泉 辺見’s scientific contributions

第3世代セファロスポリン系抗生物質の経口剤であるT-2588を用い,淋菌感染症に対する治験を,男子尿道炎140例,女子子宮頸管炎6例の計算146例について行なった.分離淋菌の110株中23株(20.9%)はβ-lactamase産生淋菌(PPNG)であった.T-2588の分離菌に対する抗菌力(MIC)は,接種菌量106 CFU/mlで0.1～0.0125 μg/ml (peak 0.025 μg/ml)であった.PPNGでもpeakは0.025 μg/mlで,最高値はnon-PPNGより1管高い0.2 μg/mlであった.C. trachomatis感染合併例は男子20.9%,女子33.3%であった.男子症例に対する有効率は,1日2回400 mg投与法で3日目90.5%,7日目95.3%,PPNG分離例に限っては3日目73.3%,7日目80.0%であった.1日3回300 mg投与では3日目93.3%,7日目100%,1日3回600 mg投与では3日目100%,7日目100%であり,PPNGに対しても3日目,7日目共に100%であった.女子症例は例数が少ないので結論づけられなかったが,やはり600 mg(分3)投与がよい成績(100%)であった.副作用は軽度のものを3例(1.7%)に認めたが,そのまま治療を続行した.以上の成績から,淋菌感染症に対するT-2588による治療は,1日分3投与600 mg 3日間投与でPPNGと関係なく,充分な臨床効果を期待できると考えている T-2588, a new oral cephalosporin antibiotic, for gonorrheal infections, was administered to 146 patients with gonorrheal infection cases (140 urethritis cases in males, 6 cervicitis cases in females). Twenty three strains (20.9%) out of 110 clinically isolated gonococci were PPNG. The MICs of T-2588 for the clinically isolated gonococci strains showed a distribution peak at 0.025 microgram/ml and ranged between 0.0125 microgram/ml to 0.1 microgram/ml when an inoculum size of 10(6)/CFU/ml was used. The distribution of MICs of PPNG also showed a peak at 0.025 microgram/ml and the maximum MIC was 0.2 microgram/ml, which is one dilution tube higher than the maximum MIC of non-PPNG. The rate of complication by Chlamydia trachomatis was 20.9% in male and 33.3% in female. At the dose of 400 mg given 2 times a day, the efficacy rate for the males on the 3rd and 7th day was 90.5% (efficacy rate against PPNG, 73.3%) and 95.3% (80.0%), respectively. At the dose of 300 mg given 3 times a day, it was 93.3% and 100%, respectively, and at the dose of 600 mg given 3 times a day, it was 100% and 100%, respectively. Therefore, the administration of T-2588 3 times a day resulted in a higher efficacy rate than that given 2 times a day. This effect was extremely marked in the case of patients with PPNG. The best clinical results were obtained at a daily dose of 600 mg t.i.d. Although the female patients were few, in number and no conclusion can be drawn, the best results were obtained with a daily dose of 600 mg t.i.d. (100%). There were three mild side effects (1.7%), which could not be attributed to the administration of T-2588 in the present study. In conclusion, T-2588 can be to be expected sufficiently clinically effective against gonorrheal infections, including PPNG, at a daily dose of 600 mg t.i.d. for 3 days.

淋菌性感染症244例(男子尿道炎212例,女子子宮頸管炎32例)に対し,Aztreonam one shot (1～2 g)治療を試みた.1)症例より分離した淋菌244株中42株(17.2%)がPPNGであった.2) Aztreonamの淋菌に対する106 CFU/mlでのMICはβ-lactamase産生に関係なく,0.025 μg/mlにpeakをもち,0.0125 μg/ml以下から0.2 μg/mlに分布していた.3) Aztreonam 1 gおよび2 g投与による淋菌の消失時間は1～8時間,平均4～4.5時間の間に消失をみており,1 gと2 gの間にほとんど差は認められなかった.4) Aztreonam 1 g one shot, 2 g one shotによる臨床効果を男女244例について検討したが,3日所見で判定するとPPNGでも治療効果は変らず,有効率は男子尿道炎では1 g 90.7%,2 g 97.1%,女子子宮頸管炎では1 g, 2 gとも100%であった.5) Aztreonamの副作用は244例中しびれ,両手に発赤,腫脹1例,倦怠感1例の計2例(0.8%)にみられたがいずれも軽度であった A clinical study of a new monocyclic beta-lactam antibiotic, AZTREONAM (hereafter referred to as AZT) for gonorrheal infections as well as epidemiologic study of gonorrheal infections were made Epidemiology: There was a reflection of the increasing sexual activity of the younger generation; both male and female patients in their twenties were most frequent (male 49.5%, female 43.7%) and the percent of teen age patients was 15.1% (male) and 34.4% (female). Forty two strains (17.2%) out of 244 clinically isolated gonococci were PPNG. Residue of serious secretion was observed in a little less than 20% suggesting a complication by Chlamydia trachomatis. Clinical Result: One shot (1-2 g) therapy by AZT was given to 244 gonorrheal infection cases (212 urethritis cases of males. 32 cervicitis cases of females) with the following highly effective rate. Although beta-lactamase producing MIC of AZT at 10(6) CFU/ml showed a peak of 0.025 microgram/ml and ranged between less than 0.0125 microgram/ml to 0.2 microgram/ml. The time required for the elimination of gonococci was studied by the administration of 1 g and 2 g AZT. Gonococci became extinct in 1-8 hours or 4-4.5 hours on average. The difference between n 1 g and 2 g was scarcely observed. Clinical effect of 1 g one shot and 2 g one shot AZT was examined on the 3rd treatment day for 244 male and females cases. The effective rate was high; 90.7% by 1 g, 97.1% by 2 g for male urethritis, 100% by 1 g also by 2 g for female cervicitis. This therapeutic efficacy was kept even in PPNG, isolated cases. There were two side effects (0.8%), one case each of numbness and, redness and swelling of both hands, out of 244 cases, but both of them were minor ones without clinical complication.

We studied the epidemiology of 109 cases of gonococcal infections (105 males with urethritis and 4 females with cervicitis), together with the basic and clinical effects of cefetamet pivoxil in the cases. The peak of age distribution of the male patients was in the younger half of their twenties, and all of the 4 female cases were between 20 and 39 years old. The major source of infections in the males younger than 25 years old was their girl friends or so-called pick-up friends, and that of the males older than 25 years old workers serving at an amusement center, for example, bars and so-called special massage parlor, which accounted for about three fourths of the male cases between 35 and 44 years old. The distribution of the MIC (inoculum size; 10(6) CFU/ml) of Cefetamet against beta-lactamase non penicillinase producing Neisseria gonorrhoeae (non-PPNG) ranged from 0.025 to 0.1 microgram/ml and that against beta-lactamase producing Neisseria gonorrhoeae ranged from 0.025 to 0.05 microgram/ml. The isolation rate of PPNG was 10.2% (9/88). In male patients with gonococcal urethritis, the efficacy rate was 100% on days 3 and 7 for 1,000 mg single dose and 7-day treatment and 500 mg single dose treatment. One of the cases treated with 250 mg single dose therapy was unchanged at 3, but the efficacy rate of the remaining cases was 100% at day 7. Complicated urethritis with C. trachomatis was noticed in 25.7% (5/105) of the male urethritis and in 25.0% (1/4) of the female cervicitis cases. The only side effect was diarrhea observed in 1 of the 124 case (0.8%).

From January through March of 1985, the Sapporo Clinical Research Group for STD treated 69 cases of gonococcal infections (61 cases of male gonococcal urethritis and 8 cases of female gonococcal cervicitis) at its facilities in Sapporo City. The therapeutic efficacy of one shot therapy of Spectinomycin (SPCM) was investigated, and an epidemiological study on the cases and bacteriological studies on the isolated strains of Neisseria gonorrhoeae were made. The male patients were between 19 and 55 years old, with a peak age distribution in the younger half of the twenties. The female patients were between 18 and 40 years old. The major source of infections was a so-called special massage parlor which accounted for 36.1% of male cases. The isolation rate of PPNG were 16.7% (11/66). The MIC (inoculum size; 10(6) CFU/ml) of SPCM ranged from 3.13 to 25 micrograms/ml regardless of beta-lactamase production. In male patients, the eradication rate (efficacy rate) of N. gonorrhoeae by SPCM was 94.7% on the first day, 93.6% on the third day and 100% on the seventh day after 2 g one shot therapy. In female patients, the rate was 100% on the third and seventh day after 2 g one shot therapy, and 75% on the first day, 66.7% on third day and 100% on seventh day after 4 g one shot therapy. We considered that one shot therapy of SPCM was effective for gonococcal infection also in the present time. Especially SPCM was effective for infections by PPNG, since it was not resolved by beta-lactamase of N. gonorrhoeae. Positive rate of Chlamydia trachomatis was 16.3% in male gonococcal urethritis, and the serous discharge tended to remain longer in the positive patients than in the negative patients. There was only one side effect (1.4%), therefore SPCM was recognized to be a safely administrated antimicrobial agent.

1)札幌における淋菌感染症例192例,女子13例では若年層の頻度が高く,10歳代症例が男子の13.5%,女子の30.8%で,本州のそれぞれ6.1%,6.3%より高率であった.2)感染源は,いわゆる特殊浴場が31.8%に達したが,本州の50%より低かった.3)友人,pick up friendの占める率が46.9%で,本州の19.9%より高い.4)分離淋菌のPPNG分離率は13.8%であった.SultamicllipのMIC (106CFU/ml)はβ-lactamase非産生株で0.05～0.39 μg/ml,産生株で0.20～1.56 μg/mlに分布した.5) Sultamicillinによる治療は1日750 mg (2錠)でも,1,125 mg (3錠)でも有効率にはほとんど差がなかった.副作用にも差が出ていない.3日間治療による淋菌消失率(有効率)は男子で96.2%(著効率38.9%),女子で83.3%(著効率8.3%)であった.7日間治療によっても,男子症例31%に漿性分泌物残存があり,Chlamydiaなどの混合感染の可能性も考慮し他剤併用を必要とする We conducted an epidemiological study including analyses of background factors of 192 male and 13 female patients with gonorrheal infection in the Sapporo area and at the same time, investigated the therapeutic efficacy of sultamicillin, an ester linked prodrug of ampicillin and beta-lactamase inhibitor sulbactam in the treatment of these patients. The percentage of infections in Sapporo was rather high in the young generation, being as high as 13.5% in teen-age boys and 30.8% in teen-age girls, which were higher than the 6.1% and 6.3% of corresponding groups in Honshu island. The source of infections was so-called special public bath-ouse which accounted for about 31.8% of all cases which however, was lower than the 50% in Honshu island. By contrast, the percentage of their friends or so-called pick-up friends as a source of infection in Sapporo was as high as 46.9% which was significantly higher than the 19.9% in Honshu. Juveniles who had nonprostitutes of the other sex as a source of infection are a characteristic of the patients in Sapporo. The isolation rate of PPNG was 13.8%. The MIC (10(6) CFU/ml) of sultamicillin ranged from 0.05 to 0.39 micrograms/ml in beta-lactamase non-producing strains and from 0.20 to 1.56 micrograms/ml in beta-lactamase producing strains showing no trend of higher MIC against beta-lactamase producing strains. There was almost no difference in the efficacy of sultamicillin between a daily dose of 750 mg (2 tablets) and 1125 mg (3 tablets) nor in side effects. The eradication rate (efficacy rate) of gonococcus following a 3-day therapy was 96.2% (38.9% excellent cure rate) in male patients and 83.3% (8.3%) in female patients. In 31% of the male patients who underwent a 7-day therapy, residual serous secretion was found though some inaccuracy is involved in this data since dropouts were not counted. This suggests the need of concurrent therapy with other appropriate drugs in consideration of possible mixed infection involving Chlamydia trachomatis or other microorganisms.

非淋菌性尿道炎症例に対し,AT-2266 1日600 mg 7日間投与し,その治療成績の検討とともにそれら症例の各種背景因子の詳細な分析も合わせて行なった.1)非淋菌性尿道炎症例106例の年齢分布は10歳代後半から30歳代前半にかけて症例が多く15歳～19歳が11.3%にもなっている.2)感染源は歓楽街女性:素人女性の比が37:53と素人女性が多く,淋菌感染症のそれと逆転していた.3)尿道分泌物培養で得られた分離菌は,ほとんどがGPCことにS. epidermidisであったが,全症例の51.6%は菌陰性であった.4)尿道分泌物の性状は膿性のものが51.9%,漿性のものが48.1%に見られた.5) AT-2266 1日600 mg(分3服用)7日間投与による有効率は膿性分泌物例群では,3日間及び7日間治療で有効率それぞれ24.3%,61.1%であり,漿性分泌物例群ではそれぞれ,36.0%,71.4%であった.6) AT-2266服用による副作用は90例中5例に軽度の胃腸障害を中心として症状発現を見たが,投与中止の必要なものはなかった AT-2266 tablets were administered orally in a daily dosage of 600 mg for 7 consecutive days as treatment of non-gonorrheal urethritis in 106 cases. The therapeutic results in 90 cases were investigated, and a detailed analysis of various background factors was also performed. Most of the patients were between 15 and 35 years old; 11.3% of the patients were between 15 and 19 years old. The source of infection was a "professional" woman such as a prostitute in 37 cases, and a non-professional woman in 53 cases. This is noteworthy because the source is more often a "professional" women in the case of gonorrhea. Bacterial isolates were obtained by culture of the urethral secretions. Most were gram-positive cocci, especially S. epidermidis, but, in 51.7% of the patients, no bacteria could be cultured. The urethral secretion was purulent in 51.9% of the patients, and serous in the remaining 48.1%. The efficacy rates obtained when AT-2266 was administered in a daily dosage of 600 mg (in 3 divided oral doses) for 7 days were as follows. In the purulent secretion group, the 3-day and 7-day therapeutic efficacy (elimination of the secretion) rates were 24.2% and 61.2%. In the serous secretion group, the corresponding efficacy rates were 36% and 71.4%. Thus the therapeutic efficacy was slightly inferior in the purulent secretion group. Oral administration of AT-2266 resulted in side effects in 5 of the patients (5.5%). These side effects consisted primarily of mild gastrointestinal disturbances, which did not require discontinued drug administration.

1981年10月～1982年2月の間の札幌での淋菌性感染症178例(男158例,女20例)につき,疫学的,治療学的に研究した.男158例は全例急性尿道炎で,最年少は15歳で,10歳代が20.3%であった.男子例の感染源は,10代では,ほとんどがディスコなどでpick upしたかりそめの女友達であるが,20歳代はトルコ,バーなどの接客婦がふえ,25歳以上ではそれが半数以上となる.最近ふえ続けるトルコ風呂接客婦の占める割合が多くなっている.女子20例中1例は1歳の腟外性器炎を除き子宮頸管炎で,16～19歳が半数を占めた.潜伏期がはっきりしている男141例で中,5日以内83例,6～10日39例,11～20日13例,21～30日4例,30日以上2例と潜伏期の長いものが増えつつある.また菌量106 cells/ml接種で,MIC 1.56 μg/ml以上の12株はβ-lactcmase産生株であった.このβ-lactamase産生株は同時にDoxycyclin (DOXY)のMICはすべて1.56 μg/ml以上で,AMPCとDOXYとの耐性獲得機序の相関性を示した.男133例,女15例に持続性アモキシシリン(L-AMPC) 1 g/日(500 mg×2)を原則とし7日間投与し,L-AMPCによる淋菌性感染症の治療プランを提唱した During the period from October of 1981 through March of 1982, our research group in Sapporo treated 178 patients (158 males and 20 females) for gonorrheal infections. We performed epidemiological and therapeutic studies on these patients. The youngest of the 158 male patients with acute gonorrheal urethritis was 15 years old. The age distribution was 32 patients (20.3%) under 20 years, 46 patients (29.1%) aged 20 to 24, 34 patients (21.5%) aged 25 to 29, 22 patients (13.9%) aged 30 to 34, 10 patients (6.3%) aged 35 to 39, and 14 patients (8.9%) aged 40 to 54. The fact that 20% of gonorrheal urethritis occurred in youths under 20 years of age, is especially noteworthy. The infection in the teenage boys was found to be picked up mostly from girls met at discos , etc., On the other hand, the patients in their 20s, were infected more frequently by contact with hostesses at massage parlors and bars, these sources making up the majority of male patients who were 25 years or older. These findings are quite interesting because they reflect the socio-economic status of the patients. In addition, the fact that hostesses working at massage parlors are a frequent source of gonorrheal urethritis infections can represent a considerable problem in terms of public hygiene. The 20 female patients with gonorrheal infections were all found to be cases of cervicitis, except for a 1-year-old girl with gonorrheal infection of external genitals. The fact that about half of these female patients were teenagers, aged 16 to 19 years is worth special note. The duration of the latent period was less than 5 days in 83 male patients (58.9%) with urethritis, 6 approximately 10 days in 39 patients (27.7%), 11 approximately 20 days in 13 patients (9.2%), 21 approximately 30 days in 4 patients (2.8%), and over 30 days in 2 patients (1.4%), It can thus be said that the number of cases showing a long incubation period is increasing. The MICs of 154 gonococci strains isolated from the urethral or vaginal discharge were determined. Thirteen (8.4%) of these clinically isolated strains were found to be beta-lactamase producers. When a bacterial inoculation level of 10(6) cells/ml was used in the in vitro MIC determination, the MIC was 1.56 micrograms/ml or higher for 12 of these beta-lactamase-producing strains; the MIC of the 13th strain was 0.78 microgram/ml. At the same time, the MICs of these beta-lactamase-producing strains to doxycycline were also high; 1.56 micrograms/ml or higher.(ABSTRACT TRUNCATED AT 400 WORDS)

The efficacy of single administration of NY-198 in the treatment of gonococcal infections was studied employing male patients with gonorrheal urethritis and female patients with gonorrheal cervicitis. The clinical efficacy was evaluated on the basis of the efficacy rates which was estimated on each observation day for each patient. In the male patients, NY-198 was administered in a dose of 200 mg in 25 cases and a dose of 400 mg in 65 cases. The rate of eradication of N. gonorrhoeae (i.e. efficacy) on the 3rd day of administration was 96% in the 200 mg administration group and 100% in the 400 mg administration group. On the 7th day after administration, the eradication rate was 100% in both the 200 mg and 400 mg administration groups. When the eradication rate on the 7th day was statistically estimated for patients who returned to the hospital only on the 3rd day, it was 97.9% in the 200 mg administration group. In the female patients, NY-198 was administered in a dose of 200 mg to 4 cases and a dose of 400 mg to 5 cases. The eradication rate on each observation day was 100% in both dosage groups. In conclusion, single administration of NY-198 in a dose of 200 mg or 400 mg was highly effective, and considered to be a therapeutic method highly useful clinically.

慢性前立腺炎症例に対し新pyridone carboxylic acid系薬剤AT-2266の治療検討および慢性前立腺炎の病態分析を行なった.前立腺液中に白血球30以上/400倍視野以上の97例を対象とし,その71%に淋菌性又は非淋菌性尿道炎の既往があった.前立腺液の細菌培養で44.1%にGPCを分離した.直前治療のない症例中56.0%に尿道又は排尿関連刺激症状を認め,他は不定愁訴のみであった.AT-2266 600 mg(分3) 14日間投与の治療効果は,直前治療のなかった未治療群と治療のあるもので,7日間治療の有効率はそれぞれ有効以上32.7%,36.0%であり,14日間治療ではそれぞれ54.3%,56.5%であった.尿道及び排尿関連刺激症状の改善はかなり見られるが,更に7日間の治療により改善度は増加した.関連不定愁訴の改善は良好でなく,前立腺内白血球の改善率も著しくはなかった.副作用は軽度のものが投与例の1.8%に見られた AT-2266 is a new antibiotic of the pyridone carboxylic acid class which possesses a broad, low-MIC antibacterial spectrum. Therapeutic studies were carried out on the use of this drug in the treatment of chronic prostatitis, and at the same time a pathological analysis was performed on chronic prostatitis. The subjects were 97 chronic prostatitis patients for whom the prostate fluid had been confirmed to contain at least 30 leukocytes per 400-power magnification field. An analysis of the background factors revealed that 71% of these patients had a past history of gonorrheal or non-gonorrheal urethritis. Culture of the prostate fluid yielded gram-positive cocci (S. epidermidis in most cases) in 44.1% of the patients. E. coli was detected in 3.2% of the patients, while the remaining cases gave negative cultures. In 53.9% of the patients who had not been receiving therapy prior to inclusion in this study, the subjective symptoms consisted of urethral irritation or irritation upon urination. In the other patients, the relationship of the complaints to the disease could not be clearly established. In the patients who had been receiving therapy, the majority did not complain of subjective symptoms. AT-2266 was administered in a daily dosage of 600 mg (in 3 divided doses) for 14 days. The therapeutic efficacy was evaluated. At the end of 7 days of AT-2266 therapy, 15.5% of the previously-untreated group and 8% of the previously-treated group were "excellent" cases, and the efficacy rate was 32.8% and 36%, respectively, when the "good" cases were also included. At the end of the full 14 days of therapy, the corresponding efficacy rates were 21.7% and 17.4%, and 54.3% and 56.5%. Considerable improvement was achieved in the subjective symptoms of urethral irritation and irritation upon urination at the end of 7 days of therapy, and the improvement was even greater following the next 7 days of treatment. With regard to the complaints for which the relationship to the disease could not be clearly established, however, the improvement was not very good: there was not much difference between the results on the 7th and 14th days, and the elimination rate even after 14 days was slightly below 30%. In the previously-untreated patients, improvement in leukocyte count in the prostate fluid to 10 or fewer cells per microscopic field was achieved in 15.6% at 7 days and 21.7% at 14 days. As side effects of AT-2266, mild symptoms were observed to occur in only 1.8% of the patients.

札幌STD研究グループにおいて1982年6月より1年間に男子淋菌性尿道炎131例を対象としてAT-2266 1日600 mgを7日間投与し,治療効果,その他を検討した.1日1回投与,2分割投与,3分割投与の3日間治療成績は著効率がそれぞれ7.7%,50%,57%となった.3分割投与群の成績は3日間治療で著効57.0%,有効39.8%,やゝ有効3.2%であり,7日間治療では著効74.6%,有効23.9%,やゝ有効1.5%であったが,7日間治療でも分泌物や尿中白血球は残存しChlamydiaなど混合感染によると思われた.77株中8株(10.4%)にβ-lactamase産生を認めた.MICは接種菌量でほとんど変化なく,106 CFU/mlで0.05～0.2 μg/mlと3.16～12.5 μg/mlに二峰性分布を示した.AT-2266の副作用は128例中2例(1.6%)に軽度のものが認められた From August of 1982 through February of 1983, the Sapporo Clinical Research Group for STD treated 131 cases of male gonorrheal urethritis at its affiliated clinical facilities in Sapporo City. The therapeutic efficacy of AT-2266 was investigated, together with an epidemiological study on the cases and bacteriological studies on the isolated strains of gonococcus. In addition, a few cases of female gonorrheal cervicitis were treated, and the therapeutic results for 3 of these cases evaluated. AT-2266 was administered at a daily dosage of 600 mg in one dose to 14 patients, 2 doses to 10 patients and 3 doses to 98 patients. At the end of 3 days of this therapy, the gonococci had been eliminated in all of the cases, but there was variation in the status of disappearance of the secretion. The "excellent" efficacy rates for these three regimens were thus 7.7%, 50% and 57%, respectively. These results showed that administration of the total dosage in two or more divided doses maintained higher minimum concentrations of the antibiotic in the blood and the urine, and were thus more clinically beneficial than when the dosage was given as one daily dose. Of the patients who were treated with 600 mg/day of AT-2266 in 3 divided doses, 93 were evaluated for the therapeutic efficacy. At the end of 3 days 57.0% were "excellent" cases, 39.8% were "good" cases and 3.2% were "fair" cases, and at the end of 7 days of therapy, 67 patients were 74.6% "excellent" cases, 23.9% were "good" cases and 1.5% were "fair" cases. The clinical efficacy rate was thus quite high. Those cases in which the secretion and leukocytes had not disappeared from the urine even at the end of the 7 days of therapy were probably cases of mixed infection involving Chlamydia, etc. Eight of the 77 gonococcal isolates (10.4%) were beta-lactamase producers. The MIC of AT-2266 hardly differed with the size of the bacterial inoculum. With an inoculum of 10(6)CFU/ml, the MIC distribution showed two peaks, i.e., at 0.05-0.2 micrograms/ml and 3.16-12.5 micrograms/ml. Only 11.7% of the strains were found to have high MICs. The distribution of these high MICs was found to be unrelated to the ability to produce beta-lactamase. Mild side effects of AT-2266 were seen in 2 out of 128 patients. (1.6%), an extremely low incidence.