Keiko Yamamura

Oral mucosal adhesive film containing local anesthetics: In vitro and clinical evaluation

In vitro and in vivo studies were conducted to gauge the effectiveness of a novel oral mucosa adhesive, moderately water-soluble, pliant polymer artificial dentifrice (AD) film containing dibucaine (DC) for relief of pain due to oral erosion. The film was prepared from a hydroxypropyl cellulose-M (HPC-M) ethanol solution containing varying amounts of DC, as well as polyethylene glycol. In the in vitro experiments, the disintegration of HPC-M showed a lag time of about 50 min, a much lower rate than that of drug release, which more or less leveled off after 50 min. Twenty-five percent of the DC was released from the film (0.113 and 0.225 mg/cm2) after the initial 5 min, which then reached about 80% after 50 min, the time at which the polymer began to break up. In the in vivo study, the local anesthetic effect of the film was evaluated in 23 patients (10 males, 13 females) suffering from the adverse effects of chemotherapy. When applied to the wet surface of the mucosa, the AD film absorbed moisture and showed excellent adhesion. Pain relief in patients lasted 2.2 +/- 0.21 and 4.3 +/- 0.25 h at DC doses of 0.113 and 0.225 mg/cm2, respectively. These results suggest that the AD film may cover mucositis sites of oral mucosa long enough to allow DC release and bring relief from pain arising from chemotherapy and/or radiotherapy.

Subcutaneous tissue distribution of vancomycin from a fibrin glue/Dacron graft carrier

We investigated the tissue distribution of vancomycin (VCM) incorporated in fibrin glue (FG) in a rat model. One VCM-loaded FG Dacron graft (VCM-FG, VCM 0.6 mg/ graft) was implanted in the subcutaneous tissue of the anterior abdominal wall of each rat. VCM was injected intravenously at an equal dose (0.6 mg/rat) after implantation of one control graft (without VCM-FG). After the implantation and the iv injection of an equal dose of VCM (0.6 mg/rat), the tissue distribution of VCM for up to 24 h was determined through analysis of the implanted VCM-FG grafts, which released VCM over a 24 h period. The area under the VCM concentration-time curve (AUC) of the tissue was 89.58 micrograms.h/g after the implantation of the VCM-FG graft, and 7.40 micrograms.h/g after the iv injection of VCM, respectively. The targeting index of the tissue, defined as the ratio of AUC after the implantation of the VCM-FG graft to that after VCM iv injection, was 12.11. None of the six VCM-FG Dacron grafts after implantation became infected following inoculation with S. aureus ATCC 25923 (0.1 mL 10(8) CFU/mL). These results suggest that this VCM-FG Dacron graft delivery may be useful in preventing local infection by enhancing the delivery of VCM to the local areas of the implanted site in rats.

Distribution and serum concentration of sisomicin released from fibrin glue-sealed dacron graft in the rat and human.

We investigated whether or not fibrin glue (FG) used as a sealant in vascular prostheses to prevent leakage might be useful as a carrier of antibiotics for the prevention of local graft infection. Sisomicin (SISO) was incorporated into fibrin glue (SISO-FG) and evaluated as to its safety and pharmacokinetics. SISO (1.75 mg) -FG Dacron grafts were implanted subcutaneously in the anterior abdominal region of Sprague-Dawley rats, and then the changes in SISO concentrations in the serum and in the tissue around the implantation sites were compared with those same sites in rats that had had intravenous injection of SISO (1.75 mg). The serum SISO concentrations were significantly lower in the SISO-FG Dacron graft group than they were in the intravenous injection group. However, until 4 h after implantation the SISO concentrations in the tissues around the implantation sites were significantly higher in the SISO-FG Dacron group than they were in the iv injection group, and the peak concentrations during that time were 5.8 times higher for the SISO-FG Dacron group than they were for the intravenous injection group. The ratio of the area under the tissue concentration time curve of SISO (AUC tissue) after implantation of the SISO-FG Dacron graft to that after intravenous injection of SISO was 13.08. Therefore, FG was considered to control the release of SISO into the serum and to maintain a high SISO concentration in the tissue around the implantation site. Clinically, SISO (45 mg) -FG was applied directly to the Dacron grafts implanted in 10 patients who underwent prosthetic vascular reconstruction. No graft infection was observed in any of the patients who received SISO-FG Dacron grafts. The mean serum concentration of SISO was 0.65+/-0.17 microg/mL after 1 h and 0.33+/- 0.21 microg/mL after 3 h. The results of these clinical applications are in close correlation with those of the animal experiment and suggest that FG is useful as a carrier of SISO, allowing its controlled release for the prevention of local infection.

Prophylaxis of Local Vascular Graft Infection with Levofloxacin Incorporated into Albumin-Sealed Dacron Graft (LVFX-ALB Graft)

An animal model was used to assess the efficacy of levofloxacin (LVFX) incorporated into albumin (ALB)‐sealed Dacron (LVFX‐ALB) graft for the prevention of vascular graft infections caused by Staphylococcus aureus. Under general anesthetic, an interposition graft was placed into dog carotid artery. On completion of the operation, 0.1 ml of normal saline containing 107 colony‐forming units (CFU) of a slime‐producing S. aureus was inoculated directly onto the graft. After 1 day, the samples were sterilely harvested. The antibacterial activity of LVFX into the LVFX‐ALB graft was evaluated by colony counting in bacterial cultures and by the fluorescent antibody method staining bacteria adhesion to the grafts. LVFX‐ALB grafts had a lower infection rate than the control grafts (1/4, 102 CFU vs 4/4, 1.50×105±1.38×105 CFU (mean±SE)). In an immunostaining study, LVFX‐ALB grafts had small fluorescent areas showing S. aureus adhesion, while fluorescence was observed over the entire surface of the control grafts. Therefore, LVFX‐ALB presumably had a bactericidal action and adhesive prevention against inoculated S. aureus. LVFX‐ALB may be useful in preventing graft infections during and immediately after vascular reconstruction.

Pain relief of oral ulcer by dibucaine-film.

A water-soluble three-layered oral mucosa-adhesive film made from hydroxypropyl cellulose containing dibucaine (0.25 mg of drug/cm(2)) was designed for alleviation of severe pain due to oral ulcers, caused by chemotherapy and/or radiotherapy. We report two patients with constant severe pain ulcers treated with the dibucaine film. Patients were asked to record the time that pain was relieved while chewing following first application of the film. Pain relief lasted for 2-5 h after application of the dibucaine film.

High-performance liquid chromatographic assay for prostaglandin E1 in various ointment vehicles. Separation and stability testing.

A high-performance liquid chromatographic method for the determination of prostaglandin E1 (PGE1) incorporated in white petrolatum, white ointment, hydrophilic petrolatum and Plastibase was investigated. The prostaglandin was separated from the oleaginous vehicles with n-hexane-aqueous acetonitrile. Most of white petrolatum, which is a principal component in the vehicles, remained in the n-hexane layer, and the recovery of the drug from any vehicle attained 100%. The method was applied to stability studies of PGE1 in white petrolatum and macrogol ointment. In which pure PGE1 and PGE1-alpha-cyclodextrin complex (PGE1-CD) were incorporated. The drug remained intact for up to 6 months when stored at 5 degrees C. At 25 and 40 degrees C, pure PGE1 was more stable than PGE1-CD and both PGE1 species were more stable in white petrolatum than in macrogol ointment.

Prevention of Vascular Graft Infection by Sisomicin Incorporated into Fibrin Glue

To examine the efficacy of sisomicin (SISO) incorporated into fibrin glue (FG) for the prevention of graft infection in animal models, the susceptibility to infection of Dacron grafts (control) and SISO‐FG Dacron grafts following the inoculation of Staphylococcus aureus or S. epidermidis was compared. The results showed that SISO‐FG Dacron grafts displayed resistance to graft infection.

effects on caregiver burden of a donepezil hydrochloride dosage increase to 10 mg/day in patients with Alzheimer's disease

Background In this study, we evaluated changes in functioning and caregiver burden in Alzheimer’s disease (AD) patients after a dosage increase that was made based on pharmacists’ evaluation of AD patients’ behavior in daily life. Methods Pharmacists used a checklist, a questionnaire, and the Repetitive Saliva Swallowing Test (RSST) to gather data on the daily life of AD patients taking donepezil 5 mg/day and their caregivers. In 27 cases, pharmacists suggested a dosage change to 10 mg/day to AD patients’ physicians. Pharmacists then evaluated these patients for 16 weeks after the increase to determine changes in functional assessment staging, caregiver burden, and swallowing function. Results During the 16-week study, 20 of the 27 patients showed at least one-stage improvement in relation to the five assessed aspects of daily life (time/place, speech, bathing, dressing, and toileting). The mean score for caregiver burden due to personal strain was significantly lower after the dosage increase than before (5.15±3.76 at baseline; from 3.89±3.42 at week 4 to 3.59±3.90 at week 16; P<0.05), as was the mean score due to role strain (2.19±2.80 at baseline; 1.56±2.64 at week 8; P<0.05). After the dosage increase, the impaired swallowing function that accompanies AD was improved in the patients with swallowing problems, as indicated by a higher mean RSST score (1.22±0.67 at baseline; from 2.78±1.72 at week 4 to 2.78±1.79 at week 16; P<0.05). Conclusion The dosage increase not only decreased caregiver burden, but also appeared to improve impaired swallowing function. Medication therapy management by pharmacists of AD patients, including the use of a checklist, contributed to the correct use of donepezil and improved quality of life for caregivers.

Iontophoretic Administration of Prostaglandin E1 in Peripheral Arterial Occlusive Disease

TO THE EDITOR: We present a case of successful treatment of peripheral arterial occlusive disease by iontophoretic delivery of prostaglandin E1 (PGE1). Iontophoresis is a means of enhancing the flux of ionic drugs across a biological membrane by the application of electrical potential gradient. Case Report. A 66-year-old man was referred to the Department of Vascular Surgery in June 2001 for treatment of an ischemic toe ulcer associated with claudication and severe rest pain. He had stage IV peripheral arterial occlusive disease as defined by Pentecost et al.1 The patient had a history of diabetes for 16 years and hypertension for 31 years. Diabetes was well controlled with insulin (glycosylated hemoglobin 6.1%) and hypertension was controlled with enalapril (average BP 130/75 mm Hg). He had received PGE1 intravenously at a dose of 20 μg twice a day for 101 days since admission. The dose is the standard fixed dose used in an adult for treatment of peripheral arterial occlusive disease. However, the toe ulcer and rest pain did not respond. On October 22, we started iontophoretic administration of PGE1 20 μg for 20 minutes with 2 mA twice a day close to the affected site. This treatment was continued until December 4, replacing intravenous PGE1 infusion. PGE1 was administered by a small portable iontophoretic device that delivers a pulsative voltage, which is less irritating to the skin. There were no systemic effects observed: HR and BP remained unchanged, and no local adverse effects were observed. There was considerable improvement in the pain at rest and reduction in the size of the ulcer after iontophoretical PGE1 treatment. The visual analog scale (0–10) for rest pain improved from 6 to 1. The maximum diameter of the ulcer was reduced from 9 to 2 mm. The patient was discharged on December 6 and is being followed, with aspirin and ticlopidine prescribed as oral antiplatelet drugs. Discussion. The treatment goals for patients with peripheral arterial occlusive disease are to relieve pain at rest and decrease complications (e.g., thrombogenesis, limb amputation, ischemic ulcers). PGE1, a potent vascular vasodilator, is known to improve impaired microcirculation in peripheral arterial occlusive disease. A recent study showed that PGE1 had positive effects on maximal treadmill walking distance and quality of life.2 When PGE1 is administered systematically, it rapidly loses twothirds of its potential activity by oxidation in the lung.3 However, higher dosages lead to substantial adverse reactions, such as headache, flushing, gastrointestinal intolerance, bradycardia, tachycardia, hypotension, hypertension, seizures, and respiratory distress. Therefore, there is considerable interest in the development of drug delivery systems that would allow high concentrations of PGE1 to be delivered directly to the site of ischemia. We previously reported the pharmacologic effects of iontophoretically applied PGE1 on peripheral microcirculation.4 This clinical case suggests that application of PGE1 iontophoresis may be useful in managing severely ischemic legs. Further discussion on the practical limitations associated with iontophoretic treatment (e.g., local irritation, portability and complexity of device, cost) for future potential uses is necessary. Tsunehisa Sakurai MD Clinical Specialist Department of Vascular Surgery School of Medicine Nagoya University Nagoya, Japan

High-performance liquid chromatographic assay of anti-inflammatory drugs incorporated in gel ointments Separation and stability testing

High-performance liquid chromatographic determinations of gabexate mesilate (FOY), prostaglandin E1 (PGE1), PGE1-alpha-cyclodextrin (PGE1-CD), prednisolone (PD) and butyl flufenamate (BF) incorporated in gel ointment were investigated. The gel ointment is composed of a carboxy vinyl polymer (1.3%, w/w) and a large amount of an aqueous organic solvent. A methanol extraction system offered simultaneous advantages of the removal of the polymer and the recovery of active ingredients from the gel phase. The recoveries of the drugs were 100%. The stabilities of PGE1, PGE1-CD, FOY, PD and BF incorporated in gel ointment, stored at 5, 25 and 40 degrees C for up to 90 days, were investigated.