Ribavirin dose reduction raises relapse rate dose-dependently in genotype 1 patients with hepatitis C responding to pegylated interferon alpha-2b plus ribavirin.

The impact of ribavirin exposure on virologic relapse remains controversial in combination therapy with pegylated interferon (Peg-IFN) and ribavirin for patients with chronic hepatitis C (CH-C) genotype 1. The present study was conducted to investigate this. Nine hundred and eighty-four patients with CH-C genotype 1 were enrolled. The drug exposure of each medication was calculated by averaging the dose actually taken. For the 472 patients who were HCV RNA negative at week 24 and week 48, multivariate logistic regression analysis showed that the degree of fibrosis (P = 0.002), the timing of HCV RNA negativiation (P < 0.001) and the mean doses of ribavirin (P < 0.001) were significantly associated with relapse, but those of Peg-IFN were not. Stepwise reduction of the ribavirin dose was associated with a stepwise increase in relapse rate from 11% to 60%. For patients with complete early virologic response (c-EVR) defined as HCV RNA negativity at week 12, only 4% relapse was found in patients given > or = 12 mg/kg/day of ribavirin and ribavirin exposure affected the relapse even after treatment week 12, while Peg-IFN could be reduced to 0.6 microg/kg/week after week 12 without the increase of relapse rate. Ribavirin showed dose-dependent correlation with the relapse. Maintaining as high a ribavirin dose as possible (> or = 12 mg/kg/day) during the full treatment period can lead to suppression of the relapse in HCV genotype 1 patients responding to Peg-IFN alpha-2b plus ribavirin, especially in c-EVR patients.

Premedication with cyclooxygenase-2 inhibitor meloxicam reduced postoperative pain in patients after oral surgery.

The efficacy of the selective cyclooxygenase-2 (COX-2) inhibitor meloxicam for treatment of postoperative oral surgical pain was assessed in a randomized controlled trial. Patients undergoing unilateral mandibular 3rd molar extraction surgery were allocated to 3 groups, A, B and C. After oral premedication of meloxicam 10 mg in group A, ampiroxicam 27 mg in group B and placebo in group C, surgery was completed within 30 min under local anaesthesia using 2% lidocaine. For postoperative pain relief the patients were allowed to take oral loxoprofen (60 mg per tablet). Postoperative pain was evaluated at the clinic on the 1st, 7th and 14th postoperative day (POD) using a visual analogue scale (VAS), as was the number of loxoprofen tablets consumed, and the results were compared among the 3 groups with statistical significance of P<0.05. VAS scores on 1 POD were significantly lower in group A than in group C. Loxoprofen consumption on the day of surgery and 1 POD was significantly lower in group A than in group C (P<0.01). Total analgesic consumption was significantly lower in groups A and B than in group C (P<0.02). The COX-2 inhibitor, meloxicam 10 mg used for premedication reduced postoperative pain compared with control in oral surgery.

Direct measurement of eustachian tube compliance.

We developed a method by which tubal compliance can be directly measured, and using this method we examined tubal compliance in 18 adults with a disease-free ear and 8 adults with chronic otitis media. This method is advantageous in that one can directly measure tubal compliance in the cartilaginous part of the eustachian tube. It is our view that each eustachian tube has its own compliance which is not influenced by mucosal swelling or muscle tension around the tube.

[Penetration of clarithromycin to saliva and its effect on normal salivary bacterial flora].

Clarithromycin (TE-031, A-56268), a new macrolide antibiotic, was administered to rats, and the distribution of the drug in the submandibular gland was studied using microautoradiography. The study revealed good accumulation of 14C-TE-031 in both the acini and the excretory ducts. TE-031 was administered to each of 3 healthy male volunteers in a single dose of 300 mg, and its concentrations in the serum and saliva was detected. Mean values of various pharmacokinetic parameters were as follows for the serum and saliva, respectively. Cmax 1.49 micrograms/ml and 1.93 micrograms/ml; Tmax 2.91 hours and 2.66 hours; T 1/2 6.31 hours and 4.15 hours; AUC 18.58 micrograms.hr/ml and 17.70 micrograms.hr/ml. Regarding the salivary bacterial flora, the total bacterial count decreased as the salivary TE-031 concentration increased, but it recovered to the initial level in 12 hours after administration. During the 24-hour period following an administration of TE-031, the salivary bacteria did not acquire resistance to the drug. Therefore, TE-031 is an antibiotic which exerts little effect on the normal salivary bacterial flora in short-term administration. Although the results differed among the individuals, the penetration of TE-031 to saliva was superior to that to the serum. Thus, TDM of TE-031 using salivary samples is possible.

[Clinical evaluation of roxithromycin in odontogenic infection].

The clinical effectiveness and safety of roxithromycin (RU 28965, RU), a new macrolide antibiotic, were compared with those of josamycin (JM) using a double-blind method in the treatment of orofacial odontogenic infections. The diseases covered in this study were periodontal infections, pericoronal infections and osteitis of jaws. Drugs were administered for 3 to 7 days at daily doses of 300 mg (RU) and 1,200 mg (JM). A total of 270 cases was evaluated in this study. Results obtained are summarized as follows: 1. The clinical efficacy was evaluated through the judgement of doctors in charge of 247 cases (128 in the RU group and 119 in the JM group) and by a committee on the 3rd day of treatment in 243 cases (126 in the RU group and 117 in the JM group). Clinical efficacy rates according to the committee judgement were 78.6% for the RU group and 82.1% for the JM group. As for the evaluation through the doctors' judgement, they were 79.7% for the RU group and 73.1% for the JM group. There was no significant difference in clinical effectiveness between 2 groups according to these 2 methods of judgement. 2. Some side effects were observed in 4 cases (2.9% out of 136) treated with RU and in 3 cases (2.4% out of 126) treated with JM. No severe symptoms were observed. Abnormal changes in laboratory test values were noted among 7.9% in the RU group and 4.0% in the JM group. There were no significant differences in their safety between the 2 groups. 3. In terms of clinical usefulness, there were no significant differences between the 2 groups as well. From these results, it has been concluded that RU (daily dose 300 mg) is as effective as JM (daily dose 1,200 mg) in the treatment of orofacial odontogenic infections.

[Clinical evaluation of the TMS-19-Q.GC tablet in odontogenic infections. A comparative double-blind study with josamycin].

Clinical efficacy and safety of TMS-19-Q.GC tablet (TMS), a new macrolide antibiotic preparation, were compared with those of josamycin (JM) in the treatment of acute odontogenic infection under multicentered double-blind controlled study at the daily dosage of 600 mg of TMS or 1,200 mg of JM. The results obtained were as follows: The patients entered into the study were 265 cases and 112 in TMS group and 111 in JM group were adopted to evaluate for the efficacy. The evaluation was made by 2 ways i.e. changes in total clinical scores of the symptom and the doctors assessment. Efficacy rating of TMS and JM were 81.3 and 82.0% judged by the score and 73.2 and 77.5% judged by doctors in charge respectively. In the cases with 15 to 20 of total scores at the initial visit, considered to be suitable for the evaluation of antibiotics, the efficacy rating of both drugs were 86.7% in TMS and 84.6% in JM. Organisms were isolated from 34 cases in TMS and 40 in JM and the clinical effectiveness in those cases were almost the same. Slight adverse reactions were observed in 6 cases (4.6%) of TMS group and 1 (0.8%) of JM. In 3 cases (4 incidences) of TMS group and 1 of JM slightly abnormal laboratory findings were found. On the statistical analysis of the data regarding efficacy, safety and usefulness, both drugs had no significant difference. From these results, TMS was considered as effective as JM in the treatment of acute odontogenic infection at a daily half doses of JM.

[Clinical evaluation of cefuroxime axetil in acute dental infections. Double blind comparative study vs. cefaclor].

To evaluate objectively clinical efficacy, safety and usefulness of cefuroxime axetil (CXM-AX) in acute dental infections (periodontitis, pericoronitis and gnathitis), we carried out a comparison study using cefaclor (CCL) as the control. Both drugs were orally given after meals in a dose level of 250 mg (potency) t.i.d. for 3-7 days. 1. Clinical efficacy rates in all the treated cases were 81.6% (102/125) in the CXM-AX group and 82.5% (104/126) in the CCL group according to the assessment by physicians in charge, and 89.6% (112/125) and 83.3% (105/126), respectively, according to the assessment based on scores. No significant difference was found between the 2 treatment groups. In clinical efficacy (assessment by score) classified by background factors, efficacy rate in the CXM-AX group (90.6%, 58/64) was significantly higher (P less than 0.05) than that in the CCL group (75.0%, 48/64) in cases receiving no surgical treatment on the first day of drug administration. Other background factors than the above (no surgical treatment) factor or scores on the first day of drug administration, however, did not appear to influence clinical efficacies of 2 treatment groups. 2. As for the bacteriological response in all the treated cases, elimination rate in the CXM-AX group was 73.7% (28/38) and that in the CCL group, 78.3% (36/46), without significant difference between the 2 groups. 3. Regarding the safety, no significant difference was found between the 2 treatment groups. Adverse reactions were observed in 1 out of 128 cases (0.8%) in the CXM-AX group and 6 out of 132 cases (4.5%) in the CCL group. Abnormal laboratory test values were noted in 8 out of 86 cases (9.3%) in the CXM-AX group and 5 out of 91 cases (5.5%) in the CCL group. None of these differences between 2 treatment groups was statistically significant. 4. Usefulness rates in all the treated cases were 81.6% (102/125) in the CXM-AX group and 81.7% (103/126) in the CCL group, thus significant difference was observed between the 2 groups. From the above results, CXM-AX is considered to be a useful drug like CCL in the treatment of acute dental infections.

[Comparative clinical study of azithromycin with tosufloxacin tosilate in the treatment of acute odontogenic infection].

To objectively assess azithromycin (AZM) for its clinical efficacy, safety and usefulness in the treatment of acute odontogenic infections (periodontitis, pericoronitis and osteitis of the jaw), a double-blind, randomized, multi-center trial was conducted in which tosufloxacin tosilate (TFLX) was used as the control drug. AZM was administered to 90 patients at a once-daily 500 mg dose for 3 days, while TFLX was given to 90 patients at a 150 mg t.i.d. dose for 7 days. 1. The clinical efficacy rates calculated according to evaluation at an endpoint set on the 3rd day of treatment by a committee of experts were 85.9% (73/85) in the AZM group and 78.9% (71/90) in the TFLX group. No statistically significant difference between the treatment groups was detected, and clinical equivalence was verified (p = 0.002). 2. The clinical efficacy rates according to evaluations made by investigators at the end-of-tail point was 87.1% (74/85) in the AZM group and 73.3% (66/90) in the TFLX group. The efficacy rate in the AZM group was higher than that in the TFLX group, and the difference was statistically significant (p = 0.006). 3. The bacteriological elimination rate in the AZM group was 97.5% (39/40) and that in the TFLX group was 85.7% (30/35), but the difference was deemed statistically not significant. 4. Adverse reactions were observed in 11 of 88 cases (12.5%) in the AZM group and 5 of 90 cases (5.6%) in the TFLX group. Six of 85 cases (7.1%) in the AZM group and 5 of 85 cases (5.9%) in the TFLX group showed laboratory abnormalities. However, neither adverse reactions nor laboratory abnormalities showed any differences in statistical significance between the treatment groups. 5. The safety rates, expressed as percentages of cases with no adverse events and no laboratory abnormalities, was 84.1% (74/88) in the AZM group and 90.0% (81/90) in the TFLX group. The difference between the two groups was found to be statistically insignificant. 6. The usefulness rates, the ratio of cases rated as either "Very useful" or "Useful", was 83.9% (73/87) in the AZM group, and it was statistically higher (p = 0.025) than 72.2% (65/90) obtained for TFLX group. Judging from the above results, it has been concluded that AZM is as useful as TFLX in the treatment of acute dental infections.

Comparison of in vitro activity of azithromycin and ampicillin against 31 isolates of Streptococcus milleri.

Antibacterial action of azithromycin against 31 strains of dental infection-derived Streptococcus milleri and tissue transfer of the agent were compared with ampicillin, the drug of first choice for dental infections. Concentrations required to inhibit 50% of isolates(MIC50) and Concentrations required to kill 50% of isolates(MBC50) were 0.10 and 0.2 microgram/ml, respectively, for azithromycin. The antibacterial action of azithromycin was 4 times more potent in than ampicillin. The MBC90 for azithromycin was 0.39 microgram/ml, for amplicill 3.13 micrograms/ml. Bactericidally, azithromycin was 8 times more active than ampicillin. The peak value of concentrations (Cmax) of azithromycin was 0.45 microgram/ml, about 1/10 that of ampicillin. The half-life of azithromycin was 10 hours, about 5 times longer than that of ampicillin. The contact time of MIC90 concentrations for azithromycin was 12 hours, distinctly longer than the 8 hours calculated for ampicillin. Azithromycin showed excellent tissue transfer concentrations: the gingival transfer concentration following oral administration of 500 mg/day ranged from 0.7-23.5 micrograms/ml.

Intravenous administration of vancomycin is ineffective against bacteremia following tooth extraction.

The incidence of transient bacteremia after tooth extraction without antimicrobial prophylaxis has been reported was high as 69.2%; that with intravenous ampicillin as 4.2% (1, 2). Currently, we tested a regime of vancomycin that was recommended by the American Heart Association as prophylaxis for oral surgery patients who were allergic to penicillin and evaluated its effectiveness. Before the surgical procedures, we started an intravenous drip infusion of vancomycin. Ten of 26 patients became blood culture positive (38.5%). Seventeen strains of bacteria were isolated. The Minimum Inhibitory Concentrations (MICs) of vancomycin were lower than 3.13 micrograms/ml, with just one exception.

In vivo experimental model of human gingival mucosa using immunodeficient mice.

BACKGROUND AND OBJECTIVE: To establish an in vivo experimental model for examining human periodontal tissue, the present study examined several transplant techniques that maintain the structure and characteristics of human gingival mucosa. MATERIAL AND METHODS: Human oral mucosal tissue samples were collected from the gingiva (n = 11), palate (n = 1), and tongue (n = 3). These mucosal grafts were transplanted onto BALB/c nu/scid mice with double-mutant immunodeficiency. Murine skin, twice the size of the graft, was cut open in an ' square superset'-shape. Next, the connective tissue side of the graft was placed onto the murine connective tissue. Immunohistochemical analysis was also performed, using polyclonal rabbit antibody to involucrin, monoclonal antibody to vimentin, monoclonal antibody to CD34, and monoclonal antibody to Ki-67, to determine whether the characteristics of human oral mucosa were maintained. RESULTS: When the connective tissue side of the graft was placed on the murine fascial membrane, the histological structure of the graft was maintained for 60 d. These grafts were examined for human characteristics using human-specific antibodies. Immunohistochemically, the expression patterns of involucrin, vimentin, and Ki-67 indicated that transplanted mucosa revealed normal human characteristics, including differentiation and proliferation up to 80 d. CD34 was not detected in the graft endothelial cells. CONCLUSION: The present study revealed that the novel technique of transplantation of human gingival mucosa in nu/scid mice may serve as an in vivo experimental model of periodontal disease.

Comparison of gyrA and parC mutations and resistance levels among fluoroquinolone-resistant isolates and laboratory-derived mutants of oral streptococci.

Laboratory-derived fluoroquinolone-resistant mutants were obtained by serial passage of Streptococcus sanguis and Streptococcus anginosus isolates on agar containing increasing concentrations of old and new fluoroquinolones, ofloxacin and DU-6859a, respectively. Sequencing of an S. sanguis isolate exposed to DU-6859a showed that resistance was associated with two mutations in the quinolone resistance determining region (QRDR) of the gyrA gene (Ser83-->Phe; Glu87-->Lys), and with a mutation in the parC gene (Ser79-->Ile). However, different mutations in the gyrA gene (Ser83-->Tyr) and parC gene (Ser79-->Phe) were found in a S. sanguis isolate exposed to ofloxacin. A fluoroquinolone-resistant isolate, QR-95101, from a dental infection, had a single mutation in the gyrA gene (Ser83-->Phe) and in the parC gene (Ser79-->Phe). Two fluoroquinolone-resistant mutants, QS-701OFm and QS-701DUm, were obtained from S. anginosus QS-701, by exposure to ofloxacin and DU-6859a, respectively. These mutants showed a common substitution at codon 83 (Ser-->Phe) in the gyrA gene but had different substitutions at codon 87 (QS-701OFm, Glu-->Gln; QS-701DUm, Glu-->Lys). They also had different substitutions at codons 79 and 135 in the parC gene (QS-701OFm, Ser79-->Leu but no change at Glu135; QS-701DUm, Ser79-->Ile and Glu135-->Gln). The resistance levels of the DU-6859a-selected resistant S. sanguis mutant QS-951DUm to DU-6859a, ofloxacin, ciprofloxacin and norfloxacin were higher than those of the ofloxacin-selected resistant mutant QS-951OFm. However, ampicillin susceptibilities of these mutants were not different from the parental strains. In S. anginosus, the DU-6859a-selected fluoroquinolone-resistant mutant QS-701DUm was resistant to all the fluoroquinolones tested, while the ofloxacin-selected mutant QS-701OFm was resistant to three fluoroquinolones, but not DU-6859a. The results indicate that different fluoroquinolones select distinct mutations in the QRDR of the gyrA and parC genes in oral streptococci. The gyrA or parC mutation in oral streptococci may determine the levels of fluoroquinolone resistance.

Studies of the development of optical fiber sensors for biochemical analysis.

An optical fiber sensor utilizing Thymol blue and an ion-exchange resin complex in a cellulose acetate membrane was developed. By monitoring several different chromophores of Thymol blue, the sensor could measure the pH of the solution from 1.0 to 12.0 with good reproducibility. An optical fiber glucose sensor utilizing a cellulose acetate membrane containing glucose oxidase, 2,7-diaminofluorene dihydrochloride, and sodium N-(3-sulfopropyl)-3,3',5,5'-tetramethylbenzidine was developed. Reflectance changes at 580 nm were large enough to trace changes in glucose concentration in physiological saline solution.

Hydroxyapatite-reactive salivary protein revealed by iso-electrofocusing electrophoresis.

Salivary protein involvement in the formation of acquired enamel pellicle, so far, has been discussed in terms of hydroxyapatite (HA)-reactive salivary proteins only from the parotid gland. This study was undertaken to seek this type of protein in the human whole (mixed) saliva and to investigate its normal and pathological variations. Several kinds of hydroxyapatite, either biogenous or synthesized by solid phase reaction, were used as a powder (250 mesh). HA was incubated with concentrated whole saliva at 25 degrees for 30 min. After centrifugation and filtration salivary proteins were analysed on a Multiphor isoelectrofocusing gel electrophoresis. The control salivary proteins were separated into three major groups; acidic (A1-A8), neutral neutral (N1-N4), and basic (B1-B3) isoelectric point (pI). In the HA incubated sample, one of the major neutral bands (NI) preferentially disappeared at about pI 7.5. This NI band was missing or scarce in the parotid saliva and had an amino acid composition rich in glycine, lysine, serine, glutamic acid, aspartic acid, and histidine. This protein was considered to be one of the major HA-reactive proteins in human whole saliva.