新生児・未熟児に対するFlomoxefの薬動力学的並びに臨床的検討  [in Japanese] PHARMACOKINETICS AND CLINICAL STUDIES ON FLOMOXEF IN NEONATES AND PREMATURE INFANTS  [in Japanese]

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新牛児及び未熟児に対するFlomoxef (6315-S, FMOX) の体内動態並びに臨床的検討を行い, 以下の成績を得た。被験対象はすべて保護者のInformed consentが得られたものである。<BR>1. 体内動態<BR>(1) 成熟児におけるOne shot静注時の血漿中濃度及び血中半減期<BR>10mg/kg静注後30分の日齢ごと (生後0~3, 4~7, 8~28日) の平均血漿中濃度は, それぞれ21.2, 21.8, 21.3μg/mlにあり, それ以降漸減した。血中半減期T1/2(β)は3.37, 1.85, 1.63時間であった。<BR>20mg/kg静注後15分の日齢ごとの平均血漿中濃度は, それぞれ54.4, 51.4, 50.7μg/mlにあり, T1/2 (β) は2.99, 2.32, 1.79時間であった。<BR>40mg/kg静注後15分の日齢ごとの平均血漿中濃度は, それぞれ104.0, 95.9, 99.2μg/mlにあり, T1/2 (β) は3.40, 1.20, 1.80時間であった。<BR>(2) 未熟児におけるOne shot静注時の血漿中濃度及び血中半減期<BR>10mg/kg静注後15分の日齢ごと (生後0~3, 4~7, 8~28日) の平均血漿中濃度は,それぞれ24.0, 28.6, 21.7μg/mlであり, それ以降漸減した。T1/2 (β) は4.10,253, 2.57時間であった。<BR>20mg/kg静注後15分の日齢ごとの平均血漿中濃度は, 54.0, 54.6, 55.5μg/mlにあり, T1/2 (β) は4.28, 2.27, 3.02時間であった。<BR>40mg/kg静注後15分の日齢ごとの平均血漿中濃度は, 98.2, 93.0, 106.0μg/mlにあり, T1/2 (β) は4.66, 2.86, 2.09時間であった。成熟児及び未熟児においてOne shot静注時の血漿中濃度は, 10, 20, 40mg/kgにいずれもDose responseがみられた。又, T1/2 (β) は成熟児及び未熟児とも日齢が経過するほど短縮する傾向にあり, 成熟児と未熟児のT1/2 (β) は, 未熟児が延長する傾向にあった。<BR>(3) 成熟児・未熟児におけるOne shot静注時の尿中回収率成熟児及び未熟児に10, 20, 40mg/kgをOne shot静注した時の6時間までの尿中回収率は, 成熟児で38.9~62.8%, 未熟児で30.7~61.5%であった。<BR>尿中回収率は成熟児及び未熟児とも生後日齢が経過するほど尿中回収率は高くなる傾向にあった。<BR>(4) 1時間点滴静注時の血漿中濃度及び尿中回収率20mg/kgを1時間かけて点滴静注した時の日齢ごと (生後0~3, 4~7, 8~28日) の平均血漿中濃度のピークは点滴静注終了時にあり, 31.0, 32.7, 23.4μg/mlであつた。T1/2 (β) は2.94, 3.68, 2.25時間であった。6時間までの尿中回収率は, 35.2~52.9%であった。<BR>2. 臨床成績<BR>(1) 疾患別臨床効果<BR>有効性評価可能の199例の疾患別臨床効果は菌検出例 (A群), 菌非検出例 (B群) に区別し, 前者を中心として分析した。<BR>A群71例中 (敗血症13例, 化膿性髄膜炎1例, 肺炎18例, その他呼吸器感染症3例, 尿路感染症13例, 皮膚軟部組織感染症20例, 胎内感染2例, その他の感染症1例) 著効40例, 有効27例, やや有効1例, 無効3例で有効率は94.4%であった。<BR>一方, B群128例中 (敗血症疑い24例, 化膿性髄膜炎1例, 肺炎42例, 気管支炎2例, その他呼吸器感染症2例, 尿路感染症2例, 皮膚軟部組織感染症7例, 胎内感染44例, その他の感染症4例) 著効54例, 有効69例, やや有効2例, 無効3例で有効率は96.1%であつた。<BR>感染の予防を目的で本剤が投与された104例は, 全例において予防の目的を達成できた。<BR>(2) 細菌学的効果<BR>細菌学的効果は73株中消失62株, 減少1株, 不変2株及び不明7株で消失率は955%であり, 菌交代は1株に認められた。<BR>(3) 副作用と臨床検査値異常<BR>副作用は316例中下痢が4例 (1.3%) だけにみられ, いずれも軽度であつた。臨床検査値異常発現例は295例中25例 (85%) にみられ, 好酸球増多13例 (4.4%), 血小板増加3例 (1.0%), S-GOT上昇11例 (3.7%), S-GPT上昇4例 (1.3%), A1-P上昇1例 (0.3%), Hb減少1例 (0.3%) で, いずれも一過性の変動で重篤な症例はなかつた。<BR>以上の成績から本剤の標準投与量は, 1回量20mg/kgを日齢0~3日は1日2~3回, 4~28日は3~4回One shot静注及び点滴静注で十分効果が期待できると考える。

We investigated pharmacokinetics and clinical effects of flomoxef sodium (6315-S, FMOX) in neonates and premature infants.<BR>These results are summarized as follows:<BR>1. Pharmacokinetics<BR>(1) Plasma concentration (Ct) and half-lives (T 1/2) were determined upon after intravenous one-shot injection (i. v.) of FMOX to neonates of different day-age groups (0-3 (n=25), 4-7 (n=18), 8-28 (n=32) days of birth).<BR>At a dose of 10mg/kg. i. v., mean C<SUB>30</SUB>(30 minutes concentration) values were 21.2, 21.8 and 21.3μg/ml, respectively, in the different groups mentioned above, and the mean T 1/2 values were 3.37, 1.85 and 1.63 hours. At 20mg/kg i. v., mean C<SUB>15</SUB>(15 minutes concentration) values were 54.4, 51.4 and 50.7μg/ml, and mean T 1/2's were 2.99, 2.32 and 1.79 hours, respectively. At a dose of 40mg/kg i. v., mean C<SUB>15</SUB> values were 104.0, 95.9 and 99.2μg/ml, and the mean T 1/2's were 3.40, 1.20 and 1.80 hours, respectively.<BR>(2) Plasma concentrations and T 1/2 after intravenous one-shot injection of FMOX in premature infants in group (0-3 (n=14), 4-7 (n=10), 8-28 (n=13) days of birth).<BR>Mean C<SUB>15</SUB>'s at doses of 10, 20 and 40mg/kg in the different groups of infants were 24.0, 28.6, 21.7 and 54.0, 54.6, 55.5 and 98.2, 93.0, 106.0μg/ml, and T 1/2's were 4.10, 2.53, 2.57 and 4.28, 2.27, 3.02 and 4.66, 2.86, 2.09 hours, respectively.<BR>Mean Cmax values were clearly dose dependent, and mean T 1/2 values tended to be longer in premature infants compared to neonates.(3) Urinary recovery rate of FMOX after intravenous injection in neonates and premature infants.<BR>Mean urinary recovery rates of FMOX in the first 6 hours after i. v.(one-shot) at doses of 10, 20 and 40mg/kg to neonates and premature infants were 38.9-62.8% in the neonates and 30.7-61.5% in the premature infants.<BR>(4) Plasma concentrations and urinary recovery rates upon 1 hour drip infusion of 20mg/kg in the neonate groups (or the premature infant groups) as follows: Mean C<SUB>50</SUB> values were 31.0, 32.7 and 23.4μg/ml, and T 1/2 were 2.94, 3.68 and 2.25 hours, respectively.<BR>The recovery rates were 35.2-52.9% in the first 6 hours after administration.<BR>2. Clinical studies<BR>The number of clinically evaluable cases in the FMOX treatment of premature infants was 199, in which the causative pathogens were indentified in 71 cases (A group) and not indentified in 128 cases (B group).<BR>Diseases among the A group were sepsis in 13 cases, purulent meningitis in 1, pneumonia in 18, other respiratory tract infections (RTI) in 3, urinary tract infection (UTI) in 13, skin and soft-tissue infection (SSTI) in 20, intrauterine infection in 2 and other infection in 1.<BR>The clinical efficacies in the A group was excellent in 40 cases, good in 27, fair in 1 and poor in 3. The over-all efficacy rate was 94.4%.<BR>Diseases in the B group included suspected sepsis in 24 cases, purulent meningitis in 1, pneumonia in 42, bronchitis in 2, other RTI in 2, UTI in 2, SSTI in 7, intrauterine infection in 44 and other infections in 4.<BR>The clinical efficacies in the B group were excellent in 54 cases, good in 69 and fair in 2. The over-all efficacy rate was 96.1%.<BR>FMOX was administered to 104 patients for prophylaxis with satisfactory results were obtained in all cases.<BR>3. Bacteriological studies<BR>Seventy three strains of pathogens were isolated from 71 cases. Bacteriological effects of FMOX were as follows, eradicated; 62 strains, decreased; 1, unchanged; 2, unknown; 7 and 1 strain was replaced. The bacteriological eradication rate was 95.5%.<BR>4. Side effects and abnormal laboratory test results were found at rates of 1.3% and 8.5%, respectively. However, all of these cases were transient and no severe incidents were observed.

Journal

  • The Japanese Journal of Antibiotics

    The Japanese Journal of Antibiotics 46(7), 518-538, 1993

    Japan Antibiotics Research Association

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