Effect of triamcinolone acetonide on retinal inflammation and angiogenesis induced by pericyte depletion in mouse.

Triamcinolone acetonide (TA) has been shown to improve morphological and functional outcome in diabetic macular edema (DME) patients. However, the functional mechanism of TA has not been elucidated yet. In this study we investigated the detailed functional mechanism of TA using culture cells and retinopathy mouse models in which retinal inflammation and abnormal angiogenesis were induced by pericyte depletion. TA significantly prevented retinal hemorrhage, edema and partially improved abnormal angiogenesis. TA decreased retinal vascular endothelial growth factor (VEGF) concentration, presumably by preventing recruitment of macrophages into retina and TA also inhibited expression of inflammatory cytokines in retina. TA inhibited proliferation/migration of vascular endothelial cells and vessel sprouting. No direct inhibition of VEGF receptor 2 (VEGFR2) autophosphorylation was observed by TA. These results suggested that TA improved inflammatory retinal events which were induced in pericyte-deleted mice by mainly decreasing macrophage-derived VEGF and expression of inflammatory cytokines followed by attenuation of vascular permeability and proliferation/migration of endothelial cells. Furthermore, in these processes, translocation of glucocorticoid receptor (GR) was partially involved.

Comparative study on pharmacokinetics and toxicity of intravitreal and sub-Tenon injection of triamcinolone acetonide in ocular tissues.

AIM: To compare the differences in kinetics, distribution, and toxicity of triamcinolone acetonide (TA) between the injection methods, sub-Tenon and intravitreal injections in rabbit ocular tissues. METHODS: TA was injected into the vitreous or the sub-Tenon in rabbits. For pharmacokinetic study, rabbits were sacrificed periodically and then TA in blood and ocular tissues (retina/choroids, vitreous, and aqueous humor) were measured over 91d. For toxicological study, clinical signs, slit-lamp microscopic examination, ophthalmological test were performed. The eyeballs and surrounding tissues were collected and fixed with glutaraldehyde-formalin solution, and then paraffin embedded for histological investigation. RESULTS: Higher levels of TA were distributed in the intraocular tissues when injected into the vitreous compared to the sub-Tenon. Conversely, TA level was remarkably lower in the rabbits which received intravitreal TA injections than those treated with sub-Tenon injection throughout the study period in plasma. Optical discharge probably caused by systemic circulation of TA was observed by receiving sub-Tenon TA injection. Meanwhile, technic-associated toxicological ocular symptoms and findings were more frequently observed in intravitreal injection than in sub-Tenon injection. CONCLUSION: There are significant differences in kinetics and distribution of TA in vitreous body, aqueous humor and plasma, between the two injection methods. Although further study is needed to explain the species difference between human and rabbit, it is assumed that the difference in the frequency of intraocular pressure elevation and cataract formation by TA between the two injection methods are directly related to the TA concentrations in aqueous humor and vitreous body in each injection methods. Systemic toxicity and technic-associated toxicity are also closely related to kinetics of TA in plasma and each injection method itself, respectively.

Toxicologic Pathology Forum: Current Status on the Use of Animal Models of Human Disease in the Pharmaceutical Industry in Japan in Nonclinical Safety Assessment-Opinion Paper.

In nonclinical safety studies for new drug development, healthy animals have been commonly used. However, in some cases, the use of animal models of human disease is considered to be more favorable in evaluating risks in patients. To elucidate the current status of the use of animal models for nonclinical safety assessment, an internal questionnaire from the Japan Pharmaceutical Manufacturers Association and surveys (questionnaire period: August 27 to September 30, 2015) of both common technical documents and review reports of approved drugs (approval period: May 1999 to May 2017) disclosed by the Pharmaceutical and Medical Devices Agency were conducted. Although there were some concerns and limitations raised, the survey results revealed that animal models have been used in nonclinical safety assessment on a case-by-case basis and that nonclinical safety studies using animal models were included in the data packages of several approved drugs in Japan. The survey results also revealed that nonclinical safety studies using animal models have become more frequent in the past few years. In almost all cases, useful information, such as signs of toxicity under disease conditions and mechanisms of toxic change, was obtained from the results of nonclinical studies using animal models. Note: This is an opinion article submitted to the Toxicologic Pathology Forum. It represents the views of the author(s). It does not constitute an official position of the Society of Toxicologic Pathology, British Society of Toxicological Pathology, or European Society of Toxicologic Pathology, and the views expressed might not reflect the best practices recommended by these Societies. This article should not be construed to represent the policies, positions, or opinions of their respective organizations, employers, or regulatory agencies.

Effect of parenteral hydration therapy based on the Japanese national clinical guideline on quality of life, discomfort, and symptom intensity in patients with advanced cancer.

CONTEXT: Although an evidence-based clinical guideline for parenteral hydration therapy was established in Japan, the efficacy of the guideline has not been assessed. OBJECTIVES: Our purpose was to explore the effect of parenteral hydration therapy based on this clinical guideline on quality of life (QoL), discomfort, symptoms, and fluid retention signs in patients with advanced cancer. METHODS: This multicenter, prospective, observational study included 161 patients with advanced abdominal cancer who received guideline-based hydration therapy. We evaluated the longitudinal changes of the global QoL (Item 30 of European Organization for Research and Treatment of Cancer Quality-of-Life Questionnaire-C30); the Discomfort Scale; the intensity of seven physical symptoms; and the severity of fluid retention signs. We also evaluated patient satisfaction and the feeling of benefit from hydration one week after the study commenced, and bronchial secretions, hyperactive delirium, communication capacity, and agitation 48 hours before a patient's death. RESULTS: The global QoL, the Discomfort Scale, and the intensities of all physical symptoms, except for vomiting and drowsiness, were stable throughout the study period. More than 80% of patients maintained all fluid retention signs. Patient global satisfaction was 76.4 (0-100) and feeling of benefit was 5.43 (range 0-7). CONCLUSION: Guideline-based parenteral hydration therapy contributed to maintaining global QoL and provided satisfaction and a feeling of benefit without increasing discomfort and worsening symptoms and fluid retention signs in patients with advanced cancer.

[Palliative home care].

Palliative home care supports the quality of life (QOL) of a patient and family as a whole. Team care is an effective method corresponding to the various needs of the patient and family. Cooperation of various types of professions can meet the need for high-quality outpatient medical care. Social work serves as a coordinator of the care team. One of its important tasks in palliative home care is support of the patient discharge procedure from the hospital. Discharge from the hospital must be carried out before the patient's condition worsens. Prompt support of the discharge is indispensable so that the patient may spend substantial time with high QOL at home. Palliative home care means care for the dying. Therefore, spirituality issues are important. Palliative home care must respect and understand the spirituality of the patient and family. The patient can be discharged from the hospital in peace when there is general support for the physical, psycho-social and spiritual needs of both patient and family.

Prospective evaluation of transition to specialized home palliative care in Japan.

The aim of this study was to clarify patients' characteristics and the level of symptom management in the transition to specialized home palliative care, and to examine prospectively real-time evaluation of both terminal cancer patients and their families. This study was conducted at one of the largest institutions offering specialized home palliative care in Japan. We asked both the patient's and the family's health status at the initial assessment and 2 weeks later. One hundred sets of patients and their families were included in this study. Regarding patient characteristics at the time of referral to the specialized home palliative care service, patients referred from outpatient settings had more severe physical symptoms than patients referred from inpatient settings. The specialized home palliative care service could contribute to patients' symptom and families' psychosocial status.

Family caregiver's experiences in caring for a patient with terminal cancer at home in Japan.

OBJECTIVES: The aim of the study was to clarify the care experience of primary caregivers when caring for a terminal cancer patient in the home with the assistance of a home palliative care service. Participants were asked to provide background data and to evaluate their experience of caregiving and of the patient's response throughout the period of home palliative care, up to the time of death. METHODS: One hundred twelve primary family caregivers were a mailed self-report questionnaire, and 74 valid questionnaires were returned (response rate 66%). RESULTS: Ninety percent felt that the patient's condition of mind and body was reasonably stable, and 75% felt that the death was peaceful. About 90% reported a deepening of their bond with the patient and that the bond of other family members deepened also. Sixty percent reported that the burden of caregiving was not too great or not felt at all. Approximately 90% judged that the patient retained his or her own personal qualities to the end. Ninety percent also felt that they had done their best in their caregiving and judged that home care had been beneficial for the deceased, for the primary caregiver him/herself, and for other family members. These primary caregivers' evaluations of caring for a terminally ill patient at home in conjunction with a home palliative care service were both high and positive. SIGNIFICANCE OF RESULTS: Our findings suggest that it is important to maintain the patient's personal qualities up to the time of death through appropriate symptom management, to respect the family bond of the household, and to provide professional support in order to reduce the load on the family. If appropriate care is provided, peaceful home death will be possible, resulting in significant benefits for patients and their families in Japan.

Identification of attenuated variants of HIV-1 circulating recombinant form 01_AE that are associated with slow disease progression due to gross genetic alterations in the nef/long terminal repeat sequences.

We identified an unusual case of human immunodeficiency virus type 1 (HIV-1) infection in a patient (GM43) who exhibited a persistently low antibody response and undetectable viral load during a 5-year follow-up period. GM43 harbored HIV-1 circulating recombinant form 01_AE with gross deletions in the nef/long terminal repeat (LTR) region. The sizes of the deletions increased progressively from 84 to >400 bp during the 5-year period. GM43 appeared to have acquired defective variants from her husband. The genetic alterations in the nef/LTR region were remarkably similar to those that have been reported in slow progressors (such as the slow progressors in the Sydney Blood Bank Cohort). The present study is the first report of slow disease progression due to gross genetic alterations in the nef/LTR region in a person infected with an HIV-1 non-subtype B strain.