Improved formulations of antisense oligodeoxynucleotides using wrapped liposomes.

Previously, we demonstrated that wrapping dextran fluorescein anionic/cationic lipid complexes with neutral lipids produced a stable formulation that markedly increased the duration of the compound in plasma after intravenous administration to rats. The improved drug-delivery properties of the wrapped liposomes (WL) relative to other formulations suggested that this technology could offer important advantages for the administration of other polyanionic drugs, including antisense oligodeoxynucleotides (ODN). In the present study, we investigated the value of WL for formulating fluorescence-labeled phosphorothioated ODN (F-ODN). WL encapsulating F-ODN/cationic lipid complexes were prepared efficiently using similar methodology to that used in our earlier study. Studies confirmed that these WL were stable in vitro. Following intravenous administration to mice, free F-ODN and naked F-ODN/cationic lipid complexes were rapidly eliminated whereas administration of the WL resulted in high blood concentrations of drug that were maintained for several hours. Additional studies were conducted in mice that were inoculated with tumor cells (Caki-1 xenograft model, human kidney); in these experiments, intravenous administration of WL delivered 13 times more F-ODN to the tumor site than achieved after injection of free F-ODN.     

A case of drug eruption induced by hydroxyzine pamoate]

A 62-year-old woman with rheumatoid arthritis, Basedow's disease and arrhythmia has been treated with antirheumatic, antiarrhythmic drugs and so on. She developed pruritic diffuse erythema with papules on the trunk and extremities 2 days after taking hydroxyzine pamoate for asteatotic eczema. Laboratory data showed increased levels of eosinophils. Histopathological examination revealed a infiltrate of inflammatory cells in the upper dermis. Patch tests with hydroxyzine pamoate and hydroxyzine hydrochloride were positive. From these findings, we diagnosed this case as drug eruption due to hydroxyzine. Her eruption subsided after she discontinued hydroxyzine pamoate and other drugs which were started within 5 days before the onset of the eruption and was treated with systemic steroid, systemic antiallergic drug and topical steroid.     

Clinical effect of LM-001, prostaglandin synthetic inhibitor, on pain from urinary tract stone and vesical urgency after operation of the bladder or prostate

Clinical effect of LM-001, a prostaglandin synthetic inhibitor developed from a drug delivery system, was evaluated in 54 patients with pain from urinary tract stones (stone pain) and 32 with vesical urgency after an operation on bladder or prostate. LM-001, felbinac ethyl incorporated in lipid microsphere, wes intravenously administered at the onset of stone pain or vesical urgency. Of 54 with stones and 32 with urgency, 53 and 29 were eligible for response, respectively. The symptoms improved or disappeared in some cases just after the administration and in the majority of patients within 15 minutes, in 49 of 53 patients with stone pain. Further, the effectiveness lasted over 24 hours in 26 of the 49 responding to this agent. On one hand, improvement or disappearance of vesical urgency was recognized in 25 of 29 patients, and the effectiveness was observed shortly after injection in 16 and lasted over 24 hours in 13 cases. Toxicities of this drug were investigated in 54 patients with stone pain and 32 with urinary urgency. Side effects consisted of pain at the injection site in 4, a slight fall of blood pressure in 1, slight visual disturbance in 1, body heat sensation in 1, leukocytosis in 3 and elevation of alkaline phosphatase in 1. These symptoms were transient and disappeared without use of any agent. LM-001 is concluded to be a useful drug for controlling stone pain and vesical urgency since an immediate effect, long durability and high response rates were obtained without severe side     

Alcohol dependence syndrome and BDIM (before-discharge intervention method)--report 4, the family members' self-reports about BDIM]

One hundred fifty-three inpatients with alcohol dependence syndrome were treated with the structured BDIM (Before-Discharge Intervention Method). 82 patients of them have participated to self-help group meetings or kept having therapy as our outpatients or inpatients during the study period. We chose the families of the 82 patients as our study subject Out of the study subjects who took part in BDIM, 64 families (117 persons) answered our questionnaire. Among them 63 families (101 persons) gave their described answers of impressions and opinions about BDIM, which were summarized as follows. (1) Through BDIM the family members gained second thought on their alcoholic family member (IP: identified patient) and they could tell their new view to IP. BDIM enabled them to tell IP their sincere feeling and hope for recovery of IP. BDIM empowered both IP and IP's family members. (2) The family members became to know IP's orientation on his or her disease. They came to know IP's denial and understand him or her as he or she was. (3) The family members felt emotional ties among themselves and IP through BDIM. When the family members of a dysfunctional family took part together in BDIM, they could know the feelings, thoughts, experiences and hopes one another. The family members had a precious experience of mutual understanding among themselves and IP to hope for recovery together. (4) The family members appreciated BDIM as a effective therapy. In BDIM many of them regarded highly of giving their letters to IP as a useful method to convey their feeling and thoughts calmly to IP. (5) On the other hand some family members pointed out the difficulty for themselves to write on BDIM. For family members who are not good at writing a letter or tend only to blame IP through their letters, writing and giving letters to IP is not appropriate as a therapy. If family members feel strong anxiety or fear, it is safe not to practice BDIM.     

Clinical study of estramustine phosphate disodium (Estracyt) on prostatic cancer--results of long-term therapy for 38 patients with prostatic cancer

Estramustine phosphate disodium (Estracyt) was used in the treatment of 38 patients with prostatic carcinoma for at least 1 year. Of these patients 37 patients were treated with Estracyt as primary treatment and 1 patient had been treated with another antiandrogenic therapy before the Estracyt treatment. Estracyt was given orally in a dose of 560 mg/day in divided oral doses. The clinical evaluation was done for the change of PAP, the relapse rate, the survival rate and the side effect. Among 22 cases which had shown abnormally high PAP values before the treatment started, the values decreased or normalized in 21 cases (95.5%) in the first year of administration of Estracyt. In 6 cases, however, the values increased again in the second year or later. Relapse was observed in 10 (26.3%) out of 38 cases. Relapse rate was 2.6%, 51.7%, and 51.7%, at the first, third, and fifth year, respectively. Survival rate was 97.4% at the first year, 88.5% at the third year, and 68.8% at the fifth year for the follow-up study. Side effects were observed in 14 (36.8%) out of 38 cases. The main side effect was gynecomastia. Gastro-intestinal disturbance and edema were also observed. However, there were only 2 cases (5.2%) in which administration of Estracyt had to be discontinued.     

Pigmented squamous cell carcinoma of the uterine cervix.

A 57-year-old female presented with an abnormal Pap smear. Colposcopic examination of the cervix revealed white mucosa with erosion and several areas of black pigmentation. After a colposcopically directed biopsy and loop conization, radical hysterectomy and bilateral salpingo-oophorectomy with pelvic and paraaortic lymphadenectomy were performed. Pathological examination disclosed an invasive squamous cell carcinoma admixed with many dendritic melanocytes. Melanin granules were present within the melanocytes and tumor cells. Although similar tumors have been reported in other sites, this is the first report to our knowledge of a pigmented squamous cell carcinoma of the uterine cervix.     

Transrectal hyperthermia for benign prostatic hyperplasia]

Transrectal hyperthermia was performed on 30 patients with benign prostatic hyperplasia twice a week for a total of ten times with the temperature of the prostatic tissue set at 43.0 degrees C. In our in vitro experiment using an agar phantom, the highest temperature was observed at approx. 1.5 cm from the point where the 915-MHz microwave was generated. Our histopathological study of the prostatic tissue, resected at open surgery after three days of hyperthermia, indicated that the effect of hyperthermia first occurred in the interstitial tissues, and then extended to the epithelial cells. Subjective symptoms and objective findings were evaluated. In almost all cases, improvement was observed in subjective symptoms after completion of the treatment. The residual urine volume improved significantly. Also, significant improvement was observed in our urodynamics study. In 16 out of 30 cases (53%), both subjective symptoms and objective findings were still improved after six months.     

Lymphokine activated killer cells in murine coxsackievirus B3 myocarditis

The purpose of the present study was to determine whether lymphokine activated killer (LAK) cells were involved in the development of coxsackievirus B3 (CB3) myocarditis in both the acute viremic (Experiment I) and the subacute aviremic (Experiment II) stages. To induce LAK cells, recombinant human interleukin-2 (IL-2) was administered to CB3-infected mice subcutaneously daily, starting on day 0 in Experiment I and on day 7 in Experiment II for 7 days, respectively. The treated groups were compared to infected controls. Splenic lymphocytes of IL-2 treated mice were further cultured in vitro in IL-2 containing medium for 7 days, and LAK cell activity, i.e., cytotoxic activity of the lymphocytes against EL-4 tumor cells and against cultured fetal myocytes, was assayed by⁵¹Cr-release method. In Experiment I, histologic scores, myocardial virus titers, and LAK cell activity did not differ significantly between IL-2 treated and untreated groups. In contrast, in Experiment II, there were more cellular infiltration associated with severe necrosis and higher LAK cell activity against EL-4 cells and cultured myocytes in IL-2 treated than in untreated groups. The presence of LAK cells was demonstrated in the subacute stage of murine CB3 myocarditis. Thus, the behavior of LAK cell activity may vary with the course of myocarditis, and enhanced LAK cell activity may be involved in the development of the disease.This work was supported by research grants from the Conference on Coronary Artery Disease, Japanese Education of Science and Walfare (Nos. 08877110 and 09470164), Kanae Shinyaku Foundation, and Japan Cardiovascular Research Foundation.