Mitsuru Furukawa’s research while affiliated with Kanazawa University and other places

Fundamental and clinical evaluations of the safety and effectivity of FMOX in treating diseases caused by bacterial infections concerning the otorhinolaryngological field were done, and the following results were obtained. 1. FMOX was effective against S. aureus, S. pyogenes, Klebsiella sp., H. influenzae, B. catarrhalis, Anaerobic streptococci and Peptostreptococcus sp. isolated from patients with Various types of otorhinolaryngological infections, most notably, suppurative otitis media. The following data correspond to the MIC of FMOX for each of the above bacteria:≤6.25μg/ml, ≤0.78μg/ml, ≤0.39μg/ml, ≤0.78μg/ml, ≤0.78μg/ml, ≤1.56μg/ ml and≤0.78μg/ml, respectiVely. For S. aureus, FMOX had a far greater antibacterial effect than CTM or LMOX. 2. The maximum concentration in tissue (Cmax) of 1g FMOX administered intravenously, was 25.6μg/g in the middle ear and 11.1μg/ml in the tonsils. 3. The percent efficiency of FMOX was measured against a standardized evaluation. FMOX was 56.9% effective against otitis media, 93.4% effective against tonsillitis, 100% effective against pharyngitis and laryngitis, and 75.2% effective against all infections. Physicians evaluated FMOX to have an efficacy of 79.7% against all infections. 4. The rate of bacterial disappearance was high: in infections of Gram-positive bacteria alone, 89.8%, and 75.0% in infections of Gram-negative bacteria alone. FMOX was also rated high at dealing with complex bacterial infections, including those with S. aureus. 5. The percent utility of FMOX was 62.1% against otitis media, 96.7% against tonsillitis, 64.7% against other infections, and 76.5% against all infections. 6. Mild side effects were noted in 5 patients (2.8%: gastrointestinal symptoms and hypersensitivity of the skin). Laboratory examinations uncovered abnormal findings primarily suggesting mild hepatic and renal dysfunction in 7 patients (6.2%), but these Were all temporary. From these results, FMOX is considered to be highly useful for the treatment of otorhinolaryngological infections, most notably suppurative otitis media.

Flomoxef (FMOX) was examined for its efficacy and safety in treating paranasal sinusitis by clinical studies and laboratory examination of its tissue concentration and antibacterial potency. 1. The Cmax of 1g of FMOX after an intravenous injection were 55.8μg/g, 57.6μg/g and 8.0μg/ ml in the maxillary sinus mucosa, nasal polyp, and maxillary sinus secretion, respectively. The T1/2 of the serum concentration was at 1.49 hours. 2. The MIC80 of FMOX against Gram-positive and Gram-negative bacteria isolated from patients with sinusitis were 0.39μg/ml and 1.56μg/ml, respectively. 3. The treatment was considered effective by the attending physicians in 88.9% of those patients with acute exacerbation of chronic sinusitis, in 41.7% of those with chronic sinusitis, and in 74.5% of all patients. 4. In a standardized evaluation, the clinical efficacy rate of FMOX was judged to be 88.9% against acute sinusitis, 88.2% against acute exacerbation of chronic sinusitis, 41.7% against chronic sinusitis, and 76.6% against all patients. 5. The rates of bacterial disappearance when using FMOX against the different types of bacteria encountered were as follows: 79.2% for Gram-positive bacteria, 89.5% for Gram-negative, and 100% for anaerobic bacteria. The overall disappearance rate for all types of bacteria was 84.7%. 6. Side effects were noted in two of the 56 patients. One reported discomfort in the lower abdomen, and the other, a strange feeling in the mouth. These side effects were minor, which the patients could tolerate, and treatment was continued. No abnormal value was observed in laboratory findings. 7. FMOX was judged to be effective in treating acute sinusitis by 83.3% of the physicians, for acute exacerbation of chronic sinusitis by 82.4%, for chronic sinusitis by 33.3% and against all sinusitis cases, by 70.2%. From these results, FMOX is considered to be highly useful for the treatment of paranasal sinusitis.

The aim of this study was to assess whether migration of thallium-201 (Tl) to the olfactory bulb were reduced in patients with olfactory impairments in comparison to healthy volunteers after nasal administration of Tl. 10 healthy volunteers and 21 patients enrolled in the study (19 males and 12 females; 26-71 years old). The causes of olfactory dysfunction in the patients were head trauma (n = 7), upper respiratory tract infection (n = 7), and chronic rhinosinusitis (n = 7). TlCl was administered unilaterally to the olfactory cleft, and SPECT-CT was conducted 24 h later. Separate MRI images were merged with the SPECT images. Tl olfactory migration was also correlated with the volume of the olfactory bulb determined from MRI images, as well as with odor recognition thresholds measured by using T&T olfactometry. Nasal Tl migration to the olfactory bulb was significantly lower in the olfactory-impaired patients than in healthy volunteers. The migration of Tl to the olfactory bulb was significantly correlated with odor recognition thresholds obtained with T&T olfactometry and correlated with the volume of the olfactory bulb determined from MRI images when all subjects were included. Assessment of the Tl migration to the olfactory bulb was the new method for the evaluation of the olfactory nerve connectivity in patients with impaired olfaction.

Nasal administration of thallium-201 ((201)Tl) has previously been shown to be useful for the assessment of olfactory nerve connectivity in vivo. We assessed the biological effects of nasal (201)Tl administration in mice to determine its safety before conducting clinical trials on humans. (201)Tl uptake was evaluated in normal mice (n = 5) in vivo by using a high-resolution gamma camera and radiography 15 min, 1, 2 and 9 d after administration of (201)TlCl to the right side of the nasal cavity (10 µl (201)TlCl per nostril, 74 MBq/ml). Murine olfactory epithelial thickness (n = 5) was measured 9 d following nasal administration of (201)TlCl. We assessed the odor detection ability of normal mice (n = 8) following nasal administration of (201)TlCl to both sides of the nasal cavity, by observing cycloheximide solution avoidance behavior. We subsequently administrated (201)TlCl (n = 4) or saline (n = 4) to both nostrils to assess the odor detection ability of mice following bilateral olfactory nerve transection. (201)Tl uptake by the nasal cavity decreased immediately following nasal administration of (201)Tl in normal mice. Nasal administration of (201)Tl did not affect the olfactory epithelial thickness or the odor detection ability of normal mice. Recovery of odor detection ability following olfactory nerve transection was not significantly different between mice nasally administered with (201)Tl, and mice administered with saline. Thus, nasal administration of (201)Tl for the diagnosis of traumatic olfactory impairment did not produce harmful biological effects in vivo.

Epstein-Barr Virus (EBV)-associated nasopharyngeal carcinoma (NPC) is distinctive among head-and-neck cancers in its undifferentiated histopathology and highly metastatic character. We have recently investigated the involvement of epithelial-mesenchymal transition (EMT) in NPC. In a previous study, we found a close association of expression of LMP1, the principal EBV oncoprotein, with expression of Twist and induction of EMT. We analysed expression of Snail in 41 NPC tissues by immunohistochemistry. The role of Twist as well as Snail in EMT of NPC was investigated by using NP69SV40T human nasopharyngeal cells. In NPC tissues, overexpression of Snail is associated with expression of LMP1 in carcinomatous cells. In addition, expression of Snail positively correlated with metastasis and independently correlated inversely with expression of E-cadherin. Expression of Twist had no association with expression of E-cadherin. Further, in a human nasopharyngeal cell line, LMP1 induces EMT and its associated cellular motility and invasiveness. Expression of Snail is induced by LMP1 in these cells, and small hairpin RNA (shRNA) to Snail reversed the cellular changes. By contrast, Twist did not produce EMT in these nasopharyngeal cells. This study strengthens the association of EMT with the metastatic behaviour of NPC. These results suggest that induction of Snail by the EBV oncoprotein LMP1 has a pivotal role in EMT in NPC.

The aim of this study was to visualize the human olfactory transport pathway to the brain by performing imaging after nasal thallium-201 ((201)Tl) administration. Healthy volunteers were enrolled in this study after giving informed consent (five males, 35-51 years old). The subjects were nasally administered (201)TlCl into either the olfactory cleft. Twenty-four hours later, uptake of (201)Tl was detected by a single photon emission computed tomography (SPECT)/X-ray computed tomography hybrid system. For each subject, an MRI image was obtained and merged with the SPECT image. The peak of the (201)Tl uptake entered into the olfactory bulb in the anterior skull base through the cribriform lamina 24 h after nasal administration of (201)Tl. No participant had olfactory disturbance after treatment. Nasal (201)Tl administration was safely used to assess the direct pathway to the brain via the nose in healthy volunteers with normal olfactory threshold.

To image olfactory nerve regeneration in vivo using a high-resolution gamma cam- era and radiography after nasal administration of thallium-201 (olfacto-scintigraphy). Six Wistar rats were trained to avoid the smell of cycloheximide as a test of olfactory function. The olfactory nerve fibers of 3 rats were then carefully transected bilaterally with a Teflon knife, avoiding damage to the olfactory bulbs. The remaining 3 rats underwent sham operations and were used as controls. Steel wires were implanted in the left olfactory bulb of each rat for locating the bulbs with plain X-rays. The rats were assessed 2, 14, 28, and 42 d after the olfactory nerve transection or sham operation for their ability to detect odours and for transport of 201Tl to the olfactory bulb area 8 h after nasal administration of 201Tl. Both transport of 201Tl to the olfactory bulb area (p < 0.04) and ability to detect odours (p < 0.04) significantly increased with a time course after olfactory nerve transection. 201Tl transport to the olfactory bulb may be useful to visually assess olfactory ability in vivo. We plan to test olfacto-scintigraphy clinically by nasal administration of 201Tl in patients with posttraumatic olfactory loss.

The common carotid artery (CCA) usually divides into the internal carotid artery (ICA) and the external carotid artery (ECA). We present an extremely rare case of a non-bifurcating carotid artery through which intra-arterial chemotherapy for laryngeal cancer was administered. The CCA angiogram, as well as ultrasonographic evaluation of the carotid arteries, demonstrated a non-bifurcating CCA that subsequently constituted the ICA. Furthermore, several branches normally given off by the ECA arose directly from the single carotid artery. Superselective intra-arterial infusion of cis-diamminedichloroplatinum (II) (CDDP) was subsequently performed.

We report the first case of three delayed complications following irradiation for laryngeal carcinoma: bilateral vocal cord immobility, obstruction of esophagus and spontaneously ruptured pseudoaneurysm of common carotid artery. Medial fixation of bilateral vocal cords and stenosis of cervical esophagus were noted at 28 years after radiotherapy. Spontaneous rupture of a pseudoaneurysm bulging into the hypopharynx and obstruction of the esophagus occurred at 35 years after irradiation. The life-threatening hemorrhage was successfully treated by microcoil embolization of the common carotid artery. The relationship between these complications and irradiation is also discussed.

The curry odorant of the odor stick identification test for Japanese (OSIT-J) is useful in screening for olfactory impairment in Japanese subjects. The present study was designed to determine the most useful odorant of the OSIT-J in screening for olfactory impairment in Japanese subjects. We studied olfactory impairment screening with the OSIT-J in 83 participants (49 male, 34 female; average age 50 years) in an executive check-up at NTT West Kanazawa Hospital. Olfactory discrimination acuity was evaluated with three odorants of the OSIT-J (rose, curry, and sweaty-smelling clothes), each known to be significantly correlated with the assessment of the Japanese standard olfaction test (T&T olfactometer). Those participants who did not score full marks in tests with the three odors were assessed with another nine odorants of the OSIT-J. The positive predictive value was 100% in the screening with the curry odorant. In 38 participants who did not identify all three odors correctly, the identification of the curry odor was significantly correlated with the scores for all 12 odors (p<0.005). Identification of the curry odor was not significantly correlated with identification of the menthol odor of OSIT-J.