Evaluation of the pharmacokinetic parameters of standard oral antibiotics in a bioequivalence study of generic products.

Pharmacokinetic parameters were summarized in clinical bioequivalence studies in Japan to confirm the validity for the use of parameters obtained from the clinical studies. Pharmacokinetic parameters, including maximum plasma/serum concentrations (Cmax), area under the plasma/serum drug concentration-time curve (AUC), time to achieve Cmax (Tmax), and half life (t1/2), of the standard products (original drugs) after oral administration of antimicrobials, including respiratory quinolones, cephalosporins, macrolides, and penicillin-based antibiotics were investigated by use of interview forms and/or package inserts from the generic products and the relationship among the pharmacokinetic parameters such as Cmax, AUC, Tmax, and t1/2 were estimated. In all the studies, the standard and generic products were administrated orally to healthy fasting subjects. Although there was more than a 1.5-fold difference in the Cmax and AUC0-24 h, but not in the Tmax and t1/2 values for levofloxacin tablets and cefacrol tablets, these parameters for other antibiotics were similar in various studies. The obtained results suggested that the parameters obtained from recent bioequivalence studies would be useful in identifying pharmacokinetic behavior of the original drugs, especially early time release; however, the pharmacokinetic results obtained from the recently conducted bioequivalence studies may be superior to those obtained from studies conducted in the past.

Behavioral evidence for modulation by sigma ligands of (+)MK-801-induced hyperlocomotion in monoamine-depleted mice.

The selective non-competitive N-methyl-D-aspartate (NMDA) antagonist (+)-5-methyl-10, 11-dihydro-5H-dibenzo(a, d)cyclohepten-5,10-imine maleate ((+)MK-801) led to a dose-dependent increase in locomotor activity in mice pretreated with a combination of reserpine and alpha-methyl-para-tyrosine (alpha-MT). A selective and potent sigma receptor "antagonist" NE-100 (N, N-dipropyl-2- [4-methoxy-3-(2-phenylethoxy)-phenyl]-ethylamine monohydrochloride), which did not per se affect spontaneous locomotor activity, did not prevent the locomotor stimulatory effects of (+)MK-801. Sulpiride, a dopamine D2 receptor antagonist, and clozapine, a dopamine D4 receptor antagonist, which decreased spontaneous locomotor activity, did not prevent the locomotor stimulatory effects of (+)MK-801. The sigma receptor "agonists" (+)N-allynormetazocine [(+)SKF10,047], (+)pentazocine and (+)-3-(3-hydroxyphenyl)-N-(1-propyl) piperidine [(+)3-PPP], which did not per se affect spontaneous locomotor activity, did dose-dependently enhance the hyperlocomotion induced by (+)MK-801. The enhancement of (+)MK-801-induced the hyperlocomotion by (+)SKF10,047, (+)pentazocine and (+)3-PPP was completely blocked by NE-100. The enhancement of (+)MK-801-induced hyperlocomotion by (+)pentazocine was not affected by treatment with sulpiride and clozapine. As sigma ligands can markedly attenuate NMDA antagonist-induced behavior, the major physiological role of sigma receptors in vivo might be to modulate functions of the NMDA receptor ion channel complex.

Microsatellite mapping of a susceptible locus within the HLA region for Behçet's disease using Jordanian patients.

Behçet's disease (BD) has been established to be associated with HLA-B51. However, it has not been revealed whether the HLA-B51 gene itself or another gene located near the HLA-B gene is directly involved in the pathogenesis of BD. Previously, using Japanese BD patients, our group has narrowed down a BD-causative gene to 46 kb between the MICA and HLA-B genes by means of fine mapping analysis with eight microsatellite markers distributed within a 1100 kb segment around the HLA-B gene. To know whether this mapping result is generally observed in BD of another population we have investigated repeat polymorphisms of the same microsatellite markers in Jordanian BD patients. Furthermore, we have evaluated these data by Mantel-Haenzel stratified analysis to find out a primarily associated locus for BD. As a result, HLA-B51 was found to be the most strongly and primarily associated marker. This result suggests that the pathogenic gene of BD is HLA-B51 itself, but unlikely to be other genes located in the vicinity of HLA-B.

Anxiety-like behavior in mice lacking the angiotensin II type-2 receptor.

The main biological role of angiotensin II type 2 receptor (AT2) has not been established. We made use of targeted disruption of the mouse AT2 gene to examine the role of the AT2 receptor in the central nervous system (CNS). AT2-deficient mice displayed anxiety-like behavior compared with wild-type mice. However, AT2-deficient mice showed no depressant-like activity and no change in hexobarbital-induced sleeping time as compared with findings in wild-type mice. Both noradrenergic and corticotropin-releasing factor (CRF) neuronal systems appear to be involved in this anxiety-like behavior. Diazepam, captopril (angiotensin I converting enzyme inhibitor), prazosin (alpha1 antagonist) reversed the anxiety-like behavior in these AT2-deficient mice, whereas yohimbine (alpha2 antagonist), phenylephrine (alpha1 agonist), clonidine (alpha2 agonist), isoproterenol (beta1/beta2 agonist), propranolol (beta1/beta2 antagonist) and alpha-helical CRF9-41 (CRF receptor antagonist) has no apparent effects on anxiety-like behavior in AT2-deficient mice. In addition, concentrations of plasma adrenocorticotropic hormone (ACTH) and corticosterone in AT2-deficient mice did not differ from these in wild-type mice, hence, there are probably no endocrine abnormalities involving the hypothalamic-pituitary-adrenal axis (HPA). The amygdala appears to play an important role in many of the responses to fear and anxiety. The number of [3H]prazosin but not [125I]CRF binding sites in the amygdala was significantly reduced in AT2-deficient mice. These findings indicate that the noradrenergic system is involved in mediating the anxiety-like behavior in AT2-deficient mice.

FH-510, a potent and selective ligand for rat brain sigma recognition sites.

FH-510 (5,8-dimethyl-4-(2-di-n-propylaminoethyl)carbazol) is a potent ligand for sigma ligand binding sites in rat brain membranes and has an IC50 value of 4.8 +/- 1.0 nM, which is comparable to that of haloperidol (2.2 +/- 0.2 nM). The high selectivity of FH-510 for sigma binding sites was evaluated by its lack of significant affinity for other binding sites, including those for dopamine D2 and phencyclidine. When administered to mice orally, FH-510 suppressed (+)-N-allylnormetazocine ((+)-SKF10,047)-induced stereotyped behavior with an ED25 value of 0.54 mg/kg, which is 14-fold more potent than that for (+)-alpha-(4-fluorophenyl)-4-(5-fluoro-2-pyrimidinyl)-1-piperazine butanol ((+)-BMY14802) (7.6 mg/kg). These results suggest that FH-510 may be a potent and selective sigma ligand.

Effect of VA-045 on a closed head injury model in rats.

The effect of VA-045, a novel apovincaminic acid derivative, was studied in a model of closed head injury (CHI) in rats. CHI was induced by dropping a 400 g weight through a tube from 70 cm above a steel helmet placed on the vertex. Intravenous administration of VA-045 and thyrotropin-releasing hormone (TRH) reduced both the duration of loss of righting reflex and the duration of disruption of spontaneous movement caused by CHI. VA-045, but not TRH attenuated the CHI-induced decreased step through latency (STL) on a passive avoidance task. Over the same time schedule, however, VA-045 did not attenuate the scopolamine-induced decreased STL. CHI-induced reduction of the amplitude of somatosensory evoked potentials (SEP) was recovered by VA-045 but not by TRH. These findings indicate that VA-045 may be useful for treating patients with CHI-induced disturbance in consciousness.

NE-100, a novel sigma receptor ligand: effect on phencyclidine-induced behaviors in rats, dogs and monkeys.

Phencyclidine (PCP)-induced psychosis is a useful animal model for studies on schizophrenia. N, N-dipropyl-2-[4-methoxy-3-(2-phenylethoxy)-phenyl]- ethylamine monohydrochloride (NE-100) had no effect on conditioned avoidance responses (CAR) in rats, whereas, the PCP-induced impairment of avoidance inhibition was attenuated by NE-100. The PCP-induced ataxia or decreased attention in rhesus monkeys was to some extent overcome by NE-100. In dogs, PCP-induced either head-weaving behavior or ataxia, effects which were blocked by NE-100. Administration of PCP led to an increase in beta-2 and a decrease in delta relative power (RP) activity in cortical background spectral electroencephalographics (ECoG) in dogs. While NE-100 in itself showed no significant change in beta-2 and delta RP, NE-100 did block the PCP-induced beta-2 increase and delta decrease. These findings indicate that NE-100 attenuates the effect of PCP in experimental animals. This drug is being considered as a therapeutic for the treatment of patients in the schizophrenia.

NE-100, a novel sigma receptor ligand: in vivo tests.

It has been suggested that sigma receptor antagonists may be useful as antipsychotic drugs. N, N-dipropyl-2-[4-methoxy-3-(2-phenylethoxy)phenyl]-ethylamine monohydrochloride (NE-100) is a novel compound with high affinity for the sigma receptor (IC50 = 4.16 nM), but low affinity (IC50 > 10,000 nM) for D1, D2, 5-HT1A, 5-HT2 and phencyclidine (PCP) receptors. The head-weaving behavior induced by either (+)SKF10047 or PCP was dose-dependently antagonized by NE-100 with oral ED50 at 0.27 and 0.12 mg/kg, respectively. NE-100 did not affect dopamine agonists-induced stereotyped behavior and/or hyperactivity. NE-100 failed to induce catalepsy in rats. These findings indicate that NE-100 may have antipsychotic activity without the liability of motor side effects typical of neuroleptics.

Effectiveness of mebendazole in Trichuris trichiura; a report on 2 cases of mild infection.

Two admitted patients, a 5-year-old Filipino girl and a 29-year-old Indonesian man, who were diagnosed otherwise were concurrently found to harbour Trichuris trichiura eggs in stoll specimens containing 3,300 and 30 eggs per gram feces (EPG), respectively. A satisfactory response was obtained with administration of mebendazole in the recommended dose of 100 mg twice daily for three consecutive days. Repeated post-treatment fecal examinations revealed 0 EPG. Adverse reaction, either physical or laboratory, due to the anthelmintic was negative. The study indicates that the effectiveness of mebendazole on mild infection with T. trichiura is excellent without any untoward effect.

[The first two cases of tsutsugamushi disease found in Toshima Island, Tokyo Metropolis].

It has been known that tsutsugamushi disease, so-called "Shichito-fever", is widely spread among the Izu Islands, Tokyo Metropolis. The cases were reported in Oshima Island, Niijima Island, Shikine Island, Kozu Island, Miyake Island, Mikura Island, and Hachijo Island previously, although no case has been reported in Toshima Island. In this paper, we report the first two cases of tsutsugamushi disease found in Toshima Island in December 1988 and December 1989. The first case was a 73 year-old male and the second case was a 83 year-old female, respectively. Fever, erythema and eschar were observed in both cases, while lymphadenopathy and hepatosplenomegaly were not detected. After tetracycline was administered, the fever immediately went down and erythema gradually disappeared in both cases. Specific immunofluorescence tests demonstrated that IgG antibody titers rose against Karp, Gilliam and Kato strains, and that IgM antibody titers rose only against Gilliam strain in both cases. Therefore, Gilliam-like strain of Rickettsia tsutsugamushi may play an important role in Toshima Island.

[In vitro antibacterial activity of fleroxacin (FLRX) against clinical isolates from bacterial enteritis].

Antibacterial activity of fleroxacin (FLRX), a new quinolone antimicrobial, against 36 strains of Shigella app., 14 strains of Salmonella spp., 11 strains of Escherichia coli, 9 strains of Vibrio spp. (including 2 strains of V. cholerae O1), 14 strains of Campylobacter jejuni/coli, 3 strains of Aeromonas spp. and 1 strain of Plesiomonas shigelloides isolated from infectious enteritis patients in this study was determined. Its activity was compared with that of ciprofloxacin (CPFX), norfloxacin (NFLX) and nalidixic acid (NA). The MIC90 values of FLRX were 0.1 microgram/ml against Shigella spp. and E. coli, 0.2 microgram/ml against Salmonella spp. and Vibrio spp., and 12.5 micrograms/ml against C. jejuni/coli MIC90 of FLRX was comparable to that of CPFX and NFLX against Vibrio spp.. Against other species, MIC90 of FLRX were 2- to 4-fold higher than those of CPFX, whereas equal to or 2-fold lower than NFLX. FLRX demonstrated excellent activity against an NA-resistant (MIC: > 100 micrograms/ml) isolate of E. coli, with MIC 0.78 microgram/ml. FLRX showed 8-fold higher activity than NA against other strains. The antibacterial activity of FLRX was compared with that of NA against stocked strains (clinical isolates from August 1989 to February 1991), consisting of 11 strains of Shigella spp., 10 strains of Salmonella spp., 8 strains of E. coli, 10 strains of V. cholerae O1, 10 strains of V. parahaemolyticus and 14 strains of C. jejuni/coli. MICs of FLRX were 0.78 and 12.5-25 micrograms/ml against Shigella spp. and C. jejuni/coli that showed resistance of NA (MIC: > or = 100 micrograms/ml), respectively. Based on the above, although the absolute MICs are low against E. coli and shigella spp., a value of 0.78 micrograms/ml for FLRX suggested that such strains should be considered to be resistant.

[In vitro antibacterial activity of pazufloxacin (PZFX) against clinical isolates from infectious enteritis].

Antibacterial activity of pazufloxacin (PZFX) against 65 strains of Shigella spp., 13 strains of Salmonella spp., 7 strains of Escherichia coli, 4 strains of Vibrio parahaemolyticus, 4 strains of V. cholerae O1, 2 strains of Aeromonas spp., 4 strains of Plesionomas shigelloides and 3 strains of V. cholerae non-O1 isolated from patients of infectious enteritis and carriers was compared with that of ofloxacin (OFLX), ciprofloxacin (CPFX), tosufloxacin (TFLX) and nalidixic acid (NA). The MIC90 of PZFX against Shigella spp., Salmonella spp. and E. coli were 0.025, 0.025 and 0.025 micrograms/ml, respectively. The MIC90 of PZFX against Shigella spp. was comparable to that of CPFX, 2-fold higher than that of TFLX and 4-fold lower than that of OFLX. Against Salmonella spp., MIC90 of PZFX was comparable to TFLX and 2- to 8-fold lower than those of CPFX and OFLX. PZFX showed the highest antibacterial activity between the drugs tested. Against other species, the MIC90 values of PZFX were < or = 0.006-0.1 micrograms/ml. No NA-resistant isolates were observed. The antibacterial activity of PZFX against stocked strains (clinical isolates from Aug 1989 to Feb 1991), containing 51 strains of Shigella spp., 50 strains of Salmonella spp., 19 strains of E. coli, 12 strains of V. cholerae O1 and 13 strains of V. parahaemolyticus, was also investigated. The MIC90 of PZFX of each strains were 0.05 micrograms/ml for Shigella spp., 0.05 micrograms/ml for Salmonella spp., 0.1 micrograms/ml for E. coli, 0.0125 micrograms/ml for V. cholerae O1, 0.2 micrograms/ml for V. parahaemolyticus, respectively. As shown above, PZFX has strong antibacterial activity against isolates from infectious enteritis and this suggests the usefulness of PZFX for the treatment of these patients and carriers.

[In vitro antibacterial activity of balofloxacin (BLFX) against isolates from patients with bacterial enteritis].

In vitro antibacterial activity of balofloxacin (BLFX), a newly developed fluoroquinoline, was compared with that of norfloxacin (NFLX), ofloxacin (OFLX) and ciplofloxacin (CPFX). Bacterial strains used in this experiment were freshly isolated from patients with infectious enteritis just before BLFX therapy. The isolates were 43 strains of Vibrio cholerae O1, 1 strain of Campylobacter sp., 4 strains of Aeromonas spp., 3 strains of Plesiomonas shigelloides, 1 strain of Vibrio mimicus and 1 strain of Vibrio cholerae non-O1. MIC90 of BLFX against 43 strains of Shigella spp., 13 strains of Salmonella spp. and 9 strains of E. coli were 0.39, 0.39, 0.2 micrograms/ml, respectively. All strains of Aeromonas spp. and P. Shigelloides were inhibited by the concentrations under 0.39 and 0.05 micrograms/ml. MIC90 of BLFX, NFLX, OFLX and CPFX against a total of 79 strains were 0.39, 0.2, 0.2 and 0.05 micrograms/ml, respectively.

[Studies on hemolytic streptococcal infection: 1). Outbreak of group C hemolytic streptococcal infection in Formosan squirrels].

Between mid-October to mid-November 1992, of 500 freely-ranging Formosan and striped squirrels kept at Garden Y in the suburbs of Kanagawa Prefecture, 414 (82.8%) suddenly died one after another by bleeding from the nasal and oral cavities after developing a mild facial swelling. Isolation of microbes including viruses were carried out from the Formosan squirrels that had suddenly died. Various organs from these animals were histologically examined. 1. In bacteriological tests, beta-hemolytic streptococcal strains were isolated in a pure culture from 5 (83.3%) of 6 Formosan squirrels that had died suddenly. By serological analysis, 14 isolated strains were serotyped as group C according to the classification of Lancefield. From their biochemical characteristics, these were identified as Streptococcus equi subsp. zooepidemicus. A drug sensitivity test revealed that ABPC, PCG, SBPC, CMX and CPZ are highly sensitive against the isolates. 2. In the virological test, the viral isolation was applied for three blind passages by primary cultured kidney cells of Formosan squirrels, but no evidence of CPE was obtained. 3. At autopsy, a pathological change was detected mainly in the lungs. Histopathological examinations revealed severe hypertrophic changes of the alveolar wall in the entire pulmonary lobe. Severe congestion, hemorrhagic pneumonia, neutrophils and macrophages infiltration were observed in the hypertrophic alveolar wall. In the other cases, thrombi were observed in the branches of the pulmonary artery. Other organs demonstrated no remarkable histopathological changes. 4. Streptococcal strains were not isolated from the pharynx in all of the employees working at this garden.

[Contamination of healthy livestock with verocytotoxin producing Escherichia coli (VTEC), the first isolation from goats in Japan].

As part of the investigation on the source and route of infection with Verocytotoxin producing Escherichia coli (VTEC) in human beings, isolation of VTEC was attempted using fresh feces collected from healthy livestock (cattle, swine and goat) raised in Sagamihra, Yokohama and Hiratsuka cities from October, 1991 to March, 1992. VTEC could be isolated from 1 (1.0%) of 105 swine, 2 (3.6%) of 55 cattle and 2 (15.4%) of 13 goats. VTEC was isolated for the first time from goats in Japan. The combinations of the serotype and toxin type of the isolated strains were O116:H21 (VT2) and O163:H19 (VT2) for those isolated from the cattle, OUT:H19 (VT2vp) for that from the swine and OUT:H21 (VT1) for those from the goats. Since VTEC isolated from the cattle and goats were found to produce VT of the same serotypes as human VTEC, domestic animals were considered to be involved as a source of VTEC infection in human beings.

[Studies on motile-Aeromonas infection 3). Phage typing of motile Aeromonas isolated from patients with diarrhea].

Phage types were determined for 102 strains of motile Aeromonas isolated from patients with diarrhea at four metropolitan hospitals in Tokyo. The following results were obtained. 1) Of the 102 strains examined, 52 (51.0%) were divided into 28 phage types. This rate was considerably higher, compared to our previous results, namely, 21.7% for strains isolated from natural environments and 25% for those isolated from meats. By bacterial species, phage types could be determined for 33 (52.4%) of 63 strains of A. hydrophila, for 16 (45.7%) of 35 strains of A. sobria, 2 (50.0%) of 4 strains of A. caviae and 1 (100%) strain of Aeromonas spp. 2) Of the 52 strains for which the phage types could be determined, the greatest number (16 strains, 30.8%) were identified as belonging to Type I group. These are followed by 5 strains (9.6%) which were identified as Type I/III group and 2 strains (3.4%) each identified as Type I/II, I/II/V, IV, V and VI groups. The remaining 21 strains were identified as belonging to one of the other phage type groups. Thirty-five (67.3%) of the strains for which the phage types were identified, were found to belong either to Type I group or to combinations with Type I. This demonstrated that 34.0% of the isolates from patients with diarrhea were related to Type I.

Repair of symptomatic perineal hernia with a titanium mesh.

PURPOSE: Surgical repair of symptomatic perineal hernia is challenging, especially via a perineal approach with limited exposure of the hernia sac. Furthermore, insecure fixation of autologous or synthetic materials to bony structures often results in recurrence. Here, we describe the application of a titanium mesh for perineal hernia repair. METHODS: We performed hernia repair with a thin titanium mesh via a perineal approach in three patients who developed secondary perineal hernia following abdominoperineal resection. After the hernia sac was isolated and dissected, the titanium mesh was molded and placed over the ischium and coccyx to support the pelvic floor. RESULTS: No major complications occurred, and all three patients were free of recurrence at follow-up after 73, 109, and 6 months, respectively. The patients experienced slight pain in the perineal region when sitting, which resolved within 6 months. CONCLUSION: Our successful preliminary results indicate that a titanium mesh is useful for perineal hernia repair by the perineal approach, as it can provide rigid support for the pelvic floor by its entire surface while ensuring stability without any fixation.