS, and attenuates neuroendocrine stress responses. This co-administration may be a beneficial treatment approach against sepsis.